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Amprenavir

A Review of its Clinical Potential in Patients with HIV Infection

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Summary

Abstract

The virological/immunological efficacy of amprenavir-containing combination regimens has been evaluated in a small number of clinical trials in patients with HIV infection.

Amprenavir plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) was more effective than 2 NRTIs (in treatment-naive patients) or amprenavir mono-therapy (in treatment-naive or -experienced patients) in double-blind trials. In the only direct comparison with another protease inhibitor as part of triple therapy, amprenavir was less effective than indinavir in treatment-experienced (protease inhibitor-naive) patients. Amprenavir was as effective as other protease inhibitors when given with abacavir in a small nonblind trial.

Amprenavir is generally well tolerated (most events are mild or moderate). GI disturbance and rash are the principal treatment-limiting effects. Preclinical data suggest that amprenavir may have a low potential for metabolic disturbances (e.g. lipodystrophy, fat redistribution); such effects have been infrequent in patients treated to date, but longer term experience is needed.

I50V is the major HIV protease substitution associated with amprenavir resistance; this mutation is not seen in isolates from patients receiving other available protease inhibitors. Amprenavir-resistant isolates evaluated to date showed no significant cross-resistance to most other protease inhibitors, although some cross-resistance to ritonavir was noted. Many isolates from patients previously treated with other protease inhibitors are susceptible to amprenavir.

Amprenavir offers the convenience of twice-daily administration with no food-timing or fluid restrictions, but this may be offset by the large number and size of the capsules. However, pharmacokinetic data support the use of coadministration of amprenavir and ritonavir at reduced dosages, thereby allowing a reduction in the number of amprenavir capsules.

Conclusions: Amprenavir-containing combination regimens have shown virological efficacy, and have generally been well tolerated, in patients with HIV infection (primarily treatment-naive or protease inhibitor-naive). The limited number of studies available and the absence of well controlled comparisons with other triple therapies limits the conclusions that can be drawn at present. The clinical value of amprenavir for patients with isolates which are resistant to other protease inhibitors but sensitive to amprenavir, and in treatment-experienced patients in general, requires further investigation. Further evaluation of the amprenavir/ritonavir combination is awaited with interest. Like other members of its class, amprenavir has a particular profile of tolerability, resistance and administration characteristics which should be carefully considered in relation to the needs of individual patients.

Pharmacodynamic Properties

Amprenavir is a sulfonamide compound which prevents the formation of infectious HIV-1 virions by inhibiting the viral protease enzyme. It produced 90% inhibition of HIV-1 replication at 0.03 to 0.08 µmol/L in human T cell lines or primary human lymphocytes; 50% inhibition was achieved with amprenavir 0.004 to 0.08 µmol/L. Mean 50%-inhibitory concentration (IC50) against 6 zidovudine-sensitive clinical isolates in peripheral blood lymphocytes was 0.012 µmol/L. Most combinations of amprenavir with other antiretroviral drugs had synergistic activity against HIV-1 in vitro.

Amprenavir had no significant cytotoxicity against human T-or B-cell lines or bone marrow progenitor cells invitro. Antiretroviral regimens containing amprenavir have produced a range of beneficial effects on markers of immune activation in patients with HIV infection. In contrast to results for other protease inhibitors, little or no effect on lipid metabolism was reported with amprenavir invitroor in mouse models.

The I50V substitution was the most common HIV protease mutation in isolates from previously protease inhibitor-naive patients who failed treatment with amprenavir, lamivudine and zidovudine (5 of 48 isolates, 4 of which showed phenotypic amprenavir resistance). In a trial in which treatment was compromised by baseline resistance to study NRTIs, I50V, I54L/M, V32I + I47V and I84V were the primary amprenavir resistance genotypes for isolates from protease inhibitor-naive patients failing treatment with amprenavir plus NRTIs. Amprenavir-resistant isolates in these 2 studies showed no significant cross-resistance to indinavir, saquinavir or nelfinavir; marked cross-resistance to ritonavir was seen for some isolates with I50V or I84V The I50V mutation has not been seen in isolates from patients receiving other available protease inhibitors. Virological data from several studies suggest that the majority of isolates from patients who have previously received other protease inhibitors are susceptible to amprenavir. I84V and I84V plus L10/I/V/F/R were the most important genotypic predictors of phenotypic amprenavir resistance at baseline for patients receiving rescue therapy with amprenavir, abacavir and efavirenz after failure of previous protease inhibitor regimens.

