Drugs

, Volume 59, Issue 3, pp 581–620 | Cite as

Nelfinavir

An Update on its Use in HIV Infection
Adis Drug Evaluation

Summary

Abstract

Nelfinavir is one of several currently available protease inhibitors used to limit viral replication and improve immune function in HIV-infected individuals. It is administered in combination with other antiretroviral agents.

Nelfinavir has been evaluated as first-line therapy with nucleoside reverse transcriptase inhibitors (NRTIs) in treatment-naive patients, or as an additional antiretroviral agent in protease inhibitor-naive patients already receiving NRTIs. These studies have shown good efficacy in terms of HIV viral load reduction and increased CD4+ cell counts. When used in combination with NRTIs, nelfinavir 1250mg twice daily produced similar results to 750mg 3 times daily. The more convenient twice-daily dosage schedule, which is now approved in the US, may be beneficial in improving patient adherence to therapy. Nelfinavir has also been used successfully in combination with non-nucleoside reverse transcriptase inhibitors and/or other protease inhibitors, with or without NRTIs.

Resistance to nelfinavir has been observed in vitro and in clinical isolates from patients experiencing insufficient or waning viral suppression during treatment. Nelfinavir primarily selects for the D30N mutation, which is not seen with other protease inhibitors, and alone does not cause resistance to other protease inhibitors in vitro. Several studies have shown that patients who experience virological failure while receiving nelfinavir can respond to salvage therapy with other protease inhibitors.

Diarrhoea is the most frequent adverse event in patients receiving nelfinavir-based combination therapy, but was generally mild and resulted in minimal discontinuation of therapy in clinical trials. Diarrhoea can usually be controlled with drugs that slow gastrointestinal motility. Metabolic disturbances associated with protease inhibitor use (hypercholesterolaemia, hyperglycaemia and lipodystrophy) have also been reported with nelfinavir. Nelfinavir is associated with a number of clinically significant drug interactions and coadministration of some drugs (e.g. astemizole, cisapride, triazolam) is contraindicated. Coadministration of nelfinavir with other protease inhibitors generally resulted in favourable pharmacokinetic interactions (usually increased area under the concentration-time curve for both drugs).

Conclusion: Nelfinavir, in combination with reverse transcriptase inhibitors and/or other protease inhibitors, is effective in limiting HIV replication and increasing CD4+ cell counts in HIV-infected adults and children. The convenience of its dosage administration, the low incidence of adverse events, and the potential for salvage therapies indicate that nelfinavir (as part of combined antiretroviral therapy regimens) should be considered as a first-line option in protease inhibitor-naive patients and in those unable to tolerate other protease inhibitors.

Pharmacodynamic Properties

Nelfinavir is a nonpeptidic, competitive HIV protease inhibitor that interferes with the processing of viral gag and gagpol polyprotein products into viral enzymes and structural proteins. Inhibition of this process blocks the production of mature infectious virus particles in both acutely and chronically infected cells.

Nelfinavir exhibited activity against HIV-1 protease in vitro with an inhibition constant (K i) of 1.7 nmol/L; other human aspartic proteases were not significantly inhibited. The mean nelfinavir concentration producing 95% inhibition of viral replication (IC95) in a variety of in vitro HIV infection models was 59 nmol/L (range 7 to 130 nmol/L). Nelfinavir inhibited replication of HIV-1 and -2 strains in acutely infected primary macrophages and peripheral blood mononuclear cells (PBMCs) and caused accumulation of gag and gagpol polyprotein intermediates in chronically infected T cell lines.

Synergistic antiviral effects were observed in vitro when nelfinavir was combined with the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine, lamivudine and zalcitabine, and additive effects were seen when combined with stavudine and didanosine. Antiviral synergism was also observed with the dual protease inhibitor combination of nelfinavir and ritonavir. A slightly antagonistic interaction was noted between nelfinavir and indinavir. Nelfinavir induced minimal in vitro cellular toxicity either alone or in combination with other protease inhibitors.

