Fosamprenavir
Clinical Pharmacokinetics and Drug Interactions of the Amprenavir Prodrug
Mary Beth Wire,1 Mark J. Shelton1 and Scott Studenberg2
1Division of Clinical Pharmacology & Discovery Medicine (CPDM), GlaxoSmithKline, Research Triangle Park, North Carolina, USA
2Division of Drug Metabolism & Pharmacokinetics (DMPK), GlaxoSmithKline, Research Triangle Park, North Carolina, USA
Abstract
Fosamprenavir is one of the most recently approved HIV-1 protease inhibitors (PIs) and offers reductions in pill number and pill size, and omits the need for food and fluid requirements associated with the earlier-approved HIV-1 PIs. Three fosamprenavir dosage regimens are approved by the US FDA for the treatment of HIV-1 PI-naive patients, including fosamprenavir 1400mg twice daily, fosam- prenavir 1400mg once daily plus ritonavir 200mg once daily, and fosamprenavir 700mg twice daily plus ritonavir 100mg twice daily. Coadministration of fosam- prenavir with ritonavir significantly increases plasma amprenavir exposure. The fosamprenavir 700mg twice daily plus ritonavir 100mg twice daily regimen maintains the highest plasma amprenavir concentrations throughout the dosing interval; this is the only approved regimen for the treatment of HIV-1 PI-exper- ienced patients and is the only regimen approved in the European Union.
Fosamprenavir is the phosphate ester prodrug of the HIV-1 PI amprenavir, and is rapidly and extensively converted to amprenavir after oral administration. Plasma amprenavir concentrations are quantifiable within 15 minutes of dosing and peak at 1.5–2 hours after fosamprenavir dosing. Food does not affect the absorption of amprenavir following administration of the fosamprenavir tablet formulation; therefore, fosamprenavir tablets may be administered without regard to food intake. Amprenavir has a large volume of distribution, is 90% bound to plasma proteins and is a substrate of P-glycoprotein.
With <1% of a dose excreted in urine, the renal route is not an important elimination pathway, while the principal route of amprenavir elimination is hepatic metabolism by cytochrome P450 (CYP) 3A4. Amprenavir is also an inhibitor and inducer of CYP3A4. Furthermore, fosamprenavir is commonly administered in combination with low-dose ritonavir, which is also extensively
metabolised by CYP3A4, and is a more potent CYP3A4 inhibitor than amprenavir.
This potent CYP3A4 inhibition contraindicates the coadministration of certain CYP3A4 substrates and requires others to be coadministered with caution. How- ever, fosamprenavir can be coadministered with many other antiretroviral agents, including drugs of the nucleoside/nucleotide reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor and HIV entry inhibitor classes. Coadministration with other HIV-1 PIs continues to be studied.
The extensive fosamprenavir and amprenavir clinical drug interaction informa- tion provides guidance on how to coadminister fosamprenavir and fosamprenavir plus ritonavir with many other commonly coprescribed medications, such as gastric acid suppressants, HMG-CoA reductase inhibitors, antibacterials and antifungal agents.
HIV-1 protease inhibitors (PIs) bind to the active Three fosamprenavir dosage regimens are ap-
site of HIV-1 protease, preventing the processing of proved by the US FDA[12] for the treatment of HIV-1
viral Gag and Gag-Pol polyprotein precursors, re- PI-naive patients, including fosamprenavir 1400mg
sulting in the formation of immature non-infectious twice daily, fosamprenavir 1400mg once daily plus
viral particles. The availability of HIV-1 PIs in the ritonavir 200mg once daily, and fosamprenavir
mid 1990s led to the use of triple antiretroviral drug 700mg twice daily plus ritonavir 100mg twice daily.
combination regimens, which significantly reduced The fosamprenavir 700mg twice daily plus ritonavir
HIV disease progression and mortality.[1,2] 100mg twice daily regimen is the only approved
Fosamprenavir (Lexiva↔, Telzir↔1) is one of the regimen for the treatment of HIV-1 PI-experienced
most recently approved HIV-1 PIs and was devel- patients and is the only regimen approved in the
oped to overcome some of the limitations associated European Union.[13]
with the earlier approved HIV-1 PIs. Fosam- This article focuses on the pharmacokinetics and
prenavir, the prodrug of amprenavir, was designed to replace the large capsule, pill burden and undesir-
drug interactions of fosamprenavir.
able excipient requirements of the amprenavir soft 1. Absorption, Distribution, Metabolism
gelatin capsule formulation (Agenerase↔). The availability of fosamprenavir allows for substantial
and Excretion
reductions in pill number and pill size, and omits the
1.1Conversion of Fosamprenavir
need for food and fluid requirements that are associ-
to Amprenavir
ated with some of the other HIV-1 PIs. A summary
of the dosing characteristics for the currently availa- Fosamprenavir is the phosphate ester prodrug of
ble HIV-1 PIs is provided in table I. The improved the HIV-1 PI amprenavir. Fosamprenavir has poor
convenience characteristics associated with fosam- membrane permeability and is rapidly and exten-
prenavir are designed to benefit patients by improv- sively converted to amprenavir after oral adminis-
ing adherence and tolerability. tration.[14] Preclinical studies demonstrate that
1 The use of trade names is for product identification purposes only and does not imply endorsement.
Table I. Dosing characteristics of HIV-1 protease inhibitors (PIs)[3-12]
HIV-1 PI Solid dosage form No. of tablets/capsules Food requirement Fluid requirement
(dosage strength [mg]) required per daya
‘Unboosted’ HIV-1 PIs
Fosamprenavir Tablet (700) 4 None None
Amprenavir Capsule (150) 16 None None
Saquinavir (Fortovase↔) Capsule (200) 18 Take with food None
Ritonavir Capsule (100) 12 Take with foodb None
Nelfinavir Tablet (625) 4 Take with food None
Tablet (250)
9(3 tid),
10(5 bid)
Indinavir Capsule (400)
6 Take without food At least 1.5L
every day
Atazanavir Capsule (200) ‘Ritonavir-boosted’ HIV-1 PI combinations
2 Take with food None
Fosamprenavir + ritonavir Tablet (700) + capsule (100) 2 + 2 None None
Amprenavir + ritonavir Capsule (150) + capsule (100) 8 + 2 None None
Saquinavir (Fortovase↔ or Capsule (200) + capsule (100) 10 + 2 Take with food None Invirase↔) + ritonavir
Tablet (500) + capsule (100) 4 + 2
Lopinavir/ritonavir (Kaletra↔) Capsule (133/33) 6 Take with food None
Tablet (200/50) 4 None None
Tipranavir + ritonavir Capsule (250) + capsule (100) 4 + 4 Take with food None
Atazanavir + ritonavir Capsule (150) + capsule (100) 2 + 1 Take with food None
aDose modifications may be required in some circumstances, such as drug interactions or special populations; refer to individual HIV-1 PI prescribing information.
bIt is recommended that ritonavir be administered with food to improve tolerability; there is no significant food effect on ritonavir pharmacokinetics.
bid = twice daily; tid = three times daily.
fosamprenavir is converted almost entirely (99%) to of corresponding plasma amprenavir AUC val-
amprenavir at or near the intestinal epithelium.[14]
Alkaline phosphatase is the primary enzyme respon- sible for conversion of fosamprenavir to am-
ues.[16]
prenavir.[15] Less than 1% of a fosamprenavir dose was detected in the portal vein of portal vein-cannu-
1.2Absorption
lated animals, suggesting that minimal fosam- Amprenavir demonstrated high membrane per-
prenavir enters the systemic circulation.[14] Mea- meability in a Caco-2 cell model.[14] Passive diffu-
surement of plasma fosamprenavir and amprenavir sion is an efficient mechanism of amprenavir ab-
concentrations in clinical studies verified that sorption; however, amprenavir is also a substrate of
fosamprenavir is rapidly and extensively converted P-glycoprotein (P-gp) and this transporter may play
to amprenavir, with negligible fosamprenavir avail- a role in amprenavir absorption.[17] In a Caco-2 cell
able systemically.[16] Very low plasma fosam- model, the ratio (B↓ A/A↓ B) for amprenavir was
prenavir concentrations were quantifiable in some 2.8 in the absence of a potent P-gp inhibitor
individuals between 0.25 and 4 hours post-dosing, (elacridar) and 1.0 in its presence; (B↓ A) is the
and plasma fosamprenavir area under the plasma apparent permeability from the basolateral to the
concentration-time curve (AUC) values were <0.6% apical side of the cell membrane and (A↓ B) is the
apparent permeability from the apical to the baso- prenavir oral suspension is currently undergoing
lateral side of the cell membrane.[17] evaluation in the paediatric population (where the
Following administration of fosamprenavir to product is being administered with food) in a con-
humans, plasma amprenavir concentrations can be quantified as early as 0.25 hours post-dosing, and
centration-controlled study, to maximise adherence.
maximum plasma amprenavir concentrations (Cmax) occur at approximately 1.5–2.5 hours following
1.3Distribution
both single- and repeat-dose administration.[16]
Following administration of fosamprenavir to
There appears to be a secondary absorption site for
humans, the apparent oral volume of distribution of
amprenavir, as evidenced by a second peak, which is
amprenavir following administration of fosam-
smaller than the first peak (Cmax) and appears 10–12 hours after dosing in individual plasma amprenavir
prenavir is approximately 430L, suggesting a large volume of distribution, with penetration of am-
concentration-time profiles. The second peak is not
prenavir into tissues beyond the systemic circula-
likely to represent enterohepatic recirculation.
tion.
