Nelfinavir

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Abstract
Nelfinavir is a selective inhibitor of HIV protease, the enzyme responsible for post-translational processing of HIV propeptides. In the presence of the drug, immature, noninfectious virus particles are produced. Nelfinavir in combination with nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors and/or other protease inhibitors profoundly suppresses viral replication. Plasma HIV RNA levels (viral load) rapidly fall below the limit of detection (LOD; usually 400 or 500 copies/ml) in the majority of patients. When used in combination with NRTIs, nelfinavir 1250mg twice daily produced similar results to 3-times-daily nelfinavir at a range of total daily dosages. In an ongoing study >70% of adults receiving a nelfinavir-based combination regimen had plasma HIV RNA levels below the LOD (in vitro. Nonetheless, in clinical use, significant cross-resistance is seen with all currently available protease inhibitors. Diarrhoea is the most frequently reported adverse event in patients receiving nelfinavir-based combination therapy and has been reported in up to 32% of nelfinavir recipients in randomised trials. Diarrhoea is generally of mild to moderate severity and does not result in weight loss. Rash, nausea, headache and asthenia were each reported in ≤5% of patients. Approximately 5% of patients enrolled in an expanded access programme in the US discontinued nelfinavir because of adverse events. Nelfinavir is metabolised by the cytochrome P450 system. Several clinically significant pharmacokinetic drug interactions between nelfinavir and other drugs (i.e. ketoconazole, rifabutin, rifampicin), including other protease inhibitors (i.e. indinavir, ritonavir, saquinavir) have been documented. As with other available protease inhibitors, hyperglycaemia, hyper-lipidaemia and abnormal fat distribution have been reported, albeit infrequently, in association with nelfinavir. Conclusion: Nelfinavir-based combination regimens are well tolerated and produce profound and prolonged suppression of HIV replication in adult and paediatric patients. Hence, nelfinavir is suitable for inclusion in antiretroviral regimens for initial therapy for HIV infection and, alternatively, in regimens for patients unable to tolerate other protease inhibitors. HIV protease cleaves viral propeptides [gag (p55) and gagpol (p160)] to yield structural and enzymatic HIV proteins and is essential for the production of infectious virus particles. Nelfinavir is a selective, nonpeptidic, competitive inhibitor of HIV protease. Immature, noninfectious viral particles are produced after exposure of acutely and chronically infected cells to nelfinavir. The concentration of nelfinavir inhibiting 50% (EC50) of reverse transcriptase production in several laboratory or clinical strains of HIV-1, including a zidovudine-resistant strain, was 10 to 60 nmol/L in acutely infected human cells. In human T lymphocytes chronically infected with HIV-1, the EC50 was 39 nmol/L. Nelfinavir when combined with most other antiretroviral drugs has either synergistic or additive activity against HIV-1. Nelfinavir resistance identified during dose-finding studies was predominantly associated with substitution of asparagine for aspartate at amino acid position 30 (D30N) of HIV protease. In vitro susceptibility to indinavir, saquinavir and ritonavir was unaffected in isolates with the D30N mutation. Significant cross-resistance is seen with all currently available protease inhibitors. In one study, 58 to 60% of clinical isolates resistant to indinavir, ritonavir or saquinavir were cross-resistant to nelfinavir. Conversely, the frequency of cross-resistance to nelfinavir-resistant isolates was 77% for indinavir, 79% for ritonavir and 64% for saquinavir. The time to maximum plasma concentration of nelfinavir was 3.4 to 4 hours after oral administration of a single 100 to 800mg dose. After a single 750mg dose, the maximum plasma concentration (Cmax) was 3.23 mg/L and the area under the plasma concentration-time curve (AUC) was 15.32 mg/L · h. In children receiving nelfinavir 23 mg/kg, median values for Cmax (3.8 mg/L) and AUC during the 8-hour dose interval (AUC8) (19 mg/L · h) were similar to those in adults receiving a single 750mg dose. Absorption of nelfinavir is reduced by 27 to 50% in the fasting versus fed state. In mice, tissue concentrations of nelfinavir generally exceed those in plasma. However, nelfinavir concentrations in mouse brain tissue are 80% of patients receiving nelfinavir 750mg 3 times daily with zidovudine and lamivudine had plasma HIV RNA concentrations below the limit of detection (LOD; 400 or 500 copies/ml) after ≥28 weeks. In contrast 18% of patients receiving zidovudine, lamivudine and placebo achieved similar reductions. More than 70% of patients had viral loads below the LOD after 84 weeks on this triple therapy regimen. When used in combination with NRTIs, nelfinavir 1250mg twice daily produced similar results to 3-times-daily nelfinavir at a range of total daily dosages. Ultrasensitive plasma HIV RNA assays (LOD 10 copies/ml have been achieved in patients receiving nelfinavir plus saquinavir SGC combination regimens with viral loads below the LOD (55% of patients after ≥24 weeks. Diarrhoea, the most common adverse effect of nelfinavir, has been reported in up to 32% of patients receiving nelfinavir-based combination regimens in clinical trials. Diarrhoea is generally of mild or moderate severity and can often be controlled with antidiarrhoeal agents. Diarrhoea was reported by 16% of a series of 1532 US patients who received nelfinavir because of contraindications to, or therapeutic failure or toxicity with other protease inhibitors. Rash, nausea, headache and asthenia were each reported by ≤5% of these patients. Approximately 5% of patients discontinued nelfinavir because of adverse events. Hyperglycaemia, hyperlipidaemia and abnormal fat distribution have been infrequently reported in association with all available HIV protease inhibitors, including patients receiving nelfinavir therapy. The recommended dosage of nelfinavir in adult patients with HIV infection is 750mg 3 times daily. Children aged 2 to 13 years should receive oral nelfinavir 20 to 30 mg/kg 3 times daily. Nelfinavir should be taken with food. Plasma glucose levels should be monitored at regular intervals in patients receiving nelfinavir. Coadministration of astemizole, amiodarone, cisapride, ergot derivatives, midazolam, quinidine, rifampicin, terfenadine or triazolam with nelfinavir is contraindicated because of the potential for drug interactions resulting in clinically significant adverse events.