Model-based Analysis of the Pharmacokinetic Interactions Between Ritonavir, Nelfinavir, and Saquinavir after Simultaneous and Staggered Oral Administration

Abstract

ABSTRACT:Eighteen healthy human immunodeficiency virus-negative subjects participated in an open-label, six-period, incomplete Latinsquare crossover pharmacokinetic study. Each subject received two of the three possible pair-wise combinations of single-dose oral ritonavir (R) (400 mg), nelfinavir (N) (750 mg), and saquinavir (S) (800 mg), each pair on three occasions (simultaneous or staggered administration), each occasion at least 2 days after the last. A model-based analysis reveals the following major drug interactions under the conditions of this study: 1) R given simultaneously with S decreases S hepatic intrinsic clearance almost 50-fold relative to that predicted for S given alone and increases its gut bioavailability 90% (but decreases its rate of absorption 40%) relative to when N is given simultaneously; 2) N given simultaneously with S decreases S hepatic intrinsic clearance 10-fold relative to that predicted for S given alone; and 3) R inhibits S hepatic intrinsic clearance even after R plasma levels have become undetectable (>48 h after dosing), implying that R, when used as a pharmacokinetic enhancer, can be dosed less frequently than might be predicted from the duration of detectable systemic concentrations.Protease inhibitors (PIs 1 ) ritonavir (R), nelfinavir (N), and saquinavir (S) are primarily metabolized by CYP3A4 (and partially by other cytochromes P450) in the liver (Eagling et al., 1997;Fitzsimmons and Collins, 1997;Hsu et al., 1998a;Kim et al., 1998;Washington et al., 1998). They exhibit extensive pharmacokinetic (PK) interactions (Merry et al., 1997;Hsu et al., 1998b;Jarvis et al., 1998), but the degree to which those interactions occur at the level of hepatic metabolism, gut metabolism, or gut efflux transporters is still uncertain. Adult AIDS clinical trial group study 378 (ACTG 378), involving staggered versus simultaneous administration of the three PIs, was designed to shed light on these issues. The findings with respect to changes of AUC (proportional to the ratio of systemic clearance to bioavailability) are reported elsewhere (C. B. Washington, C. Flexner, L. B. Sheiner, S. L. Rosenkranz, M.A. Jacobson, T. F. Blaschke, submitted); they are considerable. This paper extends those findings by presenting a physiologically based population pharmacokinetic model applied to the full ACTG 378 data to assess and quantify the gut versus hepatic mechanisms responsible for the AUC changes and for any other PK interactions. Materials and MethodsData Source. ACTG 378 was an open-label, Latin-square design study of the effect of staggered versus simultaneous dosing on the PK profiles of the following three protease inhibitors: R, N, and S (we use the symbols R, N, S to refer not only to the drugs but to their concentrations; context should make clear which meaning is intended). A total of 18 human immunodeficiency virus-negative healthy volunteers participated in the study, and each was randomized to receive two of the three pairs (N ϩ R, N ϩ S, and R ϩ S) in two series of three occasions. T...

Population pharmacokinetics of indinavir alone and in combination with ritonavir in HIV‐1‐infected patients

“…The absorption of indinavir was also influenced by ritonavir. The latter may have caused delayed gastric passage [31], since only in patients using indinavir combined with ritonavir could a lag-time be detected. Furthermore, and as observed in other studies [5,30], the maximum concentration of indinavir occurred later when given with ritonavir, whereas the absorption rate was similar.…”

Anodic coloring of titanium and its alloy for jewels production

“…The PIs have a peptidomimetic structure; in consequence, the absorption mediated by the carrier could be the most probable intestinal transport mechanism 15,16. Nevertheless, in some studies the absorption process in the intestinal tract is described as first‐order kinetics 17,18…”

Effect of simultaneous versus staggered dosing on pharmacokinetic interactions of protease inhibitors

“…If there is an effect on transport mediated by an interaction of drugs present at the luminal surface of the intestinal mucosa with P‐glycoprotein, it is small compared with the systemic effects of ritonavir on hepatic and intestinal CYP and P‐glycoprotein. Subsequent physiologic PK modeling of this interaction, reported elsewhere, 22 indicates that ritonavir decreases the intrinsic hepatic clearance of saquinavir by 50‐fold and increases gut bioavailability by 90% but decreases the rate of absorption by 40%. The modeling results are compatible with both gut‐level and hepatic‐level interaction, and the change in the rate of absorption, although consistent with an effect on gut P‐glycoprotein, could as well be the result of an effect on gut CYP3A and could not be distinguished by this approach.…”