indinavir-sulfate and fosamprenavir

Protease inhibitors (PIs) are potent competitive inhibitors of the human immunodeficiency virus (HIV) widely used in the treatment of the acquired immune deficiency syndrome (AIDS) and prescribed in combination with other antiretroviral drugs. So far ten PIs were approved by the United States Food and Drug Administration (FDA) for the treatment of HIV infection. In this mini review, quality control methods of each PI are discussed on the basis of analytical techniques published in the literature. Special attention is given to summarize the LC methods described for the analysis of the selected PIs in both drug substances and products with the available literature till date.

Topics: Anti-HIV Agents; Atazanavir Sulfate; Carbamates; Chromatography, Liquid; Darunavir; Drug Contamination; Furans; HIV Protease Inhibitors; Indinavir; Lopinavir; Nelfinavir; Oligopeptides; Organophosphates; Pyridines; Pyrimidinones; Pyrones; Quality Control; Ritonavir; Saquinavir; Sulfonamides

There are currently (July, 2002) six protease inhibitors approved for the treatment of HIV infection, each of which can be classified as peptidomimetic in structure. These agents, when used in combination with other antiretroviral agents, produce a sustained decrease in viral load, often to levels below the limits of quantifiable detection, and a significant reconstitution of the immune system. Therapeutic regimens containing one or more HIV protease inhibitors thus provide a highly effective method for disease management. The important role of protease inhibitors in HIV therapy, combined with numerous challenges remaining in HIV treatment, have resulted in a continued effort both to optimize regimens using the existing agents and to identify new protease inhibitors that may provide unique properties. This review will provide an overview of the discovery and clinical trials of the currently approved HIV protease inhibitors, followed by an examination of important aspects of therapy, such as pharmacokinetic enhancement, resistance and side effects. A description of new peptidomimetic compounds currently being investigated in the clinic and in preclinical discovery will follow.

Topics: Anti-HIV Agents; Atazanavir Sulfate; Carbamates; Clinical Trials as Topic; Dipeptides; Furans; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Models, Molecular; Molecular Mimicry; Molecular Structure; Nelfinavir; Oligopeptides; Organophosphates; Peptides; Phenylbutyrates; Pyridines; Pyrimidinones; Ritonavir; Saquinavir; Sulfonamides; Urethane

To evaluate the pharmacokinetic compatibility of a ritonavir-boosted indinavir-fosamprenavir combination among patients with human immunodeficiency virus (HIV).. Single-center, nonrandomized, prospective, multiple-dose, two-phase pharmacokinetic study.. University research center.. Eight adult patients with HIV infection who had been receiving and tolerating indinavir 800 mg-ritonavir 100 mg twice/day for at least 2 weeks. Intervention. After 12-hour pharmacokinetic sampling was performed on all patients (period A), fosamprenavir (a prodrug of amprenavir) 700 mg twice/day was coadministered for 5 days, with a repeat 12-hour pharmacokinetic sampling performed on the fifth day (period B).. Pharmacokinetic parameters were determined for indinavir, ritonavir, and amprenavir: area under the concentration-time curve from time 0 to 12 hours after dosing (AUC(0-12)), maximum plasma concentration (C(max)), and 12-hour plasma concentration (C(12)). For each parameter, the geometric mean, as well as the geometric mean ratio (GMR) comparing period B with period A, were calculated. Indinavir C(max) was lowered by 20% (GMR 0.80, 95% confidence interval [CI] 0.67-0.96), AUC(0-12) was lowered by 6% (GMR 0.94, 95% CI 0.74-1.21), and C(12) was increased by 28% (GMR 1.28, 95% CI 0.78-2.10). Ritonavir AUC(0-12) was 20% lower (GMR 0.80, 95% CI 0.54-1.19), C(max) was 15% lower (GMR 0.85, 95% CI 0.55-1.32), and C(12) was 7% lower (GMR 0.93, 95% CI 0.49-1.76). With the exception of indinavir C(max), the changes in indinavir and ritonavir pharmacokinetic parameters observed after fosamprenavir coadministration were not statistically significant. The geometric means of amprenavir AUC(0-12), C(max), and C(12) were 41,517 ng*hour/ml (95% CI 30,317-56,854 ng*hr/ml), 5572 ng/ml (95% CI 4330-7170 ng/ml), and 2421 ng/ml (95% CI 1578-3712 ng/ml), respectively.. The combination of indinavir 800 mg-ritonavir 100 mg-fosamprenavir 700 mg twice/day appears to be devoid of a clinically significant drug-drug interaction and should be evaluated as an alternative regimen in salvage HIV treatment. This combination may be suitable as part of a background regimen to optimize the therapeutic benefit of newer classes of antiretroviral agents such as the integrase and coreceptor inhibitors in the treatment of multidrug-resistant viruses.

Topics: Adult; Area Under Curve; Carbamates; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Furans; Half-Life; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Organophosphates; Prodrugs; Ritonavir; Sulfonamides

The effects of many protease inhibitor (PI)-selected mutations on the susceptibility to individual PIs are unknown. We analyzed in vitro susceptibility test results on 2,725 HIV-1 protease isolates. More than 2,400 isolates had been tested for susceptibility to fosamprenavir, indinavir, nelfinavir, and saquinavir; 2,130 isolates had been tested for susceptibility to lopinavir; 1,644 isolates had been tested for susceptibility to atazanavir; 1,265 isolates had been tested for susceptibility to tipranavir; and 642 isolates had been tested for susceptibility to darunavir. We applied least-angle regression (LARS) to the 200 most common mutations in the data set and identified a set of 46 mutations associated with decreased PI susceptibility of which 40 were not polymorphic in the eight most common HIV-1 group M subtypes. We then used least-squares regression to ascertain the relative contribution of each of these 46 mutations. The median number of mutations associated with decreased susceptibility to each PI was 28 (range, 19 to 32), and the median number of mutations associated with increased susceptibility to each PI was 2.5 (range, 1 to 8). Of the mutations with the greatest effect on PI susceptibility, I84AV was associated with decreased susceptibility to eight PIs; V32I, G48V, I54ALMSTV, V82F, and L90M were associated with decreased susceptibility to six to seven PIs; I47A, G48M, I50V, L76V, V82ST, and N88S were associated with decreased susceptibility to four to five PIs; and D30N, I50L, and V82AL were associated with decreased susceptibility to fewer than four PIs. This study underscores the greater impact of nonpolymorphic mutations compared with polymorphic mutations on decreased PI susceptibility and provides a comprehensive quantitative assessment of the effects of individual mutations on susceptibility to the eight clinically available PIs.

Topics: Atazanavir Sulfate; Carbamates; Darunavir; Furans; HIV Protease; HIV Protease Inhibitors; HIV-1; Indinavir; Least-Squares Analysis; Lopinavir; Mutation; Nelfinavir; Oligopeptides; Organophosphates; Polymorphism, Genetic; Pyridines; Pyrimidinones; Pyrones; Saquinavir; Sulfonamides