ritonavir and dexelvucitabine

The purpose of this study was to determine the effect of a single dose of 300 mg of ritonavir on the plasma pharmacokinetics (PK) of a single dose of 20 mg of elvucitabine when the two drugs were coadministered in healthy subjects. In a three-way crossover design, 30 subjects received 20 mg of elvucitabine, 300 mg of ritonavir, or 20 mg of elvucitabine coadministered with 300 mg of ritonavir. Elvucitabine concentrations were analyzed using a validated liquid chromatography-tandem mass spectrometry assay. The PK of elvucitabine was determined using both noncompartmental and compartmental analyses. Models were developed and tested using ADAPT-II, while a population analysis was performed using IT2S. Comparisons of PK parameters between groups were done with SAS. The pharmacokinetic behavior of elvucitabine was best described by a two-compartment linear model using two absorption rates and a first-order elimination rate. Ritonavir significantly impacted the PK of elvucitabine by reducing elvucitabine's bioavailability, with the most plausible explanation being an inhibition on influx transporters by ritonavir. The decrease in elvucitabine bioavailability when elvucitabine was coadministered with ritonavir may be due to ritonavir's inhibiting influx gut transporters. Continued development of elvucitabine is warranted to better characterize its PK and to determine its in vivo efficacy against human immunodeficiency virus.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Binding, Competitive; Biological Availability; Cross-Over Studies; Drug Interactions; Female; Humans; Intestinal Absorption; Linear Models; Male; Middle Aged; Population; Reverse Transcriptase Inhibitors; Ritonavir; Tandem Mass Spectrometry; Young Adult; Zalcitabine

The purpose of this study was to describe the plasma pharmacokinetics (PK) of elvucitabine at different doses when administered daily or every other day for 21 days with lopinavir-ritonavir (Kaletra) in human immunodeficiency virus (HIV)-infected subjects. Three different dosing regimens of elvucitabine were administered with lopinavir-ritonavir to 24 subjects with moderate levels of HIV. Plasma samples were collected over 35 days. Elvucitabine concentrations were analyzed using a validated liquid chromatography-tandem mass spectrometry assay. The PK of elvucitabine was determined using both noncompartmental and compartmental analyses. Models were developed and tested using ADAPT II, while a population analysis was performed using IT2S. The PK behavior of elvucitabine was best described by a two-compartment linear model using two absorption rates and an increase in the bioavailability after day 1. The augmentation in the bioavailability after day 1 was variable, with some subjects demonstrating a major increase while others had little or no increase. Elvucitabine has a long half-life of approximately 100 h. The increase in elvucitabine bioavailability may be due to ritonavir inhibiting an efflux gut transporter with activity present in various levels between subjects. The proposed PK model may be utilized and improved further by linking the PK behavior of elvucitabine to various markers of efficacy.

Topics: Anti-HIV Agents; Area Under Curve; Biological Availability; Cohort Studies; Drug Combinations; Half-Life; HIV Infections; HIV-1; Humans; Lopinavir; Models, Statistical; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Zalcitabine