Pharmacokinetic Properties

Amprenavir is rapidly absorbed after oral administration, with a time to peak plasma concentration of≈1 to 2 hours. Area under the plasma concentration-time curve was dose-proportional over the range 300 to 1200mg in a multiple-dose study. Amprenavir absorption is reduced by intake with food, although food restrictions are limited to avoidance of high fat meals (see Dosage and Administration). The drug is ≈90% protein bound. Animal data suggest that CNS penetration of amprenavir, like that of other protease inhibitors, is limited by P-glycoprotein-mediated efflux. The plasma elimination half-life is about 7 to 11 hours, the longest for any available protease inhibitor. Amprenavir is metabolised primarily by hepatic cytochrome P450 (CYP) 3A4, with most of an administered dose detected as metabolites in faeces.

Amprenavir exposure is increased in patients with moderate or severe hepatic impairment, and dosage reduction is required. The pharmacokinetics of amprenavir administered as capsules or oral solution in children are broadly similar to those in adults. Absorption of amprenavir from the oral solution is 14% lower than that from capsules; thus, the per-kilogram dose is different for the 2 formulations. Amprenavir moderately inhibits CYP 3A4 and may interact pharmacokinetically with inducers, substrates or inhibitors of this system. Amprenavir exposure was decreased by coadministration with rifampicin (rifampin) and increased by coadministration with ritonavir in healthy volunteers. Amprenavir markedly increased rifabutin exposure in a similar study.

Pharmacokinetic modelling indicates that steady-state minimum plasma amprenavir concentrations ≈14 times the invitroIC50 value for wild-type HIV can be achieved by twice-daily coadministration of amprenavir 600mg and ritonavir 100mg. This ratio is about 6-fold greater than that for amprenavir 1200mg twice daily alone (2.2). Modelled data for a once-daily regimen of amprenavir 1200mg plus ritonavir 200mg indicated that this approach would also be feasible.

Clinical Efficacy

Amprenavir was significantly more effective than placebo in a randomised, double-blind multicentre study in 221 treatment-naive patients also receiving lamivudine and zidovudine (41 vs3% of patients had HIV RNA <400 copies/ml at 48 weeks, intent-to-treat analysis). A quadruple regimen of amprenavir, abacavir, lamivudine and zidovudine produced a marked reduction in viral load (5.1 log 10 copies/ ml) after 28 weeks in 98 treatment-naive patients with primary HIV infection (interim analysis). Preliminary data from a randomised nonblind trial suggest that this quadruple regimen produces a higher rate of adverse events and withdrawals than standard protease inhibitor-based triple therapy, but is superior to the latter for patients remaining on treatment.

Amprenavir produced lower levels of viral suppression than indinavir in a randomised nonblind study in antiretroviral-experienced patients who also received 2 NRTIs (data from the manufacturer, statistical analysis not available). According to intent-to-treat analysis, 30 and 46% of amprenavir and indinavir recipients had viral load <400 copies/ml after 48 weeks; 26 and 18% of patients had virological failure at 48 weeks or had already withdrawn from treatment for this reason. Salvage therapy (after previous failure of protease inhibitor-containing treatment) with amprenavir, abacavir and efavirenz produced durable viral suppression in a small percentage of antiretroviral-experienced patients (25 and 23% of 101 patients had RNA<400 copies/ml after 16 and 48 weeks, intent-to-treat analysis) in a noncomparative study.

Triple therapy with amprenavir, lamivudine and zidovudine reduced viral load to a significantly greater extent than amprenavir monotherapy (by 2.16 vs0.91 log10 copies/ml) after 12 weeks in a double-blind study in 92 treatment-naive or -experienced patients. 14 of 19 men receiving amprenavir monotherapy had seminal viral load <400 copies/ml at 8 to 20 weeks follow-up, compared with only 7 of 23 evaluable at baseline.

Amprenavir produced similar virological efficacy to indinavir, nelfinavir, ritonavir or saquinavir when administered in combination with abacavir over 48 weeks in 81 treatment-naive patients in a randomised nonblind trial. 56% (intentto-treat) of amprenavir recipients had viral load <400 copies/ml compared with 41 to 59% for the other groups.

Triple or quadruple therapy with amprenavir plus NRTIs had moderate efficacy in protease inhibitor-naive patients, but only limited efficacy in protease inhibitor-experienced patients, in 2 clinical trials in children and adolescents (n = 229 and 40).

Tolerability

Amprenavir is generally well tolerated in adults and children, with most events either mild or moderate in severity and relatively few serious adverse events. The most common adverse events of at least moderate severity in 358 adult patients who received amprenavir twice daily in combination with 2 NRTIs in 2 phase III trials were nausea (15%), diarrhoea (14%), rash (11%), vomiting (5%), headache (6%) and gaseous symptoms (5%); 11% of amprenavir recipients had severe (grade 3 or 4) clinical events. Nausea, rash, vomiting and diarrhoea were the most common causes of treatment withdrawal (7, 3, 3 and 2%, respectively). A single case of Stevens-Johnson syndrome (severe and potentially fatal rash) has been reported.