While secondary glucuronides were found, a prima-
Amprenavir penetrates into lymphocytes. Fol-
ry glucuronide of amprenavir was not identified
lowing administration of amprenavir 600mg twice
among the metabolites from either urine or plasma
daily plus ritonavir 100mg twice daily, fosam-
in a mass-balance study.[18] Thus, cleavage of the
prenavir 700mg twice daily plus ritonavir 100mg
glucuronides by intestinal glucuronidases would not
twice daily, fosamprenavir 1400mg once daily plus
yield amprenavir but one of its oxidative metabo-
ritonavir 100mg once daily and fosamprenavir
lites. Based upon its timing, the second peak proba-
1400mg once daily plus ritonavir 200mg once daily,
bly arises from a secondary absorption site in the terminal ileum.
amprenavir concentrations at the end of the dosing interval (C↑) in mononuclear cells were 2- to 3-fold
higher than the concentrations in plasma.[21]
1.2.1 Effect of Food on Absorption In pregnant rats, radioactivity was present in the
Fosamprenavir tablets may be administered with- placenta at concentrations higher than in maternal
out regard to food intake. When subjects received blood, and present in fetal tissues at concentrations
fosamprenavir tablets with and without a high-fat lower than in maternal blood.[22] Amprenavir was
meal, plasma amprenavir AUC from time zero to transferred across the placenta in an ex vivo human
infinity (AUCμ ) and Cmax values were bioequiva- placenta model.[23] In humans, maternal-fetal trans-
lent; there was a slight delay of approximately 0.5 fer of amprenavir was demonstrated by measuring
hours in the time to reach Cmax (tmax).[19] Other amprenavir in three cord blood samples; amprenavir
HIV-1 PIs have food requirements owing to the concentrations in cord blood were approximately
effects of food on their pharmacokinetics, or to 25% of those observed in maternal plasma.[24] Am-
improve tolerability, as described in table I. prenavir was also present in the milk of lactating
A fosamprenavir oral suspension formulation is rats.[25]
approved in the European Union for the treatment of The penetration of amprenavir into semen was
adults and is recommended to be administered with- determined in two HIV-infected subjects following
out food and on an empty stomach. Administration repeat dose administration during three treatment
of the fosamprenavir oral suspension formulation phases: amprenavir 1200mg twice daily, fosam-
with a high-fat meal decreased plasma amprenavir prenavir 1400mg twice daily (one subject) or fosam-
AUCμ by 28% and Cmax by 46%.[20] The fosam- prenavir 1860mg twice daily (one subject), and am-
prenavir 600mg twice daily plus ritonavir 100mg intestinal cell line.[33] Evidence of P-gp induction
twice daily. Amprenavir concentrations measured has also been reported for other HIV-1 PIs, includ-
12 hours after dosing were quantifiable in semen ing nelfinavir,[33] ritonavir[34] and lopinavir.[35] In
and were similar between the four treatments addition, in vitro and in vivo studies suggest that
(0.10–0.42 αg/mL).[26] These results are similar to ritonavir inhibits P-gp.[34]
those previously reported for 31 HIV-infected sub-
These preclinical P-gp induction findings for am-
jects receiving amprenavir 1200mg twice daily. The
prenavir may not translate into clinically significant
median amprenavir concentration in semen mea-
drug interactions, based on the minor clinical drug
sured within 2 hours after dosing was 0.741 αg/mL
interaction observed between the potent P-gp induc-
and measured later (predominantly 8–12 hours after
er rifampicin (rifampin) and the P-gp probe sub-
dosing) was 0.217 αg/mL.[27] Cerebral spinal fluid
strate digoxin. Rifampicin, known to be one of the
(CSF) penetration of amprenavir is low in
strongest metabolic inducers, has also demonstrated
humans.[18,28,29]
potent induction of P-gp in vitro and in vivo.[33,36]
P-gp also plays a role in the distribution of am- However, in humans, rifampicin had only a minor
prenavir into tissues. Administration of 14C-ampre- impact on the plasma exposure of the P-gp substrate
navir to mice receiving elacridar and to multidrug digoxin; a 30% reduction was observed when
resistance (MDR) 1a/1b genetic double knockout rifampicin was coadministered with oral digoxin
mice demonstrated higher concentrations of radio- and a 15% reduction was observed when rifampicin
activity in blood (1.3- to 2.0-fold), tissue, including was coadministered with intravenous digoxin.[37] In
brain (13.2- to 27-fold), muscle (1.5- to 2.1-fold) a separate study, coadministration of ritonavir with
and testes (4.0- to 4.2-fold), and CSF (3.3-fold), digoxin increased plasma digoxin AUC from 0 to 72
compared with control mice.[17] hours by 22%.[38]
It has been reported that amprenavir is not a The plasma protein binding of amprenavir is
substrate or inhibitor of either the human breast approximately 90%. In vitro amprenavir binding to
cancer resistance protein (BCRP) or the multidrug human plasma proteins has been estimated to be
resistance-related protein 1 (MRP-1).[30-32] Other 96–91% over the concentration range of 1–10 αg/
HIV-1 PIs were included in these studies, with the mL, with decreased protein binding at higher con-
following findings: none of the studied HIV-1 PIs centrations.[39] In the presence of the two major
were BCRP substrates, but ritonavir, saquinavir and amprenavir metabolites (GW549445 and
nelfinavir inhibited BCRP; ritonavir and indinavir GW549544), plasma amprenavir protein binding
were MRP-1 substrates and ritonavir also demon- was reduced by approximately 2–4%.[40] Serum al-
strated inhibition of MRP-1.[30-32] bumin acts as a low affinity, high capacity binding
Administration of high doses of fosamprenavir
protein, and ®-1 acid glycoprotein acts as a high
(525 mg/kg/day [equivalent to 450 mg/kg/day of
affinity, low capacity binding protein for am-
amprenavir]) for 7–14 days increased intestinal P-gp
prenavir.[39]
protein levels in rats.[33] This P-gp induction is In vitro protein binding interactions have demon-
attributed to amprenavir, rather than fosamprenavir, strated small increases in the percent of unbound
because fosamprenavir is not readily absorbed, but amprenavir with drugs such as ritonavir, efavirenz,
rather is converted to amprenavir at or near the delavirdine, verapamil, diazepam and in-
apical side of the intestinal epithelium. Amprenavir dometacin.[41,42] Displacement of amprenavir from
also demonstrated induction of P-gp in a human plasma proteins was greatest (approximately a 6%
NH2
O
HN O
O
O
S
N
O
O
OH
P
HO O
Fosamprenavir
NH2 O OH
NH2
NH2 O OH
HO
O
O
O
HN O
OH HN O
O
HN O
OH
O
S
O
N
OH
3 x [O]
O
S
O
N
OH
2 x [O]
O
S
O
N
OH
GW549444 Amprenavir GW549445
Fig. 1. Metabolic conversion of fosamprenavir to amprenavir and its two major metabolites.
increase in the percent unbound) in the presence of of the molecule to one of two isomers. The next
ritonavir 10 αg/mL. Amprenavir did not displace most prevalent metabolite, GW549444X (22% of
ritonavir from plasma proteins. The increase in the administered dose), results from the di-oxidation of
percent of unbound amprenavir does not negatively the tetrahydrofuran portion of the molecule with
impact the clinical profile because the safety and additional oxidation of the aniline portion of the
efficacy of fosamprenavir in combination with molecule to one of two isomers.[18] Two other mono-
ritonavir has been demonstrated.[43,44]
oxidative amprenavir metabolites were detected at very low levels. Metabolites resulting from phase II
1.4Metabolism
processes are also minor metabolic products; glucuronides of the oxidative metabolites have been
The principal route of amprenavir elimination is identified.[18]
hepatic metabolism by cytochrome P450 (CYP) Amprenavir is an inhibitor of CYP3A4 at clini-
3A4. In vitro studies demonstrated that CYP3A4 cally relevant concentrations based on in vitro stud-
was responsible for the production of the oxidative ies. A side-by-side comparison of amprenavir and
metabolites and that other liver microsomal CYP other HIV PIs showed the potency of CYP3A4
isoenzymes (CYP1A2, CYP2C9, CYP2C19, inhibition to be ritonavir (most potent) >> indinavir
CYP2D6 and CYP2E1) were not significantly in- ± nelfinavir ± amprenavir > saquinavir.[46] The 50%
volved in the metabolism of amprenavir.[45] inhibitory concentration (IC50) value for inhibition
The conversion of fosamprenavir to amprenavir of CYP3A4 activity, as measured by inhibition of
and its two major metabolites is shown in fig- erythromycin N-demethylase activity, was 1.3
ure 1. The predominant amprenavir metabolite, αmol/L (0.657 αg/mL) for amprenavir and 0.037
GW549445X (42% of administered dose), results αmol/L (0.027 αg/mL) for ritonavir.[46] Fosam-
from the di-oxidation of the tetrahydrofuran portion prenavir is commonly administered in combination
with low-dose ritonavir owing to the ability of humans, plasma concentrations of CYP3A4 sub-
ritonavir to favourably enhance plasma amprenavir strates, such as delavirdine and lopinavir/ritonavir,
pharmacokinetics. Ritonavir is also primarily decreased when coadministered with fosamprenavir
metabolised by CYP3A4, is a more potent CYP3A4 inhibitor than amprenavir, and increases amprenavir
or amprenavir.[59-62]
concentrations by inhibiting amprenavir metabo- 1.5 Excretion
lism. Plasma concentrations of CYP3A4 substrates, such as ketoconazole, rifabutin, atorvastatin and nevirapine, increased when coadministered with fosamprenavir or amprenavir in clinical drug inter- action studies.[47-50]
Excretion of unchanged amprenavir in urine and faeces is minimal (<1% of the dose). Approximately 14% and 75% of an administered single dose of 14C-amprenavir can be accounted for as metabo- lites in urine and faeces, respectively.[18] The two Fosamprenavir does not activate the pregnane X primary amprenavir metabolites (GW549445 and receptor (PXR), whereas amprenavir has demon- GW549444) account for the vast majority of the strated high activation in human PXR experiments radiolabel recovered in urine and faeces. with a 50% effective concentration of 4.73 αmol/L (2.39 αg/mL) and 122% maximal PXR activation 2. Steady-State Pharmacokinetics (with rifampicin as a positive control).[51] Ritonavir has also demonstrated high activation of PXR.[52] Plasma amprenavir and ritonavir pharmacokinet- PXR, an orphan member of the nuclear hormone ic parameter values observed following administra- receptor superfamily, and CYP3A are expressed in tion of various fosamprenavir and fosamprenavir the same tissues. Activated PXR binds to xenobiotic plus ritonavir regimens to both healthy and HIV-1- response elements in CYP3A gene promoters and infected subjects are summarised in table II. Plasma induces CYP3A gene transcription.[53,54] PXR has amprenavir concentration-time profiles for the three been suggested to serve as a key regulator of approved regimens (fosamprenavir 1400mg twice CYP3A expression because structurally diverse in- daily, fosamprenavir 1400mg once daily plus ducers of CYP3A activate PXR, and PXR activation ritonavir 200mg once daily, and fosamprenavir correlates with CYP3A induction in primary hepato- 700mg twice daily plus ritonavir 100mg twice daily) cytes from different species.[55] are provided in figure 2. A separate study demonstrated amprenavir dose- 2.1Fosamprenavir related increases in recombinant human CYP3A4- like immunoreactivity in rat liver microsomes.