Pharmacokinetic Profile and Tolerability of Indinavir-Ritonavir Combinations in Healthy Volunteers

Abstract

This was a randomized, double-blind, placebo-controlled parallel study in human immunodeficiency virus type 1 (HIV-1)-uninfected healthy subjects to investigate the pharmacokinetic interaction between indinavir (IDV) and ritonavir (RTV). Subjects were allocated to treatment groups of IDV given with RTV in the following milligram doses twice daily: 800 mg of IDV-100 mg of RTV (800-100 mg), 800-200, 800-400, and 400-400 mg, placebo of IDV with RTV doses of 100, 200, and 400 mg, and placebo of both IDV and RTV. Doses of both drugs were administered for 14 days with a low-fat meal and one dose on day 15 with a high-fat meal. Blood was obtained for drug concentration measurements on days 14 and 15. Seventy-three volunteers enrolled in the study: 29 men and 44 women. Fifty-three volunteers completed the study. When compared to standard historical data for 800 mg of IDV every 8 h (q8h), the IDV area under the concentration-time curve for 24 h (AUC 24 ) of IDV-RTV regimens 400-400, 800-100, and 800-200 mg were at least 1.4, 2.3, and 3.3 times higher, respectively, regardless of meal. The concentrations at the end of the dosing interval were 10 to 25 times higher than that observed in the standard regimen of 800 mg of IDV q8h for IDV-RTV 800-100 and 800-200 mg regimens, respectively. RTV at 200 mg maximally enhanced the IDV profile. Improved tolerability was associated with IDV-RTV 800-100 mg versus IDV-RTV 800-200, 800-400, and 400-400 mg q12h. The advantages of IDV-RTV twice daily over 800 mg of IDV q8h include no food restrictions and twice-daily dosing. Also, the regimens achieve levels of IDV that may be helpful in suppressing strains of HIV-1 that have reduced susceptibility to IDV or other protease inhibitors.Pharmacokinetic drug-drug interactions have the potential to enhance drug exposure of protease inhibitors for human immunodeficiency virus (HIV) infection. Indinavir (IDV) plus ritonavir (RTV) is a combination that appears to have a very favorable pharmacokinetic interaction. The metabolic interaction of these drugs results in augmented IDV plasma levels that may prove useful in more convenient dosing intervals and removal of food restrictions. The high IDV levels may be also be active against virus strains with genotypic mutations or phenotypic profiles associated with decreased sensitivity to protease inhibitors at conventional drug concentrations. Thus, a combination regimen of IDV with RTV may be useful in antiretroviral treatment-naive patients, as well as in rescue regimens.A current regimen combines 400 mg of IDV with 400 mg of RTV twice daily (6, 9), but tolerability to RTV is sometimes difficult (NORVIR package circular, Abbott Laboratories, Abbott Park, Ill.). RTV at lower doses is being studied to see if they will provide sufficient metabolic inhibitory activity to permit dosing IDV in a twice-a-day (b.i.d.) regimen and to assess tolerability. The present study was undertaken to characterize the pharmacokinetic profiles of a wider array of dose combinations of IDV plus RTV at steady state (2 weeks)...

Effects of Ritonavir on Indinavir Pharmacokinetics in Cerebrospinal Fluid and Plasma

“…2 h. Ritonavir more dramatically altered the shape of the indinavir concentration in plasma curve, greatly increasing C min but not affecting C max or time to C max . The effect of ritonavir on the indinavir concentration profiles in plasma is generally consistent with a recent study that showed that low-dose ritonavir increased the geometric mean indinavir C max by Ͻ2-fold, the AUC 0-24 by Ͻ3-fold, and the C trough by Ͼ10-fold in HIV-negative volunteers (25). Since C min may best predict antiviral effect for HIV-1 protease inhibitors, concomitant ritonavir should enhance indinavir's antiviral effect in both peripheral and central nervous system compartments.…”

“…It is more commonly used as a "pharmacokinetic enhancer." Ritonavir increases plasma AUCs, half-lives, and trough concentrations of indinavir and other protease inhibitors by inhibiting the 3A4 isoform of cytochrome P450 (13,20,25) and overcomes the negative effect of food on indinavir bioavailability. Comparing detailed pharmacokinetic data from our previous study (17) with data from the present study allowed the effect of ritonavir on indinavir disposition into CSF to be thoroughly characterized.…”

Pharmacokinetic Modeling and Simulations of Interaction of Amprenavir and Ritonavir

“…All parameters included log-normal interindividual error terms. The absorption rate constant (K a ), V/F, and the transfer rate constants between the central and peripheral compartments (K 23 and K 32 ) were modeled separately for days 1 and 14. It cannot be determined if these effects are dependent on time or on the administration of ritonavir.…”

“…All HIV PIs are substrates and inhibitors of CYP3A4, but the HIV PI ritonavir is the most potent inhibitor of CYP3A4 (Woolley et al, 37th ICAAC). Previous studies have indicated significant increases in drug exposure from coadministration of ritonavir with indinavir, saquinavir, and nelfinavir (12,13,18,19,22,23,30; D. Burger, P. Hugen, H. Hofstede, P. Koopmans, M. Stek, Jr., P. Reiss, and J. Lange, Abstr. 37th Intersci.…”

Effect of omeprazole on the plasma concentrations of indinavir when administered alone and in combination with ritonavir

“…15,16 However, this is the first study to demonstrate that coadministration of ritonavir with indinavir may offset the pH-dependent decrease in indinavir exposure observed when coadministered in single doses with omeprazole. An increase in indinavir's AUC 0-24 after coadministration of ritonavir is well-known.…”