Nausea, vomiting, diarrhoea, fatigue and rash were markedly more common with amprenavir than with placebo in patients also receiving lamivudine and zidovudine in a randomised double-blind phase III trial (n = 222 for tolerability analysis). 19% of amprenavir recipients and 4% of placebo recipients withdrew from treatment following adverse events.

The total incidence of grade 3 clinical events (23 vs28%), grade 4 clinical events (5 vs8%) and grade 3 laboratory abnormalities (14 vs26%) was lower with amprenavir than with indinavir in a randomised nonblind phase III trial in 486 antiretroviral-experienced patients also receiving 2 NRTIs (statistical analysis not reported). Amprenavir caused more diarrhoea, nausea and rash than indinavir, whereas indinavir was more often associated with vomiting, headache, infections and fatigue. Fat redistribution was significantly less common with amprenavir than with indinavir (3 vs11%, p < 0.001; retrospective analysis), as were retinoid symptoms (dry skin, xerostomia and alopecia; p < 0.001). Long term analysis (median exposure >1 year) indicated similar rates of treatment withdrawal as a result of adverse events (19 vs18%); however, 24-week data indicate that such withdrawals were twice as common in the amprenavir group as in the indinavir group (16 vs8%), indicating that amprenavir withdrawals occur earlier in treatment.

Dosage and Administration

Amprenavir is indicated as part of combination antiretroviral therapy for HIV infection in adults, adolescents and children aged 4 or above; the indication is restricted to protease inhibitor-experienced patients in Europe, but not in the US. The drug is available as soft-gel capsules or an oral solution. The oral solution is contraindicated in children <4 years of age, pregnant women, patients with renal or hepatic impairment or patients receiving disulfiram or metronidazole because of the risk of toxicity from the large amount of propylene glycol in this formulation. The oral amprenavir solution should only be used if treatment with amprenavir capsules or another protease inhibitor is not possible.

The recommended amprenavir dosage in adults and adolescents with body-weight >50kg is 1200mg (8 x 150mg capsules) twice daily. Amprenavir can be taken with or without food but should not be taken with a high fat meal. Dosage adjustment is required for children, adolescents with bodyweight <50kg, and patients with hepatic dysfunction (and may be required in the elderly). A number of contraindications and cautions apply to coadministration of amprenavir with drugs that are metabolised by CYP 3A4. Amprenavir should be discontinued in patients who develop serious and/or life-threatening rash or in those with moderate rash accompanied by systemic symptoms. Patients receiving amprenavir should not take supplemental vitamin E.

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References

  1. Carpenter CCJ, Cooper DA, Fischl MA, et al. Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USAPanel. JAMA 2000 Jan 19; 283(3): 381–90

    Article  PubMed  CAS  Google Scholar 

  2. BHIVA Writing Committee on behalf of the BHTVA Executive Committee. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy [online]. British HIV Association, 2000 Jan 28. Available from: http://www.aidsmap.com/bhiva/bhivagdl299.htm [Accessed 2000 Apr 4]

  3. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents [online]. US Department of Health and Human Services, 2000 Jan 28. Available from: http://www. hivatis.org/guidelines/adult/text/ [Accessed 2000 Apr 26]

  4. Moyle GJ, Gazzard BG. A risk-benefit assessment of HIV pro-tease inhibitors. Drug Saf 1999 Apr; 20: 299–321

    Article  PubMed  CAS  Google Scholar 

  5. Flexner C. HIV-protease inhibitors. Drag Ther 1998 Apr 30; 338(18): 1281–92

    CAS  Google Scholar 

  6. Churchill D, Weber J. Antiretroviral drag guidelines for the treatment of HIV infection: should protease inhibitors always be included in the initial regimen or not? Biodrags 1999 Mar; 11: 147–53

    Article  CAS  Google Scholar 

  7. Kakuda TN, Strable KA, Piscitelli SC. Protease inhibitors for the treatment of human immunodeficiency viras infection. Am J Health System Pharm 1998 Feb 1; 55: 233–54

    CAS  Google Scholar 

  8. Painter GR, Ching S, Reynolds D, et al. 141W94. Drugs Future 1996 Apr; 21: 347–50

    CAS  Google Scholar 

  9. Lazdins JK, Mestan J, Goutte G, et al. In vitro effect of alphal-acid glycoprotein on the anti-human immunodeficiency virus (HIV) activity of the protease inhibitor CGP 61755: a comparative study with other relevant HIV protease inhibitors. J Infect Dis 1997 May; 175: 1063–70