[56] Fosamprenavir 1400mg and amprenavir 1200mg However, despite the high activation of PXR and the are molar equivalent doses (i.e. equivalent doses demonstrated dose-related increases in CYP3A4 when adjusted for molecular weight). Administra- protein levels, only a weak induction response has tion of these molar equivalent fosamprenavir and been observed in rats and mice receiving am- amprenavir doses twice daily to HIV-1-infected, prenavir, as measured by either no change or small antiretroviral therapy (ART)-naive patients in a increases in midazolam and 6β-testosterone metabo- phase II trial resulted in equivalent plasma am- lism, two CYP3A4 probe substrates.[33,57,58] The prenavir AUC over a dosing interval (AUC↑) values. weak induction response may be due to the inhibito- The fosamprenavir regimen delivered moderately ry effect of amprenavir on this isoenzyme, which lower (30%) plasma amprenavir Cmax values and partially masks the increase in enzyme activity. In moderately higher (28%) C↑ values.[16] A higher fosamprenavir dosage regimen (1860mg twice dai- 700mg twice daily plus ritonavir 100mg twice daily ly; equivalent to amprenavir 1600mg) was also test- regimens result in similar plasma amprenavir daily ed but did not deliver higher steady-state plasma AUC from 0 to 24 hours values; however, the amprenavir exposures than the fosamprenavir fosamprenavir 700mg twice daily plus ritonavir 1400mg twice daily regimen.[16] All three regimens, 100mg twice daily regimen delivers higher C↑ and each in combination with abacavir 300mg twice lower Cmax values (see table II). daily and lamivudine 150mg twice daily, had similar As shown in figure 2, the two fosamprenavir plus safety profiles and resulted in similar approximate ritonavir regimens maintain plasma amprenavir con- 2-log10 reductions in plasma HIV-1 RNA concen- centrations above the mean amprenavir protein trations over 4 weeks.[16] Steady-state plasma am- binding-adjusted (90%) IC50 values for amprenavir prenavir exposures achieved in HIV-1-infected pa- against HIV for patients spanning the range from PI- tients receiving the fosamprenavir 1400mg twice naive to heavily PI-experienced; however, only the daily regimen are provided in figure 2 and table II. fosamprenavir 700mg twice daily plus ritonavir Amprenavir pharmacokinetics are time variant, 100mg twice daily regimen is recommended for the characterised by reductions in plasma amprenavir treatment of PI-experienced patients. AUC until steady state is achieved at week 2. In The benefits of coadministering fosamprenavir HIV-1-infected patients enrolled in a phase II trial, and ritonavir are evidenced by: plasma amprenavir AUC values decreased to a simi- lar extent for molar-equivalent fosamprenavir • the demonstration of efficacy in ART-naive sub- jects, subjects who had received one to two prior 1400mg twice daily (–27%) and amprenavir PIs and in multiple PI-experienced pa- 1200mg twice daily (–23%) dosage regimens, and to tients;[43,44,76,77] a larger extent for the higher fosamprenavir 1860mg twice daily (–45%) dosage regimen, suggesting that the AUC decreases observed upon repeat dosing are dose-dependent.[16] •no evidence of the emergence of resistance through to 120 weeks in ART-naive subjects with no baseline resistance and with confirmed viro- logical failure (>1000 copies/mL) at or beyond
As shown in figure 2, the fosamprenavir 1400mg
week 12 of treatment;[78]
twice daily regimen maintains plasma amprenavir concentrations above the mean amprenavir protein binding-adjusted (90%) IC50 values for amprenavir against HIV for PI-naive patients, but falls below the mean amprenavir protein binding-adjusted (90%) IC50 value for amprenavir against HIV for heavily PI-experienced patients.
•the ability to maintain elevated plasma am- prenavir exposures when coadministered with potent CYP3A4 inducers such as efavirenz and nevirapine (see section 4.2);
•the availability of either once daily or twice daily dosing options for PI-naive patients.
Plasma ritonavir exposures achieved with the
2.2Fosamprenavir in Combination
fosamprenavir 700mg twice daily plus ritonavir
with Ritonavir
100mg twice daily regimen are somewhat lower than those achieved with other HIV-1 PI plus
Fosamprenavir is often coadministered with ritonavir combinations such as lopinavir plus
ritonavir, which increases plasma amprenavir con- ritonavir, saquinavir plus ritonavir and indinavir
centrations by inhibiting amprenavir metabolism. plus ritonavir.[61,79,80] Plasma ritonavir exposures
The fosamprenavir 1400mg once daily plus achieved following administration of fosamprenavir
ritonavir 200mg once daily and fosamprenavir plus ritonavir regimens are provided in table II.
100
Fosamprenavir 1400mg od + ritonavir 200mg od (n = 36) Fosamprenavir 700mg bid + ritonavir 100mg bid (n = 24) Fosamprenavir 1400mg bid (n = 22)
Mean amprenavir protein binding-adjusted (90%) IC50 for multiple protease inhibitor-resistant HIV (0.90 αg/mL) Mean amprenavir protein binding-adjusted (90%) IC50 for wild-type HIV (0.146 αg/mL)
10
1
0.1
0.01
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (h)
Fig. 2. Median plasma amprenavir concentration-time profiles and mean in vitro amprenavir protein binding-adjusted (90%) IC50 values against HIV. bid = twice daily; IC50 = 50% inhibitory concentration; od = once daily.
2.3Similar Pharmacokinetics Between 1400mg twice daily or following administration of
Healthy and HIV-Infected Subjects
fosamprenavir 1400mg once daily plus ritonavir 200mg once daily. Bootstrapping was used to calcu-
A population pharmacokinetic model was devel-
late geometric mean ratios and associated 90% con-
oped, using combined data from four phase I–III fidence intervals (CIs) for the comparison of
clinical studies, to examine steady-state plasma am- HIV-1-infected versus healthy subjects.[66,81]
prenavir pharmacokinetics in healthy subjects com-
For combined fosamprenavir 1400mg twice daily
pared with HIV-1-infected subjects following ad-
and fosamprenavir 1400mg once daily plus ritonavir
ministration of fosamprenavir 1400mg twice daily
200mg once daily regimens, the bootstrap geometric
and fosamprenavir 1400mg once daily plus ritonavir 200mg once daily. The final amprenavir model was a two-compartment model, with first-order absorp- tion and elimination. The effects of dosing regimen
mean ratio (90% CI) for AUC↑ was 1.041 (0.908, 1.174). The bootstrap geometric mean ratio (90% CI) for Cmax for the fosamprenavir 1400mg twice
(with or without ritonavir), subject population and
daily regimen was 1.108 (0.951, 1.297) and for
assay laboratory effects were included in the final
fosamprenavir 1400mg once daily plus ritonavir
population pharmacokinetic model. With the final
200mg once daily was 1.088 (0.956, 1.244). Simi-
model, plasma amprenavir AUC↑ and Cmax were larity in plasma amprenavir pharmacokinetics be-
calculated for both healthy and HIV-infected sub- tween healthy and HIV-infected subjects was con-
jects following administration of fosamprenavir firmed because the ratios were close to 1.0.[66,81]
2.4Hepatic Impairment
prenavir tablet dose cannot be reduced below 700mg.
In an amprenavir study in subjects with hepatic No data are currently available for the use of
impairment, single oral doses of amprenavir 600mg fosamprenavir plus ritonavir in patients with any
were administered to 30 subjects (10 with moderate degree of hepatic impairment; however, a study is
cirrhosis, 10 with severe cirrhosis and 10 healthy subjects).[82] Plasma amprenavir AUCμ values were
underway.
significantly different in subjects with moderate and
2.5Renal Impairment
severe hepatic impairment compared with healthy subjects. Plasma amprenavir AUCμ values were approximately 2.5- and 4.5-fold higher in the mod- erate and severe hepatic impairment groups, respec-
No dosage regimen adjustments are recommend- ed for patients with renal dysfunction because am- prenavir is extensively metabolised, with <1% of an amprenavir dose excreted in the urine as unchanged
tively, compared with healthy subjects. A linear
amprenavir and approximately 14% of the dose re-
relationship was observed between the AUCμ value
covered in urine as amprenavir metabolites.[18]
and the severity of hepatic impairment as assessed
by the Child-Pugh score and this relationship was
3.Relationships Between
used to make dose adjustments for amprenavir. An
Pharmacokinetics and
amprenavir dosage regimen of 450mg twice daily
Pharmacodynamic Response
was recommended for subjects with a Child-Pugh score ranging from 5 to 8 (moderate hepatic impair-
ment) and a dosage regimen of 300mg twice daily
3.1Pharmacokinetics and Antiviral Activity
was recommended for subjects with a Child-Pugh
Fosamprenavir 1400mg twice daily, fosampre-
score ranging from 9 to 15 (severe hepatic impair-
navir 1400mg once daily plus ritonavir 200mg once
ment). These regimens were predicted to provide
daily, and fosamprenavir 700mg twice daily plus
plasma amprenavir exposures comparable to the
ritonavir 100mg twice daily regimens have demon-
recommended 1200mg twice daily dose regimen for
strated antiviral efficacy in large-scale comparator-
amprenavir in subjects without hepatic impairment.
controlled clinical trials.[43,44,83,84]
Because fosamprenavir is rapidly and extensive- The relationships between plasma amprenavir
ly converted to amprenavir by phosphatase enzymes pharmacokinetic parameters (Cmax, average plasma
in the gut epithelium, with very little fosamprenavir concentration [Cav] and C↑) and antiviral activity
available systemically, dosage recommendations for (defined as the average area under the curve minus
fosamprenavir (without concurrent ritonavir) in this baseline [AAUCMB] for plasma HIV-1 RNA) was
population are based on the results of the am- established in ART-naive subjects receiving am-
prenavir hepatic impairment study with considera- prenavir dosages ranging from 300mg twice daily to
tion given to the fosamprenavir 700mg tablet 1200mg twice daily for 4 weeks.[85] Plasma am-
strength. Patients with mild or moderate hepatic prenavir C↑ had the strongest relationship with plas-
impairment (Child Pugh score of 5–8) should re- ma HIV-1 RNA AAUCMB and the 90% effective
ceive fosamprenavir with caution and at a reduced concentration (EC90) was determined to be 0.23 αg/
dose of 700mg twice daily. Fosamprenavir should mL. Standard regimens of fosamprenavir 1400mg
not be used in patients with severe hepatic impair- twice daily, fosamprenavir 1400mg once daily plus
ment (Child Pugh score of 9–15) because the fosam- ritonavir 200mg, and fosamprenavir 700mg twice
daily plus ritonavir 100mg twice daily all achieve Relationships between plasma amprenavir phar-
average plasma amprenavir C↑ values greater than macokinetic parameters (Cmax, AUC↑ and C↑) and
this EC90 value (table II). However, it is clear that adverse events were examined in ART-naive sub-
the elevated plasma amprenavir concentrations jects receiving amprenavir dosages ranging from
achieved with the fosamprenavir plus ritonavir dos- 300mg twice daily to 1200mg twice daily for 4
age regimens provide benefit to ART-naive patients weeks.[85] Oral/perioral paresthesia was correlated
over longer-term dosing because there was no evi- with both plasma amprenavir Cmax and AUC↑, and
dence of the emergence of resistance through to 120 headache was correlated with Cmax. A trend towards
weeks in ART-naive subjects with no baseline resis- a relationship between combined nausea and vomit-
tance and with confirmed virological failure (>1000 ing and plasma amprenavir AUC↑ was also ob-
copies/mL) at or beyond week 12 of treatment.[78] served.