Nelfinavir in combination with reverse transcriptase inhibitors (RTIs) reduced HIV replication in compartmental viral reservoirs including CSF, semen and cervicovaginal mucosa.

HIV-infected CD4+ T cells undergo accelerated apoptosis leading to severe immunodeficiency. T cell apoptosis was reduced by 23% in PBMCs cultured from patients treated with nelfinavir in combination with RTIs for 48 weeks. Protease inhibitor-naive patients treated with nelfinavir and RTIs generally showed sustainable increases in CD4+ cell counts for the duration of clinical trials (up to 96 weeks).

An HIV variant with 7-fold resistance to nelfinavir was isolated in vitro after repeated passages of virus with increasing concentrations of the drug. This variant contained a mutation at HIV protease residue 30 (D30N), a substitution not selected by other protease inhibitors. This was subsequently identified as the predominant mutation in clinical isolates from patients who failed to respond to nelfinavir-based therapies. Although the isolates exhibited high level resistance to nelfinavir, susceptibility to other protease inhibitors (indinavir, ritonavir, saquinavir or amprenavir) was not substantially diminished.

In vitro, nelfinavir inhibited epithelial barrier function, an effect possibly related to the diarrhoea reported by patients receiving nelfinavir therapy.

Nelfinavir interacts with the multidrug transporter protein MDR1, an efflux pump protein which limits uptake of drugs into major organs and the CNS. This interaction could potentially limit nelfinavir exposure in some reservoirs of HIV infection.

Pharmacokinetic Properties

Nelfinavir reached a maximum plasma concentration (Cmax) of 3 and 4 mg/L, respectively, after 28 days’ administration of nelfinavir 750mg 3 times daily (n = 11) or 1250mg twice daily (n = 10) in patients with HIV infection. Single-dose studies in healthy volunteers showed that the time to achieve Cmax is approximately 3.4 hours after administration with food. The oral bioavailability of nelfinavir has been reported as 70 to 80% when administered with food. Bioavailability is substantially reduced when the drug is taken in the fasting state.

Preclinical studies in rats showed extensive distribution of nelfinavir to tissues, with particularly high concentrations in lymph nodes and spleen. Lower concentrations of nelfinavir were observed in brain and testes, which are known to be reservoirs for HIV. Nelfinavir is extensively bound to plasma proteins (>98%) and has a volume of distribution of 2 to 7 L/kg.

Nelfinavir is metabolised by the cytochrome P450 (CYP) enzyme system in the liver, where it is converted to its major active hydroxy-t-butylamide metabolite M8, and a minor metabolite M1. The area under the concentration-time curves (AUC0–8) of nelfinavir and M8 at steady state were 23 and 6.6 μmol/L · h, respectively, following administration of nelfinavir 750mg 3 times daily in patients with HIV infection. The elimination half-life of nelfinavir is 3.5 to 5 hours. Urinary excretion is minimal (1 to 2%).

Like other protease inhibitors, nelfinavir inhibits CYP3A4 and is associated with a number of clinically significant pharmacokinetic drug interactions. Among currently available protease inhibitors, in vitro inhibition of CYP3A4 activity is greatest with ritonavir and lowest with nelfinavir and saquinavir. Whether this reduced potential for CYP-mediated drug interactions with nelfinavir translates into fewer clinically significant drug interactions in patients is unclear. Concomitant administration of nelfinavir and some CYP3A4 substrates (e.g. astemizole, cisapride, triazolam) is contraindicated because of the potential for serious adverse events. Various other CYP3A4 substrates should be used cautiously (e.g. dihydropyridine calcium antagonists, sildenafil), in some cases at reduced dosages (e.g. rifabutin), or are not recommended (e.g. lovastatin, simvastatin), in patients receiving nelfinavir. Inducers of CYP3A4 [e.g. rifampicin (rifampin), phenytoin] markedly reduce plasma concentrations of nelfinavir and concomitant administration is not recommended. Nelfinavir has the potential to lower plasma concentrations and thus therapeutic efficacy of oral contraceptives.