    Article  PubMed  CAS  Google Scholar 

  10. Painter GR, St Clair MH, Demiranda P, et al. An overview of the preclinical development of the HIV protease inhibitor VX-478 (141W94) [abstract no. LB5]. 2nd National Conference on Human Retroviruses; 1995 Jan 29–Feb 2; Washington, DC, 167

  11. Livingston DJ, Pazhanisamy S, Porter DJT, et al. Weak binding of VX-478 to human plasma proteins and implications for anti-human immunodeficiency virus therapy. J Infect Dis 1995 Nov; 172: 1238–45

    Article  CAS  Google Scholar 

  12. St Clair MH, Millard J, Rooney J, et al. In vitro antiviral activity of 141W94 (VX-478) in combination with other antiretroviral agents. Antiviral Res 1996 Jan; 29: 53–6

    Article  CAS  Google Scholar 

  13. Zhang X-Q, Schooley RT, Gerber JG. The effect of increasing α1-acid glycoprotein concentration on the antiviral efficacy of human immunodeficiency virus protease inhibitors. J Infect Dis 1999 Dec; 180: 1833–7

    Article  PubMed  CAS  Google Scholar 

  14. Bilello JA, Drasano GL. Relevance of plasma protein binding to antiviral activity and clinical efficacy of inhibitors of human immunodeficiency virus protease [letter]. J Infect Dis 1996 Jun; 173: 1524–5

    Article  PubMed  CAS  Google Scholar 

  15. Livingston DJ, Pazhanisamy S, Partaledis JA, et al. Relevance of plasma protein binding to antiviral activity and clinical efficacy of inhibitors of human immunodeficiency virus protease. Reply [letter]. J Infect Dis 1996 Jun; 173: 1525–6

    Article  Google Scholar 

  16. Drusano GL, D’Argenio DZ, Symonds W, et al. Nucleoside analog 1592U89 and human immunodeficiency virus protease inhibitor 141W94 are synergistic in vitro. Antimicrob Agents Chemother 1998 Sep; 42: 2153–9

    PubMed  CAS  Google Scholar 

  17. Drasano GL, Preston SL, Bilello JA, et al. A new method for evaluation of combination chemotherapy regimens: application to abacavir (1592U89-ABC) and amprenavir (141W94-APV) [abstract no. A-5]. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998 Sep 24–27; San Diego, 2

  18. Bilello JA, Bilello PA, Symonds W, et al. Amprenavir (141W94) in combination with 1592U89 is highly synergistic in vitro [abstract no. 1-21]. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998 Sep 24–27; San Diego, 369

  19. Cherrington J, Mulato AS. Adefovir (PMEA) and PMPA show synergistic or additive inhibition of HIV replication in vitro in combination with other anti-HIV agents [abstract no. 41195]. 12th World AIDS Conference; 1998 Jun 28–Jul 3; Geneva, 781

  20. Tremblay C, Merrill DP, Chou TC, et al. Two-and three-protease inhibitor combinations against zidovudine-sensitive and zidovudine-resistant HIV-1 isolates in vitro [abstract no. 41201]. 12th World AIDS Conference; 1998 Jun 28–Jul 3; Geneva, 782

  21. Kinloch S, Phillips A, Cooper D, et al. Parallel decrease of CD38++CD8 cell and viremia in primary HIV infection (PHI) patients on quadruple HAART (ZDV/3TC/abacavir/ amprenavir) [abstract no. 1821]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999 Sep 26–29; San Francisco, 508

  22. Cooper D, Perrin L, Kinloch S, et al. Intervention with quadruple HAART [Combivir (COM)/abacavir (ABC)/amprenavir (APV)] intervention during primary HIV-1 infection (PHI) is associated with rapid viraemia clearance and decrease of immune activation [abstract/poster no. 552]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco, 179

  23. Mellors JW, Lederman J, Haas D, et al. Durable activity of Ziagen (abacavir, 1592, ABC) combined with protease inhibitors (PI) in antiretroviral therapy-naïve subjects [abstract/ poster no. 625]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago, 185

  24. Bart P-A, Rizzardi GP, Tambussi G, et al. Immunological and virological responses in HIV-1-infected adults at early stage of established infection treated with highly active antiretroviral therapy. AIDS 2000; 14(13): 1887–97

    Article  PubMed  CAS  Google Scholar 

  25. Lenhard JM, Weiel JE, Paulik MA, et al. Stimulation of vitamin A1 acid signaling by the HIV protease inhibitor indinavir. Biochem Pharmacol 2000; 59: 1063–8