In the HIV-1 PI-experienced population, only the Relationships between plasma amprenavir
fosamprenavir 700mg twice daily plus ritonavir pharmacokinetic parameters (Cmax, AUC↑ and C↑)
100mg twice daily regimen is recommended. A and adverse events were examined in a pooled anal-
retrospective multivariate analysis demonstrated ysis of healthy adult subjects receiving fosam-
that the genotypic inhibitory quotient (GIQ), which prenavir 700mg twice daily plus ritonavir 100mg
is the plasma amprenavir C↑ divided by the number twice daily.[88] In that analysis, diarrhoea was signif-
of baseline protease resistance mutations, is an inde- icantly correlated with plasma amprenavir Cmax.
pendent predictor of week 12 virological response In a study evaluating higher doses of fosam-
( 1 log decrease in plasma HIV-1 RNA or a viral prenavir plus ritonavir, including fosamprenavir
load <400 copies/mL) and appeared to be correlated 1400mg twice daily plus ritonavir 100mg twice dai-
with week 24 and week 48 virological responses to ly, and fosamprenavir 1400mg twice daily plus
fosamprenavir 700mg twice daily plus ritonavir ritonavir 200mg twice daily, compared with the
100mg twice daily in PI-experienced patients.[86] standard fosamprenavir 700mg twice daily plus
Subjects with a GIQ <250 had a reduced virological ritonavir 100mg twice daily regimen in healthy adult
response compared with subjects with a GIQ >250. subjects, marked AST and ALT level elevations
A separate study in HIV-1 PI-experienced subjects (>2.5 times the upper limit of normal) were ob-
receiving amprenavir 600mg twice daily plus served in 6 of 42 subjects, predominantly in those
ritonavir 100mg twice daily also demonstrated that receiving the fosamprenavir 1400mg twice daily
GIQ was a predictor of week 12 virological response plus ritonavir 200mg twice daily regimen.[75] A rela-
( 1 log decrease in plasma HIV-1 RNA or a viral tionship between plasma amprenavir and ritonavir
load <400 copies/mL).[87] pharmacokinetics and elevations in AST and ALT levels could not be established, potentially due to the 3.2Pharmacokinetics and Adverse Events limited dataset; however, both plasma amprenavir and ritonavir concentrations were elevated with the The most commonly reported grade 2–4 drug- increased dosage regimens. related adverse events in HIV-1-infected subjects taking fosamprenavir or fosamprenavir plus 4. Drug Interactions ritonavir regimens in the large-scale comparator- controlled clinical trials were diarrhoea, rash, nau- As mentioned in section 1.1 and section 2.1, sea, vomiting, abdominal pain, fatigue, headache, fosamprenavir is rapidly and extensively converted weakness and insomnia.[43,83,84] to amprenavir, with molar equivalent fosamprenavir and amprenavir doses delivering comparable plasma coadministered with fosamprenavir or fosam- amprenavir exposure and negligible fosamprenavir prenavir plus ritonavir without dose adjustment. The exposure. Given this profile, metabolic drug interac- enteric-coated capsule formulation of didanosine al- tions previously established for amprenavir should so can be coadministered with fosamprenavir or be applicable to fosamprenavir. The ability to extra- fosamprenavir plus ritonavir without dose adjust- polate metabolic drug interactions between the two ment. compounds was confirmed in a study in which 4.1.2Lamivudine and Abacavir ritonavir increased plasma amprenavir exposures to a similar extent when coadministered with either fosamprenavir or amprenavir.[72] Lamivudine is renally eliminated and coadminis- tration of amprenavir with lamivudine did not alter exposures of either drug.[95] Abacavir is metabolised The absorption, distribution, metabolism and ex- via glucuronidation and alcohol dehydrogenase. The cretion (ADME) of fosamprenavir and amprenavir safety and efficacy of fosamprenavir and fosam- are described in section 1. Coadministration of prenavir plus ritonavir, in combination with fosamprenavir with drugs that alter amprenavir AD- lamivudine and abacavir, have been established in ME may result in changes in plasma amprenavir the pivotal phase III trials.[43,83] exposure, and coadministration of fosamprenavir or fosamprenavir plus ritonavir may result in changes 4.1.3Zidovudine in plasma concentrations of other drugs, such as The principal route of zidovudine elimination is those that are CYP3A4 substrates. The results of through glucuronidation. A study was conducted to fosamprenavir and amprenavir clinical drug interac- evaluate the safety, tolerability and pharmacokinet- tion studies are summarised in table III. ics of fosamprenavir 1400mg twice daily and fosam- prenavir 700mg twice daily plus ritonavir 100mg 4.1.3.1Nucleoside and Nucleotide Reverse twice daily, each in combination with either Transcriptase Inhibitors zidovudine/lamivudine (twice daily) or zidovudine/ The nucleoside and nucleotide reverse trans- criptase inhibitors (NRTIs), including didanosine, zidovudine, lamivudine, abacavir, stavudine, em- tricitabine and tenofovir, are eliminated renally or metabolised by non-CYP pathways. Because drug interactions with fosamprenavir and ritonavir are primarily CYP-mediated, no significant interactions are expected between fosamprenavir or fosam- prenavir plus ritonavir and these NRTIs. Data avail- able for some of these NRTIs are discussed further. lamivudine/abacavir (twice daily) in ART-naive HIV-1-infected patients treated for 24 weeks.[63] There was no significant effect on zidovudine pharmacokinetics when either fosamprenavir (n = 13) or fosamprenavir plus ritonavir (n = 12) was coadministered with zidovudine/lamivudine, com- pared with historical control subjects receiving zidovudine/lamivudine twice daily (two control groups, n = 12 in each group). The geometric mean values for plasma zidovudine AUC↑ (αg h/mL) were 1.75 with fosamprenavir plus zidovudine/ 4.1.3.1.1Didanosine lamivudine twice daily; 1.48 with fosamprenavir Because coadministration of fosamprenavir with plus ritonavir plus zidovudine/lamivudine; and 1.38 a high dose of a potent antacid (30mL of Maalox and 1.46 in the historical controls. The geometric TC↔ [aluminium hydroxide/magnesium hydrox- mean values for plasma zidovudine Cmax (αg/mL) ide]) did not result in clinically significant changes were 0.91 with fosamprenavir plus zidovudine/ in plasma amprenavir exposure[97] (see section lamivudine twice daily; 1.17 with fosamprenavir 4.5.2), the buffered didanosine formulation can be plus ritonavir plus zidovudine/lamivudine twice dai- ly; and 1.19 and 1.15 in the historical controls. From inducers, whereas delavirdine is a CYP3A4 inhibi- a safety perspective, compared with historical con- tor. trol safety data for either fosamprenavir or fosam- prenavir plus ritonavir in combination with 4.2.1 Efavirenz lamivudine plus abacavir, an increased proportion of Efavirenz is a potent CYP3A4 inducer and has subjects receiving either fosamprenavir or fosam- been shown to significantly reduce plasma concen- prenavir/ritonavir in combination with zidovudine/ trations of HIV-1 PIs, including indinavir, lopinavir, lamivudine reported mild to moderate drug-related and atazanavir.[3,102,103] In an amprenavir study, plas- nausea. Nausea was generally not treatment-limiting ma amprenavir concentrations were reduced by 24% over the 24-week study, with the exception of one when efavirenz 600mg once daily was coadminis- subject who withdrew from the study owing to se- tered with amprenavir 1200mg twice daily.[92] vere nausea. Coadministration of fosamprenavir with the CYP3A4 inhibitor ritonavir obviates the impact of 4.1.4Tenofovir Disoproxil Fumarate efavirenz on plasma amprenavir pharmacokinetics. Tenofovir disoproxil fumarate is renally elimi- The pharmacokinetic findings from two fosam- nated. The safety and efficacy of fosamprenavir plus prenavir plus ritonavir plus efavirenz drug interac- ritonavir, in combination with tenofovir disoproxil tion studies demonstrate that the dose of ritonavir fumarate, was established in a pivotal phase III trial. required to overcome the CYP3A4 inductive effect Plasma amprenavir concentrations were similar for of efavirenz and maintain plasma amprenavir con- subjects receiving fosamprenavir plus ritonavir and centrations depends on the dosing schedule.[67] tenofovir disoproxil fumarate and subjects not re- When efavirenz 600mg once daily is coadministered ceiving tenofovir disoproxil fumarate.[70] Further- with fosamprenavir 700mg twice daily plus more, a drug interaction study demonstrated that ritonavir 100mg twice daily, no dose adjustment is coadministration of tenofovir disoproxil fumarate required because plasma amprenavir concentrations 300mg once daily with either fosamprenavir are maintained. However, when efavirenz 600mg 1400mg once daily plus ritonavir 200mg once daily once daily is coadministered with fosamprenavir or fosamprenavir 1400mg once daily plus ritonavir 1400mg once daily plus ritonavir 200mg once daily, 100mg once daily did not alter plasma amprenavir plasma amprenavir concentrations are reduced, ne- exposure, and plasma tenofovir disoproxil fumarate cessitating an increase in the ritonavir dose to exposures for the combination were similar to his- 300mg once daily. The findings from these fosam- torical control values, suggesting no drug interac- prenavir plus ritonavir plus efavirenz studies are in tion.[96] agreement with data for amprenavir plus ritonavir plus efavirenz.[93,104] Efavirenz concentrations are 4.2Non-Nucleoside Reverse Transcriptase Inhibitors not altered by either amprenavir or ritonavir.[92,105] 4.2.2Nevirapine Efavirenz, nevirapine and delavirdine are the cur- Nevirapine is also a potent CYP3A4 inducer and rently approved non-nucleoside reverse trans- the effect of nevirapine on plasma amprenavir criptase inhibitors (NNRTIs). NNRTIs and HIV-1 pharmacokinetics is similar to that described for PIs, including fosamprenavir, may be administered efavirenz (see section 4.2.1). Coadministration of in combination for the treatment of HIV-1 infection. nevirapine 200mg twice daily with fosamprenavir Both efavirenz and nevirapine are potent CYP3A4 1400mg twice daily significantly reduced plasma amprenavir AUC↑ by 33% and C↑ by 35%; plasma by inhibiting their metabolism by CYP3A4. nevirapine exposures were increased: AUC↑ by 29% Coadministration of ritonavir 100mg twice daily and C↑ by 34%.