, Volume 65, Issue 15, pp 2209-2244
Date: 17 Sep 2012

Nelfinavir

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Summary

Abstract

Nelfinavir (Viracept®) is an orally administered protease inhibitor. In combination with other antiretroviral drugs (usually nucleoside reverse transcriptase inhibitors [NRTIs]), nelfinavir produces substantial and sustained reductions in viral load in patients with HIV infection. Nelfinavir may be used in the treatment of adults, adolescents and children aged ≥2 years with HIV infection. It can also be used in pregnancy. Resistance to nelfinavir may develop, but the most common mutation (D30N, appearing mainly in HIV-1 subtype B) does not confer resistance to other protease inhibitors, thereby conserving these agents for later use. Although less effective than lopinavir/ritonavir, the preferred first-line treatment in US guidelines, nelfinavir is positioned as an alternative agent for the treatment of adults and adolescents with HIV infection and is an option for those unable to tolerate other protease inhibitors. Nelfinavir also has a role in the management of pregnant patients as well as paediatric patients with HIV infection.

Pharmacological Properties

Nelfinavir is a selective, nonpeptidic competitive inhibitor of the HIV-1 protease. The drug shows good in vitro activity against HIV-1 strains, including strains resistant to zidovudine or non-nucleoside reverse transcriptase inhibitors. The activity of the major metabolite of nelfinavir (M8) against HIV-1 in vitro is similar to that of the parent drug. Additive activity against HIV-1 is observed with nelfinavir in combination with stavudine, didanosine or saquinavir; synergistic activity against HIV-1 is observed with nelfinavir in combination with zidovudine, lamivudine or zalcitabine.

Resistance to nelfinavir is mediated most commonly via a substitution at residue 30 (D30N) in HIV protease and has been identified in clinical isolates of HIV from patients receiving treatment with the drug in combination with other agents. This mutation appears to be unique to nelfinavir. Less commonly, a substitution at residue 90 (L90M) may occur during treatment with nelfinavir; this mutation can confer resistance to several other protease inhibitors.

Nelfinavir produces beneficial effects on immune function with increases in CD4+ cell counts observed in patients treated with nelfinavir-containing combination regimens. Treatment with nelfinavir was associated with a decrease in Fas expression and Fas-mediated apoptosis and an increase in CD4+ cell counts in patients with HIV infection.

The absorption of nelfinavir from the currently available oral formulations is increased when the drug is administered after food, compared with the fasted state. Both nelfinavir and its active metabolite M8 are highly bound to serum proteins and nelfinavir shows extensive tissue distribution. Transplacental passage of the drug appears limited. Nelfinavir is metabolised in the liver by multiple cytochrome P450 (CYP) enzymes. M8 is its major metabolite. The plasma terminal half-life of nelfinavir ranges from 3.7 to 5.3 hours. Almost 90% of the drug is eliminated via the faeces; 1–2% is recovered in urine mostly as unchanged drug. In children, systemic exposure to nelfinavir is highly variable. Clearance in this population is increased by ≈2–3 times compared with that in adults. However, in children aged 2–13 years, adequate systemic exposure to the drug is achieved at recommended dosages.

Plasma concentrations of nelfinavir are markedly lower in pregnant women with HIV infection during the third trimester than concentrations in nonpregnant patients. A dosage of 1250mg twice daily produces adequate plasma concentrations in pregnant women, whereas plasma concentrations in recipients of 750mg three times daily may be lower and more variable. Nelfinavir interacts with a number of other drugs via induction or inhibition of CYP isoenzymes in the liver.

Therapeutic Efficacy

The efficacy of oral nelfinavir has been investigated in HIV-infected, antiretroviral therapy (ART)-naive or -experienced patients, including adults, adolescents, children and pregnant women. Key clinical trials were ≤48 weeks in duration and measured plasma HIV RNA levels as a virological surrogate marker of disease progression.

ART-naive adults and adolescents: In randomised, double-blind or open-label, multicentre studies, nelfinavir demonstrated similar virological efficacy at both recommended dosage levels (750mg three times daily or 1250mg twice daily) when administered as a component of triple therapy (with zidovudine and lamivudine). Treatment with the regimen containing nelfinavir 750mg three times daily resulted in significantly better virological and/or immunological outcomes compared with the placebo-containing regimen.

Administered as part of triple therapy in randomised, double-blind, partially blind or open-label, multicentre studies, nelfinavir 750mg three times daily or 1250mg twice daily showed virological efficacy similar to that of atazanavir 200–600mg and was noninferior to fosamprenavir/ritonavir 1400mg/200mg once daily in the SOLO trial. In the NEAT trial, which was also a noninferiority trial, a larger proportion of fosamprenavir than nelfinavir recipients achieved HIV RNA levels of <400 copies/mL at the end of treatment. Nelfinavir was less effective than lopinavir/ritonavir 400mg/100mg twice daily, each given in combination with lamivudine and stavudine.