    Article  PubMed  CAS  Google Scholar 

  26. Lenhard JM, Furfine ES, Jain RG, et al. HIV protease inhibitors block adipogenesis and increase lipolysis in vitro. Antiviral Res 2000; 47: 121–9

    Article  PubMed  CAS  Google Scholar 

  27. Lenhard JM, Croom DK, Weiel JE, et al. HIV protease inhibitors stimulate hepatic triglyceride synthesis. Arterioscler Thromb Vasc Biol 2000. In press

  28. Lenhard J, Furfine E, Paulik M, et al. Effect of HIV-protease inhibitors on in vitro adipogenesis and in vivo fat deposition [abstract no. 001]. 1st International Workshop on Adverse Drag Reactions and Lipodystrophy in HIV; 1999 Jun 26–28; San Diego, 8

  29. Lenhard JM, Croom DK, Weiel JE, et al. Dietary fat alters HIV protease inhibitor-induced metabolic changes in mice. J Nutr 2000; 130(9): 2361–6

    PubMed  CAS  Google Scholar 

  30. Weiel J, Croom D, Furfine E, et al. Influence of diet and genetics on metabolic abnormalities in mice treated with HIV protease inhibitors. In: Seventh European Conference on Clinical Aspects and Treatment of HIV-Infection. Bologne: Monduzzi Editore S.p.A, 1999: 31–4

    Google Scholar 

  31. Sadler BM, Piliero PJ, Preston SL, et al. Pharmacokinetic (PK) drug-interaction between amprenavir (APV) and ritonavir (RTV) in HIV-seronegative subjects after multiple, oral dosing [abstract/poster no. 77]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco, 90

  32. Tisdale M, Myers RE, Maschera B, et al. Cross-resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors. Antimicrob Agents Chemother 1995 Aug; 39: 1704–10

    Article  PubMed  CAS  Google Scholar 

  33. Partaledis JA, Yamaguchi K, Tisdale M, et al. In vitro selection and characterization of human immunodeficiency virus type 1 (HIV-1) isolates with reduced sensitivity to hydroxy-ethylamino sulfonamide inhibitors of HJV-1 aspartyl protease. J Virol 1995 Sep; 69: 5228–35

    PubMed  CAS  Google Scholar 

  34. Pazhanisamy S, Partaledis JA, Rao BG, et al. In vitro selection and characterization of VX-478 resistant HIV-1 variants. Adv Exp Med Biol 1998; 436: 75–83

    Article  PubMed  CAS  Google Scholar 

  35. Tisdale M, Myers R, Randall S, et al. Resistance to the HIV protease inhibitor amprenavir in vitro and in clinical studies: a review. Clin Drug Invest 2000 Oct; 20(4): 267–85

    Article  CAS  Google Scholar 

  36. Tisdale M, Myers RE, Ait-Khaled M, et al. HIV drug resistance analysis during clinical studies with the protease inhibitor amprenavir [abstract/poster no. 118]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago, 89

  37. Ait-Khaled M, Rakik A, Tisdale TD, et al. HIV-1 baseline genotype/phenotype and virological response following salvage therapy with Ziagen (abacavir, ABC), amprenavir (APV), and efavirenz (EFV) [abstract/poster no. 133]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago, 92

  38. Elston R, Myers R, Randall S, et al. Agenerase in dual PI combination therapy with saquinavir, indinavir, or nelfinavir: emergence of resistance [abstract/poster no. 727]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco, 211

  39. Randall S, Blanche S, Yeo J, et al. Genotypic and phenotypic analysis of HIV-1 isolates from paediatric subjects receiving amprenavir/NRTI combination therapy [abstract]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco

  40. Race E, Dam E, Obry V, et al. Analysis of HIV cross-resistance to protease inhibitors using a rapid single-cycle recombinant virus assay for patients failing on combination therapies. AIDS 1999; 13(15): 2061–8

    Article  PubMed  CAS  Google Scholar 

  41. Schmidt B, Walter H, Marcus U, et al. Crossresistance to amprenavir in PI treated patients [abstract/poster no. 726]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco, 211

  42. Masur H, Faloon J, Thomas D, et al. Durability of abacavir/ amprenavir/efavirenz combination salvage therapy —preliminary 48-week response (CNA2007) [abstract no. 206]. 7th European Conference on Clinical Aspects and Treatment of fflV-Infection; 1999 Oct 23–27; Lisbon, 19

  43. Glaxo Wellcome Inc. Agenerase® (amprenavir) capsules product information [online]. Glaxo Wellcome Inc. (Research Triangle Park, NC), 2000 Sep. Available from: URL: http://www.glaxowellcome.com/pi/agencap.pdf [Accessed 2000 Oct 10]