[50] When nevirapine 200mg twice with fosamprenavir 700mg twice daily increased daily is coadministered with fosamprenavir plus plasma amprenavir Cmax by approximately 51%, 700mg twice daily plus ritonavir 100mg twice daily, while plasma amprenavir AUC↑ and C↑ values were no dose adjustment is required because neither plas- increased 3.4- and 12.7-fold, respectively, compared ma amprenavir nor nevirapine concentrations were with those observed after administration of fosam- significantly altered.[50] prenavir 700mg twice daily without ritonavir.[72] 4.2.3Delavirdine Coadministration of amprenavir 600mg twice daily with delavirdine 600mg twice daily increased plasma amprenavir AUC↑ by 130%, Cmax by 40% These increases are similar to the increases observed when an equimolar amprenavir dose (600mg twice daily) was coadministered with ritonavir 100mg twice daily.[72] and C↑ by 125%, while plasma delavirdine expo- 4.3.2 Atazanavir sures were significantly decreased: AUC↑ by 61%, When fosamprenavir 700mg twice daily plus Cmax by 47% and C↑ by 88%.[60] A similar interac- ritonavir 100mg twice daily was coadministered tion was observed in a second study.[59] Because of with atazanavir 300mg once daily, there was no the significant reduction in delavirdine concentra- change in plasma amprenavir pharmacokinetic pa- tions, fosamprenavir should not be coadministered rameters.[73] Plasma atazanavir AUC↑ was decreased with delavirdine. The interaction between fosam- by 22% and Cmax by 24%, but C↑ remained un- prenavir (or amprenavir) plus ritonavir plus de- changed, compared with administration of lavirdine has not been studied. atazanavir 300mg once daily plus ritonavir 100mg once daily. The clinical utility of a combination 4.3HIV-1 Protease Inhibitors regimen of fosamprenavir/ritonavir plus atazanavir has not been established. The following clinical drug interaction data are presented in this section: 4.3.3 Lopinavir/Ritonavir •the ritonavir-boosting effect observed when coadministered with fosamprenavir; When fosamprenavir 700mg twice daily was coadministered with lopinavir/ritonavir 400mg/ •studies evaluating fosamprenavir or amprenavir in dual ritonavir-boosted HIV-1 PI regimens, in- cluding fosamprenavir/ritonavir plus atazanavir, fosamprenavir plus lopinavir/ritonavir, fosam- prenavir plus saquinavir/ritonavir, and am- prenavir plus tipranavir/ritonavir; •studies evaluating amprenavir in combination with other HIV-1 PIs (without ritonavir boost- ing), including saquinavir, indinavir and nelfinavir. 100mg twice daily to HIV-1-infected patients, plas- ma amprenavir AUC↑ decreased by 63% and C↑ decreased by 69% compared with the standard fosamprenavir 700mg twice daily plus ritonavir 100mg twice daily regimen, while plasma lopinavir AUC↑ decreased by 48% and C↑ decreased by 61% compared with the standard lopinavir/ritonavir 400mg/100mg twice daily regimen.[61] In another study conducted in healthy volunteers, similar re- ductions in plasma amprenavir pharmacokinetics were observed when fosamprenavir 700mg twice 4.3.1Ritonavir daily was coadministered with lopinavir/ritonavir Ritonavir is often coadministered with other 400mg/100mg twice daily and an additional dose of HIV-1 PIs to increase their plasma concentrations ritonavir 100mg twice daily (for a total dose of ritonavir 200mg twice daily), whereas plasma 4.3.4 Saquinavir lopinavir exposures increased (AUC↑ by 37%, Cmax Plasma amprenavir AUC↑ decreased by 32%, by 30% and C↑ by 52%) compared with the standard Cmax decreased by 37% and C↑ decreased by 14% lopinavir/ritonavir 400mg/100mg twice daily regi- when amprenavir 750mg three times daily was men, likely due to the increased ritonavir dose.[71] coadministered with saquinavir 800mg three times Based on these studies, adding ritonavir to a fosamprenavir plus lopinavir/ritonavir combination regimen does not improve plasma amprenavir daily, while plasma saquinavir exposure was not statistically significantly reduced, although there was a trend towards reduced plasma saquinavir C↑ compared with historical data.[90] When fosam- pharmacokinetics but increases plasma lopinavir prenavir 700mg twice daily was added to the combi- concentrations above those typically seen. Another nation of saquinavir 1000mg twice daily plus dosing strategy (fosamprenavir 1400mg twice daily ritonavir 100mg twice daily, saquinavir AUC↑ de- plus lopinavir/ritonavir 533mg/133mg twice daily) creased by 15%, Cmax decreased by 9% and C↑ has been evaluated in healthy volunteers. This dos- decreased by 24%, and ritonavir concentrations ing strategy showed that there were no significant were also reduced.[79] Plasma amprenavir AUC↑, changes in lopinavir pharmacokinetics compared Cmax and C↑ values were decreased by 27%, 29% with lopinavir/ritonavir 400mg/100mg twice daily and 40%, respectively, compared with historical and that plasma amprenavir AUC↑ decreased by control data. The addition of an extra 100mg of 26%, Cmax decreased by 13% and C↑ decreased by ritonavir to this regimen increased both plasma sa- 42% compared with fosamprenavir 700mg twice quinavir and ritonavir concentrations but did not daily plus ritonavir 100mg twice daily.[71] Although alter plasma amprenavir concentrations. The clinical plasma amprenavir concentrations were reduced, utility of a combination regimen of fosamprenavir this combination regimen delivered comparable or plus saquinavir/ritonavir has not been established. higher plasma amprenavir exposure than that of all 4.3.5 Tipranavir the fosamprenavir (or amprenavir) plus lopinavir/ When tipranavir 500mg twice daily plus ritonavir ritonavir combination regimens reported to date and 100mg twice daily was added to the combination of higher exposure than that of the standard unboosted amprenavir 600mg twice daily plus ritonavir 100mg dose of fosamprenavir 1400mg twice daily. twice daily, plasma amprenavir AUC↑ decreased by There is interest in evaluating dual-boosted PI 45%, Cmax decreased by 40% and C↑ decreased by therapy in the treatment of heavily ART-exper- 56%.[91] The addition of tipranavir 500mg twice ienced patients who have very few remaining treat- daily plus ritonavir 100mg twice daily to lopinavir/ ment options and as a class (NNRTI and NRTI)- ritonavir 400mg/100mg twice daily or to saquinavir sparing approach in ART-naive patients. Despite the 1000mg twice daily plus ritonavir 100mg twice dai- negative pharmacokinetic interaction between ly similarly reduced plasma lopinavir or saquinavir fosamprenavir (or amprenavir) and lopinavir/ concentrations.[91] The clinical utility of a combina- ritonavir,[61,62,71] the poor tolerability observed in tion regimen of fosamprenavir plus tipranavir/ healthy volunteers[71] and the lack of large, well ritonavir has not been established. controlled clinical trials, there have been reports of 4.3.6 Indinavir good virological responses and acceptable tolerabil- Plasma amprenavir AUC↑ increased by 33%, ity for these combinations in heavily ART-exper- Cmax increased by 18% and C↑ increased by 25% ienced HIV-1-infected patients.[106-108] when amprenavir 750mg three times daily was coadministered with indinavir 800mg three times could lead to significant toxicity (e.g. myopathy) in daily, while plasma indinavir AUC↑ decreased by patients with HIV infection. Simvastatin, lovastatin, 38%, Cmax decreased by 22% and C↑ decreased by atorvastatin and cerivastatin (removed from the 27% compared with historical data.[90] The interac- market) are primarily metabolised by CYP3A4, an tion between fosamprenavir (or amprenavir) plus isoenzyme inhibited by HIV-1 PIs, including am- ritonavir and indinavir has not been studied. prenavir. 4.3.7 Nelfinavir Simvastatin and lovastatin are contraindicated There was no change in plasma amprenavir with all marketed HIV-1 PIs because of the potential AUC↑, whereas plasma amprenavir Cmax decreased for significant increases in exposure and potential by 14% and C↑ increased by 189% when amprenavir toxicity. A drug interaction study was completed to 750mg three times daily was coadministered with quantify increases in atorvastatin exposure to sup- nelfinavir 750mg three times daily, while plasma port dosing recommendations in combination with nelfinavir AUC↑ increased by 15%, Cmax increased fosamprenavir and fosamprenavir plus ritonavir.[49] by 12% and C↑ increased by 14% compared with historical data.[90] The interaction between fosam- prenavir (or amprenavir) plus ritonavir and nelfi- navir has not been studied. Coadministration of either fosamprenavir 1400mg twice daily or fosamprenavir 700mg twice daily plus ritonavir 100mg twice daily significantly increased plasma atorvastatin exposure. When fosamprenavir 4.4Entry Inhibitors 1400mg twice daily was coadministered, plasma atorvastatin AUC↑ and Cmax values were increased 4.4.1Enfuvirtide 2.30- and 4.04-fold, respectively, compared with Enfuvirtide is a peptide and is not dependent on those observed with atorvastatin 10mg once daily the CYP system for metabolism. No interaction is alone. When fosamprenavir 700mg twice daily plus expected between fosamprenavir or fosamprenavir ritonavir 100mg twice daily was coadministered, plus ritonavir and enfuvirtide based on clinical stud- plasma atorvastatin AUC↑ and Cmax values were ies demonstrating no significant impact of either a increased 2.53- and 2.84-fold, respectively, com- potent CYP3A4 inhibitor (ritonavir) or a potent pared with those observed with atorvastatin 10mg CYP3A4 inducer (rifampicin) on enfuvirtide phar- once daily alone.[49] The highest approved atorvasta- macokinetics.