Nelfinavir interacts to variable extents with other protease inhibitors. The most substantial interaction is with saquinavir, the AUC of which was increased 5-fold when coadministered with nelfinavir. Interactions of nelfinavir with other protease inhibitors may increase the exposure of one or the other drug (i.e. nelfinavir is a substrate as well as an inhibitor of CYP3A4). This may allow for less frequent dosage administration in patients on dual protease inhibitor therapy (with or without NRTIs).

Clinical Efficacy

The clinical efficacy of nelfinavir in HIV-infected individuals has been evaluated through the use of surrogate end-points, primarily HIV viral load and CD4+ cell count, to assess treatment outcomes. These markers have been shown to correlate well with progression to AIDS.

Nelfinavir has been evaluated as first-line therapy with NRTIs in treatment-naive patients, or as an additional antiretroviral agent in protease inhibitor-naive patients already receiving NRTIs.

Multicentre, randomised controlled studies of nelfinavir in antiretroviral therapy-naive patients have generally included lamivudine and zidovudine. Two multicentre trials (AVANTI 3 and Study 511), in which a total of >400 patients were randomised to 2- or 3-drug combinations, showed greater reductions from baseline in mean/median HIV viral load in patients who received triple therapy with nelfinavir 750mg 3 times daily in combination with lamivudine and zidovudine than in patients who received dual therapy with lamivudine plus zidovudine (plasma HIV RNA levels reduced by ≥2.3 vs ≤1.5 log10 copies/ml by week 24). The response to triple therapy was durable through 52 weeks of treatment with nelfinavir-based combination therapy at this dosage (plasma HIV RNA levels reduced by >2.3 log10 copies/ml vs baseline).

Patients with extensive experience with NRTIs but naive to protease inhibitors experienced reductions in plasma HIV RNA levels and increases in CD4+ cell counts following the addition of nelfinavir, sometimes in combination with another protease inhibitor and/or a non-nucleoside reverse transcriptase inhibitor (NNRTI), to their treatment regimens. Combinations of nelfinavir with saquinavir or efavirenz and 1 or more NRTIs have been most extensively studied.

The relatively long plasma half-life (3.5 to 5 hours) and slow oral absorption of nelfinavir (compared with, for example, indinavir) has led investigators to evaluate the efficacy of twice-daily administration as a means of improving patient adherence to therapy. Twice-daily administration of nelfinavir 1250mg was as effective as 750mg 3 times daily in a nonblind, randomised, multicentre trial in 554 patients for up to 96 weeks. Nelfinavir in combination with various other protease inhibitors (saquinavir, indinavir or ritonavir) in twice-daily administration schedules has also proved effective in protease inhibitor-naive patients. The US Food and Drug Administration recently approved twice daily administration of nelfinavir 1250mg as an alternative to 750mg 3 times daily.

Other clinical studies have evaluated the efficacy of nelfinavir treatment in patients switching from another protease inhibitor-based regimen for reasons of drug intolerance or virological failure. In general, patients with undetectable plasma HIV RNA levels (<400 copies/ml) who switched to nelfinavir because of intolerance to another protease inhibitor experienced continued suppression of viral load for at least 12 weeks, and longer in some studies. Success was limited, however, in patients switching to nelfinavir as a salvage therapy after failure of another protease inhibitor regimen.