  44. Sadler BM, Yogev R, Kovacs A, et al. Pharmacokinetics of 141W94 after single dose administration in HIV-infected children [poster no. 330]. 6th European Conference on Clinical Aspects and Treatment of HIV-Infection; 1997 Oct 11–15; Hamburg, 330

  45. Glaxo Wellcome. European product information (summary of product characteristics). Research Triangle Park, NC: Glaxo Wellcome, 2000. (Data on file)

  46. Nishiyama M, Koishi M, Fujioka M, et al. Phase I clinical trial with a novel protease inhibitor for HIV, KVX-478, in healthy male volunteers [abstract no. 59]. Antiviral Res 1996 Apr; 30: 35

    Google Scholar 

  47. Barry M, Mulcahy F, Merry C, et al. Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection. Clin Pharmacokinet 1999 Apr; 36: 289–304

    Article  PubMed  CAS  Google Scholar 

  48. Sereni D, PROA1002 and PROA2002 International Study Groups. Antiviral activity of amprenavir in combination with zidovudine/3TC in plasma and CSF in patients with HJV infection [abstract]. J Neurovirol 1998 Jun; 4(3): 365

    Google Scholar 

  49. Kim RB, Fromm MF, Wandel C, et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 1998; 101: 289–94

    Article  PubMed  CAS  Google Scholar 

  50. Polli JW, Jarrett JL, Studenberg SD, et al. Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor. Pharm Res 1999 Aug; 16: 1206–12

    Article  PubMed  CAS  Google Scholar 

  51. Pereira A, Eron J, Dunn J, et al. Analysis of amprenavir (APV)/3TC/ZDV in blood and seminal plasma: penetration of APV into the male genital tract [abstract no. 317]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco, 136

  52. Decker CJ, Laitinen LM, Bridson GW, et al. Metabolism of amprenavir in liver microsomes: role of CYP3A4 inhibition for drug interactions. J Pharm Sci 1998 Jul; 87: 803–7

    Article  PubMed  CAS  Google Scholar 

  53. Woolley J, Studenberg S, Boehlert C, et al. Cytochrome P-450 isozyme induction, inhibition, and metabolism studies with the HIV protease inhibitor, 141W94 [abstract no. A-60]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto, 45

  54. Veronese L, Rautaureau J, Sadler BM, et al. Single-dose pharmacokinetics of amprenavir, a human immunodeficiency virus type 1 protease inhibitor, in subjects with normal or impaired hepatic function. Antimicrob Agents Chemother 2000 Apr; 44(4): 821–6

    Article  PubMed  CAS  Google Scholar 

  55. Sadler B, Gillotin C, Chittick GE, et al. Pharmacokinetic drug interactions with amprenavir [poster no. 12389]. 12th World AIDS Conference; 1998 Jun 28–Jul 3; Geneva, 91

  56. Stein DS, Sadler B, Sale M. Pharmacodynamic effects of amprenavir (APV) + ritonavir (RTV) on different vital populations [poster no. 5.2]. 1 st International Workshop on Clinical Pharmacology of HIV Therapy; 2000 Mar 30–Apr 1; Noordwijk

  57. Sale M, Stein DS, Sadler B. Concomitant ritonavir decreases the clearance of amprenavir-a pharmacokinetic model and simulation of protease inhibitor interaction [poster no. 2.1]. 1 st International Workshop on Clinical Pharmacology of HIV Therapy; 2000 Mar 30–Apr 1; Noordwijk

  58. Sadler BM, Eron J, Wakeford J, et al. Pharmacokinetics of 141W94 and indinavir (IDV) after single-dose coadministration in HIV-positive volunteers [abstract no. A-56]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto, 12

  59. Falloon J, Piscitelli S, Vogel S, et al. Combination therapy with amprenavir, abacavir, and efavirenz in human im-munodeficciencyvirus (HIV)-infected patients failing a protease-inhibitor regimen: pharmacokinetic drug interactions and antiviral activity. Clin Infect Dis 2000 Feb; 30: 313–8

    Article  PubMed  CAS  Google Scholar 

  60. Brophy DF, Israel DS, Pastor A, et al. Pharmacokinetic interaction between amprenavir and clarithromycin in healthy male volunteers. Antimicrob Agents Chemother 2000 Apr; 44(4): 978–84

    Article  PubMed  CAS  Google Scholar 

  61. Polk RE, Crouch MA, Israel DS, et al. Pharmacokinetic interaction between ketoconazole and amprenavir after single doses in healthy men. Pharmacotherapy 1999; 19(12): 1378–84