[109,110] tin dosage is 80 mg/day. Therefore, when used in 4.5Non-anti-HIV Drugs combination with fosamprenavir or fosamprenavir plus ritonavir, atorvastatin should be administered at 4.5.1HMG-CoA Reductase Inhibitors doses 20 mg/day, with careful monitoring for HIV infection is accompanied by disturbances in atorvastatin toxicity. Alternatively, HMG-CoA lipid and glucose metabolism. These metabolic ab- reductase inhibitors that do not depend on CYP3A4 normalities are further confounded by changes in- metabolism, such as pravastatin, rosuvastatin and duced by ART. HMG-CoA reductase inhibitors (sta- fluvastatin, should be considered. There was no tins) have decreased morbidity and mortality in sub- significant impact of atorvastatin on plasma am- jects with elevated cholesterol levels and are being prenavir pharmacokinetics; therefore, no alteration used in the ART-experienced population. However, in the fosamprenavir or fosamprenavir plus ritonavir it is important to recognise that drug interactions dosage regimen is required when coadministered between HMG-CoA reductase inhibitors and ART with atorvastatin. 4.5.2Antacids, Histamine H2 Receptor Antagonists prenavir may have allowed a sufficient time for and Proton Pump Inhibitors fosamprenavir to dissolve in the stomach before Fosamprenavir exhibits pH-dependent solubility, maximal gastric pH values were achieved.[113-115] with maximal solubility at pH 3.3 and reduced solu- bility at higher pH.[14] When a single dose of fosam- 4.5.3Clarithromycin prenavir 1400mg was coadministered with the po- Coadministration of amprenavir 1200mg twice tent antacid Maalox TC↔ (magnesium hydroxide daily with clarithromycin 500mg twice daily did not 1800mg and aluminum hydroxide dried gel 3600mg significantly alter plasma clarithromycin pharma- [equivalent to aluminum hydroxide 2754mg]), plas- cokinetics; however, there was a minor increase in ma amprenavir Cmax decreased by 35%, plasma plasma amprenavir pharmacokinetics.[98] Therefore, amprenavir AUCμ decreased by 18% and the con- when fosamprenavir 1400mg twice daily is centration at 12 hours after dosing (C12) was in- coadministered with clarithromycin, no dose adjust- creased by 14%; these changes are not considered ment of either drug is necessary. Considering the clinically significant.[97] Administration of a single moderate increase in clarithromycin exposure when dose of fosamprenavir 1400mg 1 hour after adminis- ritonavir was coadministered,[116] a reduction in the tration of the histamine H2 receptor antagonist rani- clarithromycin dose should be considered in patients tidine 300mg resulted in larger decreases in plasma with renal impairment concurrently receiving amprenavir exposure – Cmax decreased by 51% and fosamprenavir plus ritonavir. AUCμ decreased by 30%, whereas C12 was un- 4.5.4 Azole Antifungal Agents changed.[97] Coadministration of single doses of amprenavir In general, proton pump inhibitors are considered 1200mg and ketoconazole 400mg resulted in a 44% to be more potent inhibitors of gastric pH than H2 increase in plasma ketoconazole AUCμ and a 31% receptor antagonists, based upon higher median or increase in plasma amprenavir AUCμ .[47] Coadmin- mean gastric pH values over a 24-hour period.[111] istration of fosamprenavir 700mg twice daily plus However, in contrast to the results of the single dose ritonavir 100mg twice daily with ketoconazole study of fosamprenavir and ranitidine,[97] steady- 200mg once daily increased plasma ketoconazole state plasma amprenavir exposures were unchanged Cmax by 25% and increased AUC↑ values 2.69-fold when esomeprazole 20mg once daily was compared with those observed with administration coadministered with either fosamprenavir 1400mg of ketoconazole 200mg once daily alone, whereas twice daily or fosamprenavir 700mg twice daily plus there was no change in plasma amprenavir pharma- ritonavir 100mg twice daily for 10 days.[65] Plasma cokinetics.[74] As expected, the increase in plasma esomeprazole AUC↑ was increased by 55% with ketoconazole exposure was greater for ritonavir- fosamprenavir 1400mg twice daily, but Cmax was boosted fosamprenavir than previously observed for unchanged; both plasma esomeprazole AUC↑ and unboosted amprenavir. The extent of increase in Cmax were unchanged with fosamprenavir 700mg plasma ketoconazole exposure is in agreement with twice daily plus ritonavir 100mg twice daily.[65] data for ritonavir (plasma ketoconazole AUC↑ in- The different results obtained for the ranitidine creased 3.4-fold)[117] and lopinavir/ritonavir (plasma and esomeprazole studies may be due to the differ- ketoconazole AUC↑ increased 3-fold).[9,10] Itracona- ences in dosing times. Pretreatment with ranitidine zole concentrations are expected to increase in the allowed maximal gastric pH values to be achieved same manner as for ketoconazole. Dose reduction prior to fosamprenavir dosing;[112] whereas, simulta- and monitoring for ketoconazole and itraconazole- neous administration of esomeprazole and fosam- associated adverse events should be considered when coadministering either of these azole antifun- 64%. Therefore, when coadministered with fosam- gal agents with fosamprenavir or fosamprenavir prenavir 700mg twice daily plus ritonavir 100mg plus ritonavir. twice daily, a 75% reduction in the rifabutin dose Coadministration of voriconazole with ritonavir (i.e. 150mg every other day) is recommended. In is contraindicated owing to significant reductions in either case, when fosamprenavir or fosamprenavir plasma voriconazole exposures;[118] neither the in- plus ritonavir are coadminstered with rifabutin, pa- teraction between fosamprenavir and voriconazole tients should be monitored for rifabutin-associated nor the interaction between fosamprenavir plus toxicity and further reductions in the rifabutin dose ritonavir and voriconazole has been studied. No significant interaction is expected between may be required. fosamprenavir or fosamprenavir plus ritonavir and 4.5.6Rifampicin (Rifampin) fluconazole because of their different elimination Coadministration of amprenavir 1200mg twice pathways (i.e. fluconazole is primarily eliminated daily with rifampicin 600mg once daily reduced renally and amprenavir is metabolised) and because plasma amprenavir AUC↑ by82% and C↑ by 92%;[48] fluconazole is a relatively less potent CYP3A4 in- therefore, fosamprenavir and rifampicin should not hibitor.[119] be coadministered. Data for other HIV-1 PIs, such as lopinavir/ritonavir and atazanavir, demonstrate 4.5.5 Rifabutin that coadministration of ritonavir 100 or 200mg Coadministration of amprenavir 1200mg twice daily with rifabutin 300mg once daily increased twice daily does not counteract the potent CYP3A4 induction effects of rifampicin.[121,122] Although plasma rifabutin Cmax by 119%, AUC↑ by 193% and C↑ by 271%.[48] Because of the significant increase in rifabutin exposures, the rifabutin dose should be much higher doses of ritonavir (i.e. 400mg twice daily) did counteract the effect of rifampicin on lopinavir concentrations, the regimen was associat- reduced (i.e. to 150mg once daily) when used in ed with a high incidence of withdrawals owing to combination with fosamprenavir 1400mg twice dai- ALT and AST level elevations.[123] Furthermore, ly. When fosamprenavir plus ritonavir is coadminis- coadministration of saquinavir 1000mg twice daily tered with rifabutin, larger increases in rifabutin plus ritonavir 100mg twice daily with rifampicin exposures are expected.[120] This was confirmed in a 600mg once daily was also associated with marked study that evaluated the combination of fosam- ALT and AST level elevations. Because similar prenavir 700mg twice daily plus ritonavir 100mg ALT and AST level elevations would be expected in twice daily with a reduced dose and dosing frequen- the situation where fosamprenavir plus ritonavir was cy of rifabutin 150mg every other day compared coadministered with rifabutin, their coadministra- with a standard rifabutin dosage regimen of 300mg once daily.[101] The fosamprenavir plus ritonavir tion is not recommended. plus rifabutin combination regimen delivered a sim- 4.5.7Hormonal Contraceptives ilar AUC from 0 to 48 hours (AUC48) and a 14% Because hormonal contraceptive concentrations lower Cmax for rifabutin compared with rifabutin may be altered when combined with fosamprenavir alone. 25-O-desacetyl-rifabutin AUC48 and Cmax or fosamprenavir plus ritonavir, alternate or addi- values were increased 11-fold and 6-fold, respec- tional reliable barrier methods of contraception are tively, and total antimycobacterial (i.e. rifabutin plus recommended for women of childbearing poten- 25-O-desacetyl-rifabutin) AUC48 was increased by tial.[6,99] 4.5.8Methadone Additional drugs not recommended for coadmin- Coadministration of amprenavir 1200mg twice istration with fosamprenavir or fosamprenavir plus daily with individualised doses of methadone once ritonavir due to potential serious toxicity include daily reduced plasma R-methadone (active enanti- bepridil, halofantrine, lovastatin and simvastatin. omer) Cmax by 25%, AUC↑ by 13% and C↑ by 21%, Caution should be used when prescribing inhaled with larger reductions observed for S-methadone corticosteroids metabolised by CYP3A4 (e.g. (inactive enantiomer).[100] Coadministration of ri- budesonide and fluticasone propionate) in subjects tonavir with methadone also reduced plasma metha- receiving fosamprenavir; coadministration with done concentrations.[124] Therefore, patients receiv- fosamprenavir plus ritonavir is not recommended ing concurrent fosamprenavir or fosamprenavir plus unless the benefits outweigh the risk. Coadministra- ritonavir and methadone should be monitored for tion of fluticasone propionate aqueous nasal spray signs of opioid withdrawal and the dosage of metha- with ritonavir 100mg twice daily significantly in- done may need to be increased. creased plasma cortisol AUC values.[125] An alterna- tive inhaled corticosteroid that is not dependent on 4.6Contraindications and CYP3A4, such as beclomethasone, should be con- Special Precautions sidered for use with fosamprenavir or fosamprenavir plus ritonavir. In the labelling of several HIV-1 PIs, including fosamprenavir, there are consistent lists of drugs Particular caution should be used when prescrib- that are contraindicated or necessary to use with ing phosphodiesterase (PDE5) inhibitors (e.g. caution owing to the drug interaction profile (prima- sildenafil, vardenafil tadalafil) in subjects receiving rily involving CYP3A4) of the HIV-1 PIs.