Approximately one-half to two-thirds of the nelfinavir-treated patients in these studies had undetectable viral loads (<400 copies/mL) after 48 weeks of treatment (various intent-to-treat analyses). Immunological responses were similar for each of these protease inhibitor-based regimens. Quadruple regimens containing nelfinavir have also shown efficacy in therapy-naive patients with HIV infection. Triple therapy with efavirenz, zidovudine and lamivudine was the optimal regimen in a study comparing three- and four-drug regimens containing nelfinavir and/or efavirenz in combination with either stavudine and didanosine or zidovudine and lamivudine.

ART-experienced adults and adolescents: Quadruple therapy containing nelfinavir 750mg three times daily plus efavirenz 600mg once daily and triple therapy containing efavirenz 600mg once daily generally resulted in higher rates of viral suppression than triple therapy containing nelfinavir 750mg three times daily in a randomised, partially blinded, multicentre study. Quadruple therapy produced the most durable virological response. In other randomised studies in ART-experienced patients, nelfinavir 750mg three times daily or 1250mg twice daily demonstrated similar virological efficacy to ritonavir 400mg twice daily, indinavir 800mg three times daily and delavirdine 400mg twice daily, when each drug was administered as a component of triple therapy, and similar long-term clinical efficacy (expressed in terms of the incidence of AIDS-defining conditions/death) to ritonavir 600mg twice daily.

Paediatric patients: Triple therapy with nelfinavir, administered twice or three times daily, plus zidovudine and stavudine (all dosages unspecified) was more effective than placebo in children aged ≥2 years (but not in those aged <2 years) in a randomised, double-blind trial. Approximately one-quarter of the nelfinavir-treated patients in this study had an undetectable viral load (<400 copies/mL) after 48 weeks of treatment, compared with around one-third to one-half of the children who received three- and four-drug regimens containing nelfinavir in an open-label study.

Tolerability

Nelfinavir, as part of combination therapy, was generally well tolerated by adults and adolescents with HIV infection in clinical trials; a small proportion of patients (4%) discontinued treatment due to adverse events. Diarrhoea, generally of mild to moderate intensity and manageable, was the most common adverse event (incidence 20% in two randomised trials) in ART-naive adults and adolescents who received recommended dosages of nelfinavir (750mg three times daily or 1250mg twice daily).

In 48-week, randomised, comparative trials in ART-naive patients, recommended dosages of nelfinavir were usually as well tolerated as atazanavir 200–600mg once daily, fosamprenavir 1400mg twice daily, fosamprenavir/ ritonavir 1400mg/200mg once daily, lopinavir/ritonavir 400mg/100mg twice daily, nevirapine 200mg twice daily and abacavir 300mg twice daily, when each of these agents was administered as a component of a three-drug regimen. Likewise, quadruple and triple therapies containing nelfinavir and/or efavirenz had similar adverse event profiles when evaluated in HIV-infected, ART-experienced patients. However, nelfinavir was better tolerated than indinavir 800mg three times daily and ritonavir 600mg twice daily in terms of the treatment discontinuation rate, when each of these protease inhibitors was assessed as part of combination therapy in ART-experienced patients. A retrospective meta-analysis indicated that nelfinavir was associated with the lowest rate of occurrence of hepatotoxicity relative to indinavir, saquinavir, ritonavir and saquinavir/ ritonavir.

The tolerability profile of nelfinavir in paediatric patients was similar to that in adults. Diarrhoea was the most common, drug-related adverse event. A postmarketing adverse event review did not reveal any unexpected safety concerns relating to the use of nelfinavir in paediatric patients.

The first study with sufficient power to detect a two-fold increase in the risk of overall birth defects with nelfinavir found no such increase. Triple therapy containing nelfinavir was well tolerated by HIV-infected, pregnant women.

Various sections of the manuscript reviewed by: G.W. Amsden, Department of Pharmaceutical Care Services, Bassett Healthcare, Cooperstown, New York, USA; A.D. Badley, Division of Infectious Diseases, Mayo Clinic and Foundation, Rochester, Minnesota, USA; B. Clotet, HIV Unit, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; J.E. Gallant, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; O. Kirk, EuroSIDA Coordinating Centre, Copenhagen HIV Programme, Hvidovre Hospital, Hvidovre, Denmark; C.J.L. la Porte, Department of Clinical Pharmacy, University Medical Centre Nijmegen, Nijmegen, The Netherlands.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘nelfinavir’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). 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: MEDLINE and EMBASE search term was ‘nelfinavir’. AdisBase search terms were ‘nelfinavir’ or ‘AG1343’. Searches were last updated 30 September 2005.
Selection: Studies in patients with HIV infection who received nelfinavir. 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: Nelfinavir, HIV, pharmacodynamics, pharmacokinetics, drug interactions, therapeutic use, tolerability.