Salvage therapy with other protease inhibitors has been investigated in patients experiencing virological failure while receiving nelfinavir. With dual protease inhibitor salvage regimens (combination of saquinavir and ritonavir with 2 NRTIs), viral load was reduced to below 500 RNA copies/ml in most patients and suppression was maintained in some patients for more than 24 weeks. One study comparing the potential for virological rescue from various failing protease inhibitor regimens determined that initial therapy with nelfinavir gave a better chance of successful salvage with a subsequent protease inhibitor than did primary initial therapy with either indinavir or ritonavir. Failed nelfinavir regimens were associated with HIV isolates carrying the D30N protease mutation conferring resistance to nelfinavir, but not with changes at residues critical to the development of resistance to other protease inhibitors.

Nelfinavir therapy in children has not been evaluated in randomised clinical trials. However, observational studies of clinical cohorts have suggested that nelfinavir is effective in reducing viral load in paediatric patients who are naive to protease inhibitors. Children with prior antiretroviral therapy experience tended to show rebounding plasma HIV RNA levels after initial suppression on nelfinavir therapy in some (but not all) studies. A marked and sustained antiviral effect was observed in a prospective study of 57 NRTI-experienced HIV-infected children receiving nelfinavir 20 to 30 mg/kg 3 times daily, efavirenz and 1 or more NRTI; intention-to-treat analysis showed that 76 and 63% of children had viral load <400 and <50 copies/ml, respectively, after 48 weeks. Twice daily administration of nelfinavir 45 to 55 mg/kg was effective in a small paediatric study, and may be preferable to the recommended dosage of 20 to 30 mg/kg 3 times daily in children who find it difficult to adhere to therapy.

Tolerability

Nelfinavir was generally well tolerated in clinical studies. The proportion of patients who discontinued the drug because of adverse events was 4% in 3 phase II/III trials (n = 696) and 1.5% in a large observational patient cohort (n = 3312). The most common adverse event associated with nelfinavir treatment was diarrhoea; this was the only adverse event of grade 2 or greater severity with an incidence of ≥10% in 2 large randomised trials (14 to 20%; Studies 511 and 542). Most cases of diarrhoea reported in clinical trials have been mild, responded to treatment with antidiarrhoeal agents (e.g. loperamide) and were not dose-limiting.

Metabolic disturbances including elevated serum triglyceride, cholesterol and glucose levels have been associated with the use of protease inhibitors including nelfinavir. Body fat redistribution (lipodystrophy) appears to be a common adverse event among patients with HIV infection treated with antiretroviral agents including protease inhibitor-containing combination therapies, although a direct causal link between protease inhibitors and lipodystrophy has not been established. New-onset diabetes mellitus occurred infrequently in patients with HIV infection receiving nelfinavir, and was typically associated with a family history of diabetes mellitus and elevated serum cholesterol and triglyceride levels.

Other adverse events reported with nelfinavir-based combination therapy included nausea, flatulence, abdominal pain, asthenia and rash. Laboratory abnormalities, including reductions in haemoglobin, neutrophils and lymphocytes and increases in ALT, AST and creatine kinase, occurred infrequently.

Dosage and Administration

The recommended dosage of nelfinavir in adult patients with HIV infection is 750mg 3 times daily, and the US Food & Drug Administration recently approved an alternative regimen of 1250mg twice daily. The recommended dosage in children aged 2 to 13 years is 20 to 30mg/kg 3 times daily. Nelfinavir should be taken with food. Patients unable to swallow tablets may place whole tablets or crushed tablets in a small amount of water to dissolve before ingestion or they may mix crushed tablets in a small amount of food.

Coadministration of astemizole, cisapride, triazolam, midazolam, amiodarone, ergot derivatives, amiodarone, quinidine and terfenadine (removed from most markets) with nelfinavir is contraindicated because of the potential for drug interactions resulting in serious adverse events. Various drugs that are CYP3A4 substrates should be used cautiously or are not recommended in patients receiving nelfinavir. Plasma concentrations of nelfinavir can be affected by inducers of CYP3A4, and concomitant use is not recommended (see summary section on Pharmacokinetics). The therapeutic efficacy of oral contraceptives cannot be guaranteed in patients receiving nelfinavir.

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© Adis International Limited 2000

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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