Pharmacokinetics of Indinavir and Nelfinavir in Treatment-Naive, Human Immunodeficiency Virus-Infected Subjects

Abstract

AIDS Clinical Trials Group protocol 388 was designed to compare a three-drug regimen (indinavir with dual nucleosides) to a four-drug regimen (indinavir plus nelfinavir or indinavir plus efavirenz with dual nucleosides). Blood samples from patients taking indinavir and nelfinavir were collected over 8 to 12 h following a specified dose and were analyzed with high-performance liquid chromatography. Pharmacokinetic data were derived by using noncompartmental analysis. Following administration of indinavir every 8 h in the absence of nelfinavir (n ‫؍‬ 8), the median predose indinavir concentration (C 0 ) was 369 ng/ml (range, <10 to 949 ng/ml; one subject had a concentration of <10 ng/ml), and the concentration 8 h after administration of the study dose was 159 ng/ml (range, 85 to 506 ng/ml). In the group receiving 1,000 mg of indinavir every 12 h with nelfinavir (n ‫؍‬ 10), the median indinavir C 0 was <10 ng/ml (range, <10 to 3,740 ng/ml; six subjects had a value of <10 ng/ml), and the C 12 h was 44 ng/ml (range, <10 to 4,236 ng/ml; five subjects had a value of <10 ng/ml), while the subjects who received 1,200 mg of indinavir every 12 h with nelfinavir (n ‫؍‬ 7) had a C 0 of 146 ng/ml (range, 58 to 5,215 ng/ml) and a C 12 h of 95 ng/ml (range, 12 to 954 ng/ml). Indinavir clearance was significantly lower in the presence of nelfinavir (median [interquartile range], 34.1 liters/h [range, 22.6 to 45.8 liters/h] versus 47.9 liters/h [range, 42.7 to 70.3 liters/h]; P < 0.017). For subjects receiving 1,000 mg of indinavir every 12 h, the median C 0 value for nelfinavir (n ‫؍‬ 9) was 1,779 ng/ml (range, <187.5 to 4,579 ng/ml), and the C 12 h was 1,554 ng/ml (range, <187.5 to 5,540 ng/ml). Due to the unacceptable number of undetectable indinavir trough concentrations, 1,200 mg of indinavir appears to be the preferred dose in a twice-daily regimen that includes nelfinavir.Following the introduction of protease inhibitors and nonnucleoside reverse transcriptase inhibitors, various strategies were evaluated to determine optimal combinations to achieve viral suppression for human immunodeficiency virus (HIV)-infected patients. In addition, the strategy of combining protease inhibitors based on anticipated positive pharmacokinetic interactions was an area of active clinical investigation. To further study these clinical questions in antiretroviral-naive subjects, AIDS Clinical Trials Group protocol (ACTG) 388 was designed to compare a three-drug regimen (indinavir with dual nucleosides) to a four-drug regimen (either indinavir plus nelfinavir or indinavir plus efavirenz with dual nucleosides) (6). At the time that ACTG 388 was implemented, limited data were available describing the drug-drug interaction between indinavir and nelfinavir. For this protease inhibitor combination, early pharmacokinetic information suggested that the combination of the two protease inhibitors would lead to a favorable pharmacokinetic profile for each drug, allowing for every-twelfth-hour dosing, and one report has demonstrated antiviral activity o...

Population pharmacokinetic analysis for nelfinavir and its metabolite M8 in virologically controlled HIV‐infected patients on HAART

“…The former value is very similar to that found by DiCenzo et al. [30] in naïve patients treated with indinavir plus 1250 mg nelfinavir twice daily (mean AUC of 33 106 ng ml −1 h and 33 269 ng ml −1 h in two groups of nine and seven patients also receiving either 1000 mg twice daily or 1200 mg twice daily of indinavir, respectively). The mean AUC obtained by van‐Dijke et al.…”

Pharmacokinetics of Nelfinavir and Efavirenz in Antiretroviral-Naïve, Human Immunodeficiency Virus-Infected Subjects when Administered Alone or in Combination with Nucleoside Analog Reverse Transcriptase Inhibitors

“…Prior studies have reported the halflife of efavirenz after repeated dosing to be approximately 40 to 50 h with no major influence noted when a protease inhibitor is combined (1,5,9). These data also provide new information, in that efavirenz pharmacokinetics were stable over 32 weeks.…”

“…426, 2000). Induction effects of efavirenz on other HIV-1 protease inhibitors have also been described (1,5). In addition, a stable AUC ratio of metabolite to parent was observed in both arms; thus, a possible reduction in oral bioavailability could also contribute to the observed results.…”

Drug interactions with antiretrovirals

“…Saquinavir and indinavir increase nelfinavir concentrations, whereas nelfinavir has variable effects on indinavir [16,17]. Atazanavir increases saquinavir plasma concentrations, but it is commonly prescribed with low-dose ritonavir [18].…”