A study was conducted in healthy adults (n = 19) to evaluate the pharmacokinetics of lopinavir/ritonavir when coadministered with efavirenz. Participants were administered lopinavir/ritonavir 400/100 mg alone twice daily (bid) from the morning of day 1 through the morning of day 10, and then lopinavir/ritonavir 500/125 mg bid was coadministered with efavirenz 600 mg every evening (qhs) from the evening of day 10 through day 20. Lopinavir and ritonavir exposures when administered alone versus with efavirenz were determined on days 10 and 20 and compared using point estimates and 90% confidence intervals. The point estimates for the ratios of lopinavir maximum observed plasma concentration (Cmax), plasma concentration prior to morning dosing (Ctrough), and area under the plasma concentration‐time curve over a dosing interval (AUC12) were 1.121, 0.954, and 1.060, respectively. The lopinavir/ritonavir dose of 500/125 mg bid administered with efavirenz most closely approximates the pharmacokinetic exposure of lopinavir/ritonavir 400/100 mg bid administered alone.

A total of 71 HIV‐negative healthy adults were randomized to 1 of 6 regimens to receive lopinavir/ritonavir tablets 400/100 mg twice daily (bid) or 800/200 mg once daily (qd) or atazanavir 300 mg + ritonavir 100 mg qd from study days 1 to 15 with a moderate‐fat meal. One hour before breakfast, either omeprazole 40 mg qd was administered on study days 11 through 15, or a single dose of ranitidine 150 mg was administered on study day 11. Lopinavir, atazanavir, and ritonavir pharmacokinetics were determined on study days 10, 11, and 15 and compared using point estimates and 90% confidence intervals (CIs). The point estimates for lopinavir Cmax and AUCτ were in the range of 0.92 to 1.08, with 90% CI contained within the range of 0.80 to 1.25 after coadministration of omeprazole or ranitidine. The point estimates for atazanavir Cmax and AUCτ were decreased by 48% to 62% with the upper bound of the 90% CI 0.55 after coadministration of omeprazole or ranitidine. The results indicated that lopinavir bioavailability was not affected by the coadministration of omeprazole or ranitidine. In contrast, atazanavir bioavailability was decreased by 48% to 62% when coadministered with ritonavir and either omeprazole or ranitidine.

Background: Acid reducing agents, including proton pump inhibitors (e.g. omeprazole, OME) and H2 antagonists (e.g. ranitidine, RAN), are used extensively by HIV-infected patients and decrease bioavailability of some antiretroviral agents. The effect of acid reducing agents on LPV/r in any formulation has not been formally assessed, and the influence of decreased stomach acidity on drug bioavailability from a novel melt-extrusion LPV/r tablet is unknown. We determined the effect of OME and RAN on the PK of LPV/r tablet administered once or twice daily (QD or BID) and atazanavir (ATV) boosted by ritonavir (RTV) capsule. Methods: 71 healthy (HIV-negative) adults were randomized to receive LPV/r tablets 400/100 mg BID or 800/200 mg QD or RTV capsule 100 mg + ATV 300 mg QD from Study Days 1 to 15 approximately 30 minutes after a meal. Either OME 40 mg QD was administered 1 hour before breakfast on Study Days 11 to 15 or RAN 150 mg was administered 1 hour before breakfast on Study Day 11. Serial blood samples were collected during a dosing interval (for 12 or 24 hours after dosing) on Study Days 10, 11, and 15. The PK parameters of lopinavir (LPV), RTV and ATV were compared with and without OME or RAN using point estimates and 90% confidence intervals. Results: The comparison of LPV and RTV PK with and without OME or RAN for LPV/r is shown below. Abstract

Background: A ritonavir tablet formulation is being developed which does not require refrigeration. The bioavailability of a new tablet formulation, which may have improved physical stability compared to previous pilot formulations, was compared to the marketed soft gelatin capsule (SGC) in this Phase 1, open-label, randomized, crossover study. Methods: Twenty-four subjects participated in a randomized, two-period, single-dose, open-label study to receive a 100 mg dose of ritonavir test tablet or the marketed SGC after a moderate-fat meal. Serial blood samples were collected for 36 hours after dosing in each period. The pharmacokinetic parameters of ritonavir were determined using non - compartmental methods, including area under the plasma concentration time curve (AUC) and maximum plasma concentration (C max ). The bioavailability of the tablet formulation relative to the SGC was assessed by the two one-sided tests procedure via 90% confidence intervals. Safety was assessed throughout the study. Results: Ritonavir AUC and C max were approximately 12% and 21% higher, respectively, after administration of the ritonavir tablets compared to administration of the marketed SGCs. The point estimates for ritonavir C max and AUC after administration of the ritonavir tablet are lower than those observed for ritonavir after administration of the lopinavir/ritonavir tablet. The point estimate for ritonavir AUC was 20% higher and C max was 35% higher after administration of the lopinavir/ritonavir tablet compared to the SGC. Both regimens were generally safe and well tolerated. Conclusions: Ritonavir AUC after administration of the tablet was bioequivalent to the marketed SGC. The ritonavir C max upper bound of the 90% confidence interval exceeded 1.25, which may be due, in part, to more efficient absorption of the tablet formulations. Further formulation refinements were made and the results of the pivotal biostudy will be presented at this conference. (Session #THAB04) The higher C max of ritonavir tablet is unlikely to impact the safety profile or pharmacokinetic enhancing profile compared to the ritonavir SGC.