Coadministration of Indinavir and Nelfinavir in Human Immunodeficiency Virus Type 1-Infected Adults: Safety, Pharmacokinetics, and Antiretroviral Activity

Abstract

Combinations of protease inhibitors (PIs) can have potentially beneficial pharmacokinetic interactions, resulting in higher drug levels and less frequent dose administration. Indinavir (IDV) and nelfinavir (NFV) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) protease and are commonly prescribed antiretroviral agents. Pilot pharmacokinetic data suggested a bidirectional enhancing interaction between IDV and NFV. A phase II study was conducted to evaluate the safety, pharmacokinetics, and antiviral activity of IDV plus NFV given in a combination every 12 h in HIV-1-infected subjects. IDV plus NFV was given as a twice-daily regimen to 20 HIV-1-infected subjects who were PI naive (11 of 20 were antiretroviral naive). After week 18, nucleoside reverse transcriptase inhibitors were added to the treatment regimen in seven subjects. The enrolled subjects had a geometric mean baseline plasma HIV-1 RNA of 63,095 copies/ml and a mean CD4 ؉ cell count of 266 cells/mm 3 . Pharmacokinetic evaluations were performed at the following doses: IDV at 1,000 mg every 12 h (q12h) plus NFV at 750 mg q12h, IDV at 1,000 mg q12h plus NFV at 1,000 mg q12h, and IDV at 1,200 mg q12h plus NFV at 1,250 mg q12h. The coadministration of IDV plus NFV resulted in a modest inhibition of IDV elimination, resulting in a plasma profile of IDV 1200 mg q12h (with NFV at 1,250 mg q12h) that was comparable to the standard IDV dose of 800 mg q8h. In contrast, IDV had no apparent effect on the pharmacokinetic profile of NFV. The combination of IDV and NFV was generally well tolerated and resulted in sustained virologic suppression with 45% of the subjects having an HIV-1 RNA level in plasma of <400 copies/ml at week 72 (intent-to-treat).Indinavir (IDV) and nelfinavir (NFV) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) protease that when used in a combination regimen produce marked and durable reductions in HIV-1 RNA levels in treated patients (4, 5, 7). Although protease inhibitors (PIs) are commonly prescribed individually in combination with nucleoside reverse transcriptase inhibitors (NRTIs), the evaluation of regimens with two or more PIs has progressed for several reasons. First, combinations of PIs can have potentially beneficial pharmacokinetic interactions such as higher drug levels (1). Second, these pharmacokinetic interactions allow for less-frequent dose administration and reduced dietary restrictions that may lead to improved adherence (2). Finally, combinations of PIs may have increased potency as a result of complementary resistance profiles and enhanced activity against viral quasispecies.This study describes the results of a multiple-dose (steadystate) analysis that was designed to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of the IDV plus NFV combination given every 12 h (q12h) to HIV-1-infected patients. Although at present dual PIs are usually administered in combination with NRTIs, the present study was conducted at a time when combinations of dual PI therapy...

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

“…2) and higher 24-h AUCs. This interaction was not evident in the only other report of this combination (12). For example, Fig.…”

“…Subsequently, a small study demonstrated the antiviral effect of indinavir-nelfinavir combinations, with 45% of subjects achieving Ͻ400 viral copies/ml at week 72 (12). Interestingly, the pharmacokinetic profiles in the subjects we studied suggest that some type of interaction is at work when indinavir and nelfinavir are taken together.…”

“…The median C max was 10,740 ng/ml (range, 3,379 to 18,210 ng/ml), and T max occurred at 1.0 to 7.5 h after administration of the dose. The median dosing interval AUC (AUC 12 ) and half-life values for subjects receiving 1,000 mg of indinavir every 12 h were 38,863 h ⅐ ng/ml (range, 10,623 to 135,665 h ⅐ ng/ml) and 1.8 h (range, 1.1 to 2.4 h), respectively. In the group receiving 1,200 mg of indinavir every 12 h, the median predose indinavir concentration was 146 ng/ml (range, 58 to 5,215 ng/ml) and the median C 12 h was 95 ng/ml (range, 12 to 954 ng/ml).…”

“…The median (range) C max was 5,826 ng/ml (range, 2,437 to 9,337 ng/ml), and T max occurred at 2.0 to 6.0 h after administration of the dose. The median AUC for one 12-h dosing interval (AUC 12 ) and half-life were 33,106 h ⅐ ng/ml (range, 15,434 to 81,717 h ⅐ ng/ml) and 3.6 h (range, 1.8 to 31 h), respectively. The following results are from seven subjects who received 1,250 mg of nelfinavir with 1,200 mg of indinavir every 12 h. The median predose nelfinavir concentration was 1,805 ng/ml (range, 611 to 8,307 ng/ml), and the median C 12 h was 534 ng/ml (range, 189 to 4,270 ng/ml).…”

Double-Blind Pilot Study of Mesalamine vs. Placebo for Treatment of Chronic Diarrhea and Nonspecific Colitis in Immunocompetent HIV Patients

“…Many drugs used in the treatment of HIV (nucleosides, nonnucleosides, and protease inhibitors) include diarrhea among their documented side effects. This side effect has been well documented in regimens that include protease inhibitors (PIs) (15)(16)(17)(18). Studies have shown that saquinavir, ritonavir, and nelfinavir impair the epithelial barrier in the human intestinal cell line HT-29/B6 as one mechanism of action for diarrhea (19).…”