[3-12] fosamprenavir. In these cases, PDE5 inhibitor dose The following drugs are contraindicated for ad- reductions are recommended. Coadministration of ministration with fosamprenavir because coadminis- fosamprenavir or fosamprenavir plus ritonavir with tration may result in competitive inhibition of me- PDE5 inhibitors is expected to increase plasma tabolism of these medications and may cause serious PDE5 inhibitor concentrations by competitive inhi- or life-threatening adverse events: astemizole, bition of metabolism and may result in an increase in cisapride, dihydroergotamine mesilate, encainide, PDE5 inhibitor-associated adverse events, such as ergometrine, ergotamine, methylergometrine, mida- hypotension, visual changes and priapism. zolam, pimozide, terfenadine and triazolam. In addi- Caution should be used when prescribing tion, when fosamprenavir is coadministered with trazodone in subjects receiving fosamprenavir be- ritonavir, coadministration of flecainide or propafe- cause plasma trazodone concentrations may be in- none is contraindicated. creased, leading to adverse events such as nausea, Fosamprenavir should not be coadministered dizziness, hypotension and syncope. If coadminis- with rifampicin or St John’s Wort (hypericum) be- tered, a lower dose of trazodone should be consid- cause plasma amprenavir concentrations may be ered. significantly decreased, reducing its efficacy. Other The following medications are examples of drugs drugs that could potentially significantly reduce that require concentration and therapeutic effect plasma amprenavir concentrations, and thus should monitoring when administered in combination with be used with caution, include carbamazepine, dex- fosamprenavir or fosamprenavir plus ritonavir ow- amethasone, phenobarbital (phenobarbitone), ing to the potential for serious and/or life-threaten- phenytoin and primidone. ing drug interactions: amiodarone, ciclosporin, lidocaine (lignocaine), quinidine, sirolimus (ra- 100mg twice daily for the treatment of HIV-1 PI- pamycin), tacrolimus, tricyclic antidepressants (e.g. experienced patients. Patients with hepatic impair- amitriptyline, desipramine, imipramine) and warfa- ment require reduced doses of fosamprenavir be- rin. cause plasma amprenavir concentrations are signifi- Other drugs that should be used with caution and cantly increased in this population.[82] An ongoing with clinical monitoring include benzodiazepines study is evaluating the pharmacokinetics of reduced and calcium channel antagonists. fosamprenavir plus ritonavir dosage regimens in HIV-1-infected patients with various degrees of 5. Conclusion hepatic impairment. Several drug interaction studies have been com- Fosamprenavir is one of the most recently ap- pleted for fosamprenavir (or amprenavir) and proved HIV-1 PIs and its availability allows for fosamprenavir (or amprenavir) plus ritonavir. These substantial reductions in pill number and pill size, studies demonstrate that fosamprenavir or fosam- and omits the need for food and fluid requirements prenavir plus ritonavir can be combined with many associated with other HIV-1 PIs (table I). Fosam- other antiretroviral agents, including potent prenavir is the phosphate ester prodrug of the HIV-1 CYP3A4 inducers such as efavirenz and nevirapine, PI amprenavir and is rapidly and extensively con- as well as with other non-HIV drugs, such as proton verted to amprenavir in vivo.[14,16] Amprenavir is pump inhibitors, antifungals and antimycobacteri- highly permeable and maximum plasma amprenavir als, that are commonly administered to HIV-1- concentrations are achieved within 1.5–2.5 hours infected patients. after fosamprenavir dosing. Amprenavir is a P-gp substrate and preclinical animal studies demonstrate that potent P-gp inhibition can increase amprenavir concentrations in blood and body tissues.[17] Am- Acknowledgements prenavir has a wide apparent oral volume of distri- bution and penetrates into semen but not the No sources of funding were used to assist in the prepara- tion of this review. All authors are employees of Glaxo- SmithKline, the company that manufactures and markets CSF.[18,26-29] The plasma protein binding of am- fosamprenavir. prenavir is approximately 90%. Amprenavir is ex- tensively metabolised by CYP3A4 and is commonly administered in combination with low doses of the References potent CYP3A4 inhibitor ritonavir in order to main- 1. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with tain elevated plasma amprenavir concentrations.[72] human immunodeficiency virus infection and CD4 cell counts Fosamprenavir and ritonavir are both CYP3A4 in- of 200 per cubic millimeter or less. N Engl J Med 1997; 337: 725-33 hibitors and inducers. 2. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbid- Plasma amprenavir pharmacokinetic data, in combination with clinical safety and efficacy trial ity and mortality among patients with advanced human immu- nodeficiency virus infection. N Engl J Med 1998; 338: 853-60 3.Crixivan (indinavir) complete prescribing information. White- data, support flexible dosage regimen options for house Station (NJ); Merck & Co Inc.; 2005 HIV-1 PI-naive patients, including the option to dose with or without concurrent ritonavir as well as 4.Agenerase (amprenavir) capsules: complete prescribing infor- mation. Research Triangle Park (NC): GlaxoSmithKline, 2004 5.Invirase (saquinavir mesylate) capsules and tablets: complete once daily and twice daily dosing options. Further- prescribing information. Nutley (NJ): Roche Laboratories, more, these data support the coadministration of Inc., 2005 6.Norvir (ritonavir) capsules: complete prescribing information. fosamprenavir 700mg twice daily plus ritonavir North Chicago (IL): Abbott Laboratories, 2005 7.Viracept (nelfinavir mesylate) tablets: complete prescribing in- tients receiving different dosage regimens [abstract no. 5, formation. La Jolla (CA): Agouron Pharmaceuticals, Inc., poster no. 1.5]. 6th International Workshop on Clinical Phar- 2005 macology of HIV Therapy; 2005 April 28-30; Quebec City 8.Reyatax (atazanavir sulfate) capsules: complete prescribing in- (QC) formation. Princeton (NJ): Bristol-Myers Squibb Company, 22. Studenberg SD, Woolley JL. 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J Clin inhibitors but not substrates of the human breast cancer resis- Pharmacol 2001; 41: 386-96 tance protein (BCRP/ABCG2). J Pharmacol Exp Ther 2004; 19.Wire MB, Lou Y, Shelton MJ, et al. Evaluation of plasma 310: 334-41 amprenavir (APV) pharmacokinetics (PK) following adminis- 31. van der Sandt ICJ, Vos CMP, Nabulsi L, et al. Assessment of tration of fosamprenavir (FPV) formulations with a high-fat active transport of HIV protease inhibitors in various cell lines breakfast (HFB; APV10008) [abstract no. A-448]. 44th Inter- and the in vitro blood-brain barrier. AIDS 2001; 15: 483-91 science Conference on Antimicrobial Agents and Chemothera- 32. Olsen DP, Scadden DT, D’Aquila RT, et al. The protease py; 2004 Oct 30-Nov 2; Washington, DC inhibitor ritonavir inhibits the functional activity of the mul- 20.Baker K, Lou Y, Aggarwal G, et a. A pivotal, phase I, single- tidrug resistance related-protein 1 (MRP-1). AIDS 2002; 16: dose, open-label, randomized, four period, balanced crossover 1743-7 study to assess the relative bioavailability of the GW433908 33. Huang L, Wring SA, Woolley JL, et al. Induction of P-glycopro- oral suspension and oral film-coated 700mg tablet formula- tein and cytochrome P450 3A by HIV protease inhibitors. tions and the effect of food on the bioavailability of these Drug Metab Dispos 2001; 29: 754-60 formulations in healthy adult subjects (APV10016). Research 34. Perloff MD, Von Moltke LL, Marchand JE, et al. Ritonavir Triangle Park (NC); GlaxoSmithKline, 2002 (Data on file) induces P-glycoprotein expression, multi-drug resistance-asso- 21.Garraffo R, Lavrut T, Heripret I, et al. Fosamprenavir (FPV) ciated protein (MRP1) activity, and drug transporter-mediated trough concentrations (Cmin) and inhibitory quotients (IQ), at activity in a human intestinal cell line. J Pharm Sci 2001; 90: steady-state, in plasma and lymphocytes of HIV infected pa- 1829-37 35.Vishnuvardhan D, von Moltke LL, Richert C, et al. Lopinavir: and 908/ritonavir (RTV) with ATO (APV10013) [abstract no. acute exposure inhibits P-glycoprotein; extended exposure in- A-1622]. 43rd Interscience Conference on Antimicrobial duces P-glycoprotein. AIDS 2003; 17: 1092-4 Agents and Chemotherapy; 2003 Sep 14-17; Chicago (IL) 36.Schuetz EG, Beck WT, Schuetz JD. Modulators and substrates 50. DeJesus E, Piliero P, Summers K, et al. Evaluation of the drug of P-glycoprotein and cytochrome P4503A coordinately up- interaction between fosamprenavir (FPV), FPV plus ritonavir regulate these proteins in human colon carcinoma cells. Mol (RTV) and nevirapine (NVP) in HIV-infected patients Pharmacol 1996; 49: 311-8 (APV10014) [abstract no. A-447]. 