    Article  PubMed  CAS  Google Scholar 

  62. Glaxo Wellcome Inc. Agenerase® (amprenavir) oral solution product information [online]. Glaxo Wellcome Inc. (Research Triangle Park, NC), 2000 Sep. Available from: URL: http://www.glaxowellcome.com/pi/agenerase.pdf [Accessed 2000 Oct 10]

  63. Wintergerst U, Engelhorn C, Kurowski M, et al. Pharmacokinetic interaction of amprenavir in combination with efavirenz or delavirdine in HIV-infected children. AIDS 2000; 14(12): 1866–8

    Article  PubMed  CAS  Google Scholar 

  64. Degen O, Kurowski M, van Lunzen J, et al. Steady-state plasma pharmacokinetics of amprenavir (APV) 450 mg bid and ritonavir (RTV) 200 mg bid with or without efavirenz (EFV) in HIV-1 infected individuals [abstract no. WeOrB547]. 13th International AIDS Conference; 2000 Jul 9–14; Durban, 50

  65. Duval X, Le Moing V, Longuet P, et al. Efavirenz-induced decrease in plasma amprenavir levels in human immunodeficiency virus-infected patients and correction by ritonavir. Antimicrob Agents Chemother 2000 Sep; 44(9): 2593

    Article  PubMed  CAS  Google Scholar 

  66. The Avanti Steering Committee. Analysis of HIV-1 clinical trials: statistical magic? Lancet 1999 Jun 12; 353: 2061–4

    Article  Google Scholar 

  67. Goodgame J, Hanson C, Vafidis I, et al. Amprenavir (141W94, APV)/3TC/ZDV exerts durable antiviral activity in HIV-1 infected antiretroviral therapy-naïve subjects through 48 weeks of therapy [abstract no. 509]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999 Sep 26–29; San Francisco, 473

  68. Goodgame J, Stein A, Jablonowski H, et al. Amprenavir (141W94, APV)/3TC/ZDV exerts potent and durable antiviral activity over 48 weeks of therapy in HIV-1 infected antiretroviral therapy-naive subjects [abstract no. 521]. 7th European Conference on Clinical Aspects and Treatment of HIV-infection; 1999 Oct 23–27; Lisbon, 109

  69. Glaxo Wellcome. Letter to investigators. Research Triangle Park, NC: Glaxo Wellcome, 1999. (Data on file)

  70. Murphy RL, Gulick RM, DeGruttola V, et al. Treatment with amprenavir alone or amprenavir with zidovudine and lamivudine in adults with human immunodeficiency virus infec-tion. J Infect Dis 1999 Apr; 179: 808–16

    Article  PubMed  CAS  Google Scholar 

  71. Haubrich R, Thompson M, Schooley R, et al. A phase II safety and efficacy study of amprenavir in combination with zidovudine and lamivudine in HIV-infected patients with limited antiretroviral experience. AIDS 1999; 13(17): 2411–20

    Article  PubMed  CAS  Google Scholar 

  72. Goodgame CJ. Amprenavir (141 W94, APV USAN approved)/ 3TC/ZDV is superior to 3TC/ZDV in HIV-1 infected antiretroviral naive subjects [abstract no. P76]. AIDS 1998 Nov; 12 Suppl. 4: 36

    Google Scholar 

  73. Vernazza P, Perrin L, Vora S, et al. Increased seminal shedding of HIV during primary infection augments the need for earlier diagnosis and intervention [abstract/poster no. 564]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco, 182

  74. Eron J, Junod P, Becker S, et al. NZT4002: 64 week analysis of Combivir (COM)-based triple and quadruple therapy in anti-retroviral-naive, HIV-1 infected subjects [abstract no. WeOrB608]. 13th International AIDS Conference; 2000 Jul 9–14; Durban, 51

  75. Eron J, Jr, Smeaton LM, Fiscus SA, et al. The effects of protease inhibitor therapy on human immunodeficiency virus type 1 levels in semen (AIDS Clinical Trials Group Protocol 850). J Infect Dis 2000 May; 181: 1622–8

    Article  PubMed  CAS  Google Scholar 

  76. Eron J, Haubrich R, Richman D, et al. Safety and efficacy of amprenavir in combination with other protease inhibitors [abstract no. P84]. AIDS 1998 Nov; 12 Suppl. 4: 38

    Google Scholar 

  77. Church J, Rathore M, Rubio T, et al. A phase III study of amprenavir (APV, Agenerase™) in protease-inhibitor naïve and experienced HIV-infected children and adolescents [abstract/poster no. 693]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco, 205

  78. Blanche S, Fetter A, Cox H, et al. Aphase II study of amprenavir (APV, IWIW94, Agenerase™) in antiretroviral-experienced children with HIV-infection [abstract/poster no. 695]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco, 205