44th Interscience Confer- 37.Greiner B, Eichelbaum M, Fritz P, et al. The role of intestinal P- ence on Antimicrobial Agents and Chemotherapy; 2004 Oct glycoprotein in the interaction of digoxin and rifampin [pub- 30-Nov 2; Washington, DC lished erratum appears in J Clin Invest 2002; 110: 571]. J Clin 51. Rosemond J, Moore L. In vitro investigation of human PXR Invest 1999; 104: 147-53 activation by GI268188A (amprenavir), GW433908A (fosam- 38.Penzak SR, Shen JM, Alfaro RM, et al. Ritonavir decreases the prenavir), and GW433908X (fosamprenavir) [RD2003/01212/ nonrenal clearance of digoxin in healthy volunteers with 00]. Research Triangle Park (NC); GlaxoSmithKline, 2003 known MDR1 genotypes. Ther Drug Monit 2004; 26: 322-30 (Data on file) 39.Gooding AE, Woolley JL. Plasma protein binding and erythro- 52. Moore JT, Kliewer SA. Use of the nuclear receptor PXR to cyte partitioning studies in rat, dog and humans with 141W94 predict drug interactions. Toxicology 2000; 153: 1-10 (RD1996/00626/00). Research Triangle Park (NC); Glaxo- 53. Quattrochi LC, Guzelian PS. CYP3A regulation: from pharma- SmithKline, 1996 (Data on file) cology to nuclear receptors. Drug Metab Dispos 2001; 29: 40.Studenberg SD, Woolley JL. Determination of human plasma 615-22 protein binding interaction between amprenavir (141W94) and 54. Jones SA, Moore LB, Shenk JL, et al. The pregnane X receptor: the amprenavir metabolites GW549445X and GW549444A a promiscuous xenobiotic receptor that has diverged during (RD2001/00984/00). Research Triangle Park (NC); Glaxo- evolution. Mol Endocrinol 2000; 14: 27-39 SmithKline, 2001 (Data on file) 55. Luo G, Cunningham M, Kim S, et al. CYP3A4 induction by 41.Studenberg SD, Woolley JL. Determination of human plasma drugs: correlation between a pregnane X receptor reporter gene protein binding interaction between amprenavir (141W94) and assay and CYP3A4 expression in human hepatocytes. Drug ritonavir, delavirdine, and efavirenz (RD2001/00527/01). Re- Metab Dispos 2002; 30: 795-804 search Triangle Park (NC); GlaxoSmithKline, 2001 (Data on 56. de Serres M. RHuCYP3A4-like immunoreactivity in rat liver file) microsomes from 3-month amprenavir (TOX771) and 1- 42.Studenberg SD, Gooding AE, Woolley JL. Human plasma pro- month GW433908G (R40427) toxicology studies (RD1999/ tein binding interaction between 141W94 and diazepam, ver- 02460/02). Research Triangle Park (NC); GlaxoSmithKline, apamil, and indomethacin in vitro (RD1997/01807/00). Re- 1999 (Data on file) search Triangle Park (NC); GlaxoSmithKline, 1997 (Data on 57. Gardner GH, Wall HG. GW433908G: a 4-week oral gavage file) toxicity study in Han Wistar rats (RD1998/02573/00). Re- 43.Gathe JC, Ive P, Wood R, et al. SOLO: 48-week efficacy and search Triangle Park (NC); GlaxoSmithKline, 1998 (Data on safety comparison of once-daily fosamprenavir/ritonavir ver- file) sus twice-daily nelfinavir in naive HIV-1-infected patients. 58. Boehlert CC, Studenberg SD, Woolley JL. A re-examination of AIDS 2004; 18: 1529-37 hepatic microsomal activity in rats given 141W94 in a 3-month 44.Elston R, Yates P, Tisdale M, et al. GW433908 (908)/ritonavir toxicity study (RD1998/00348/00). Research Triangle Park (r): 48-week results in PI-experienced subjects: a retrospective (NC); GlaxoSmithKline, 1998 (Data on file) analysis of virologic response based on baseline genotype and 59. Tran JQ, Petersen C, Garrett M, et al. Pharmacokinetic interac- phenotype [abstract no. MoOrB1055]. XV International AIDS tion between amprenavir and delavirdine: evidence of induced Conference; 2004 Jul 11-16; Bangkok clearance by amprenavir. Clin Pharmacol Ther 2002; 72: 45.Boehlert CC, Sinhababu AK, Woolley JL. Identification of the 615-26 cytochrome P450 isozymes involved in the metabolism of 60. Justesen US, Klitgaard NA, Brosen K, et al. Pharmacokinetic 141W94 (RD1998/00349/00). Research Triangle Park (NC); interaction between amprenavir and delavirdine after multiple- GlaxoSmithKline, 1998 (Data on file) dose administration in healthy volunteers. Br J Clin Pharmacol 46.Studenberg SD, Woolley JL. Inhibition of human microsomal 2003; 55: 100-6 cytochrome P450 isozymes by 141W94 (RD1996/00356/00). 61. Kashuba AD, Tierney C, Downey GF, et al. Combining fosam- Research Triangle Park (NC); GlaxoSmithKline, 1996 (Data prenavir with lopinavir/ritonavir substantially reduces am- on file) prenavir and lopinavir exposure: ACTG protocol A5143 re- 47.Polk RE, Crouch MA, Israel DS, et al. Pharmacokinetic interac- sults. AIDS 2005; 19: 145-52 tion between ketoconazole and amprenavir after single doses 62. Taburet AM, Raguin G, Le Tiec C, et al. Interactions between in healthy men. Pharmacotherapy 1999; 19: 1378-84 amprenavir and the lopinavir-ritonavir combination in heavily 48.Polk RE, Brophy DF, Israel DS, et al. Pharmacokinetic interac- pretreated patients infected with human immunodeficiency tion between amprenavir and rifabutin or rifampin in healthy virus. Clin Pharmacol Ther 2004; 75: 310-23 males. Antimicrob Agents Chemother 2001; 45: 502-8 63. Griffith S, Ledford E, Lou Y, et al. A phase IIIb/IV, randomized, 49.Wire MB, Baker KL, Moore KHP, et al. The pharmacokinetic open label, multicenter, pilot trial to explore the safety and (PK) interaction of GW433908 (908) with atorvastatin (ATO) tolerability of GW433908 ritonavir (1400mg twice daily or © 2006 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2006; 45 (2) 700mg/100mg twice daily) when used in combination with a 72. Wire MB, Shelton MJ, Lou Y, et al. Ritonavir increases plasma zidovudine-containing regimen (Trizivir↔or Combivir↔twice amprenavir (APV) exposure to a similar extent when co- daily) over a 24-week period in antiretroviral therapy-naive administered with either fosamprenavir (FPV) or APV HIV-1 infected subjects (AZL30006) [RM2003/00478/00]. (APV10022) [abstract no. A-450]. 44th Interscience Confer- Research Triangle Park (NC); GlaxoSmithKline, 2004 (Data ence on Antimicrobial Agents and Chemotherapy; 2004 Oct on file) 30-Nov 2; Washington, DC 64.Baker K, Shelton M, Wire MB, et al. A pivotal, phase I, open- 73. Wire MB, Shelton MJ, Lou Y, et al. The pharmacokinetic label, randomized, four-period, single and multiple dose, interaction between fosamprenavir/ritonavir and atazanavir in crossover study to assess the bioequivalence of two healthy adult subjects (APV10018) [abstract no. PE4.3/9]. GW433908 700mg oral film-coated tablet variants following 10th European AIDS Conference; 2005 Nov 17-20; Dublin administration of single 1400mg doses and following adminis- 74. Borland J, Yuen G, Wire MB, et al. A phase I, open-label, tration of 1400mg bid for 14 days in healthy adult subjects single-sequence, drug-drug interaction study comparing (APV10023) [RM2004/00109/01]. Research Triangle Park ketoconazole and amprenavir pharmacokinetics following ad- (NC); GlaxoSmithKline, 2004 (Data on file) ministration of ketoconazole 200mg qd for 4 days, fosam- 65.Shelton MJ, Ford SL, Wire MB, et al. Co-administration of prenavir 700mg bid + ritonavir 100mg bid for 10 days, and esomeprazole (ESO) with fosamprenavir (FPV) has no impact ketoconazole 200mg qd + fosamprenavir 700mg bid + on steady-state plasma amprenavir (APV) pharmacokinetics ritonavir 100mg bid for 4 days in healthy adult subjects (APV10031) [abstract no. 24, poster no. 2.17]. 6th Internation- (APV10026) [RM2005/00398/00]. Research Triangle Park al Workshop on Clinical Pharmacology of HIV Therapy; 2005 (NC): GlaxoSmithKline, 2005 (Data on file) April 28-30; Quebec City (QC) 75. Shelton MJ, Wire MB, Lou Y, et al. Pharmacokinetic and safety 66.Kim Y, Hu C, Wire M, et al. Steady-state amprenavir pharma- evaluation of high dose combinations of fosamprenavir (FPV) cokinetics are similar between healthy and HIV-infected sub- and ritonavir (RTV) (APV10028) [abstract no. A-451]. 44th jects following GW433908 ritonavir using population Interscience Conference on Antimicrobial Agents and Chemo- pharmacokinetic analysis [abstract no. 7.5]. 5th International therapy; 2004 Oct 30-Nov 2; Washington, DC Workshop on Clinical Pharmacology of HIV Therapy; 2004 76. Pulido F, Katlama C, Marquez M, et al. A randomised study Apr 1-3; Rome investigating the efficacy and safety of amprenavir in combi- 67.Wire MB, Ballow C, Preston SL, et al. Pharmacokinetics and nation with low-dose ritonavir in protease inhibitor-exper- safety of GW433908 and ritonavir, with and without efavirenz, ienced HIV-infected adults. HIV Med 2004; 5: 296-302 in healthy volunteers. AIDS 2004; 18: 897-907 77. Cattelan A, Pulido F, Stark T, et al. Switch to amprenavir/ 68.Baker K, Lou Y, Wire MB, et al. A phase I, open-label, ritonavir demonstrated superior efficacy compared to the con- randomized, two-period, balanced crossover, study to compare tinuation of a protease inhibitor in multiple PI-experienced steady-state plasma amprenavir pharmacokinetics following HIV-1 infected subjects with virological failure [abstract no. administration of two GW433908 tablet variants, each admin- P1]. 2nd International HIV Workshop On Management of istered as 1400mg qd in combination with ritonavir 200mg qd Treatment Experienced Patients; 2002 Sep 25-27; San Diego in healthy adult subjects (APV10029) [RM2003/00494/00]. (CA) Research Triangle Park (NC); GlaxoSmithKline, 2004 (Data 78. Gathe J, Wood R, Bellos N, et al. Sustained virologic and on file) immunologic response over 120 weeks in antiretroviral ther- 69.Ruane P, Wire M, Shelton M, et al. Plasma amprenavir (APV) apy (ART)-na¨ive subjects receiving fosamprenavir/ritonavir pharmacokinetics (PK) and safety following co-administration (FPV/r) qd [abstract no. 61]. HIV DART 2004: Frontiers in of fosamprenavir (FPV) with a reduced ritonavir (RTV) dose Drug Development for Antiretroviral Therapies; 2004 Dec 12- once daily (qd) (COL10053) [abstract no. A-449]. 44th Inter- 16; Montego Bay science Conference on Antimicrobial Agents and Chemothera- 79. Boffito M, Dickinson L, Hill A, et al. Steady-state pharmacoki- py; 2004 Oct 30-Nov 2; Washington, DC netics of saquinavir hard-gel/ritonavir/fosamprenavir in HIV- 70.Amir-Ansari YA, Elston R, Granier C, et al. A phase III, 1-infected patients. J Acquir Immune Defic Syndr 2004; 37: randomised, multicenter, parallel group, open-label, three arm 1376-84 study to compare the efficacy and safety of two dosing regi- 80. Rhame FS, Rawlins SL, Petruschke RA, et al. Pharmacokinetics mens of GW433908/ritonavir (700mg/100mg twice daily or of indinavir and ritonavir administered at 667 and 100 milli- 1400mg/200mg once daily) versus lopinavir/ritonavir (400mg/ grams, respectively, every 12 hours compared with indinavir 100mg twice daily) for 48 weeks in protease inhibitor exper- administered at 800 milligrams every 8 hours in human immu- ienced HIV-infected adults experiencing virological failure nodeficiency virus-infected patients. Antimicrob Agents (APV30003) [GM2003/00236/00]. Research Triangle Park Chemother 2004; 48: 4200-8 (NC); GlaxoSmithKline, 2003 (Data on file) 81. Hu C, Moore KHP, Kim Y, et al. Statistical issues in a modeling 71.Wire MB, Naderer OJ, Masterman AL, et al. 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