  79. Fetter A, Naccl P, Yeo.J, et al. Tolerability profile of amprenavir (APV, 141W94) in combination with various NRTIs [poster no. 813]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco, 227

  80. Pedneault L, Fetter A, Hanson C, et al. Amprenavir (141W94, APV): review of overall safety profile [poster no. 386]. 6th Conference on Retroviruses and Opportunistic Infections; 1999 Jan 31–Feb 4; Chicago, 140

  81. Lo JC, Mulligan K, Tai VW, et al. ‘Buffalo hump’ in men with HIV-1 infection. Lancet 1998 Mar; 351(9106): 867–70

    Article  PubMed  CAS  Google Scholar 

  82. Madge S, Kinloch-de-Loes S, Mercey D, et al. Lipodystrophy in patients naive to HIV protease inhibitors. AIDS 1999 Apr 16; 13(6): 735–7

    Article  PubMed  CAS  Google Scholar 

  83. Saint-Marc T, Partisani M, Poizot-Martin I, et al. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS 1999 Sep 10; 13(13): 1659–67

    Article  PubMed  CAS  Google Scholar 

  84. Moyle GJ, Baldwin C, Comitis S, et al. Changes in visceral adipose tissue and blood lipids in persons with lipodystrophy switched from protease inhibitor (PI) therapy to efavirenz (EFV) [abstract no. 462]. 7th European Conference on Clinical Aspects and Treatment of HIV-Infection; 1999 Oct 23–27; Lisbon

  85. Grunfeld C, Kotier D, Shigenaga J, et al. Circulating interferon-alpha levels and hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med 1991; 90: 154–62

    PubMed  CAS  Google Scholar 

  86. Pedneault L, Hanson C, Nacci P, et al. Amprenavir: a new protease inhibitor with a favorable metabolic profile [abstract no. 034]. 1st International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV Infection; 1999 Jun 26–28; San Diego, 33

  87. Fetter A, Nacci P, Lenhard J, et al. Fat distribution and retinoid-like symptoms are infrequent in NRTI-experienced subjects treated with amprenavir [abstract/poster no. 18]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco, 78

  88. Reddy P, Ross J. Amprenavir: a protease inhibitor for the treatment of patients with HIV-1 infection. Formulary 1999 Jul; 34: 567–77

    CAS  Google Scholar 

  89. The US FDA has approved twice daily dosing of nelfinavir [‘Viracept’; Agouron]. Inpharma 1999; 1216: 22

    Google Scholar 

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Stuart Noble & Karen L. Goa

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  1. Stuart Noble
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Correspondence to Stuart Noble.

Additional information

Various sections of the manuscript reviewed by: S. Blanche, Departement de Pediatrie, Unite d’Immunologie Hematologie, Hôpital Necker Enfants Malades, Paris, France; A. Carr, HIV Medicine Unit and Centre for Immunology, Darlinghurst, New South Wales, Australia; B. Conway, St. Pauls’s Hospital, Vancouver, British Columbia, Canada; E. De Clercq, Katholieke Universiteit Leuven, Rega Institute, Leuven, Belgium; R.M. Gulick, Cornell Clinical Trials Unit, New York, New York, USA; G.J. Moyle, Chelsea & Westminster Healthcare National Services Trust, London, England; R.L. Murphy, Comprehensive AIDS Center, Northwestern University, Chicago, Illinois, USA; L. Naesens, Katholieke Universiteit Leuven, Rega Institute, Leuven, Belgium; S.C. Piscitelli, Clinical Pharmacokinetics Research Laboratory, National Institutes of Health, Bethesda, Maryland, USA; R. Yogev, Division of Infectious Diseases, Children’s Memorial Hospital, Chicago, Illinois, USA.

Data Selection

Sources: Medical literature published in any language since 1966 on amprenavir, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand), Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘amprenavir’ or ‘141W94’ or ‘VX-478’ and ‘HIV infection’. Medline search terms were ‘amprenavir’ or ‘141W94’ or ‘VX-478’ and ‘HIV infection’. EMBASE search terms were ‘amprenavir’ or ‘141W94’ or ‘VX-478’ and ‘HIV infection’. Searches were last updated 2000 Nov 16.

Selection: Studies in patients with HIV infection who received amprenavir. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: amprenavir, HIV infection, protease inhibitors, antiretroviral therapy, pharmacodynamics, pharmacokinetics, therapeutic use.

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Noble, S., Goa, K.L. Amprenavir. Drugs 60, 1383–1410 (2000). https://doi.org/10.2165/00003495-200060060-00012

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