Lopinavir, an HIV protease inhibitor, is coformulated with ritonavir to enhance the bioavailability and pharmacokinetics of lopinavir. The original solid oral formulation of lopinavir/ritonavir, a soft-gelatin capsule (SGC), requires refrigerated storage, is taken as 6 capsules daily at the recommended adult dose, and is administered with food to maximize the bioavailability of lopinavir. Melt extrusion technology was used to produce a tablet formulation reducing the number of dosage units administered per day and simplifying storage requirements. Three studies assessed the bioavailability of tablet doses of lopinavir/ritonavir at 800/200 mg or 400/100 mg under different meal conditions compared with equal doses of the SGC after a moderate-fat meal. The tablet was bioequivalent to the SGC after a moderate-fat meal with respect to lopinavir and ritonavir areas under the concentration-time curve. Compared with the SGC formulation, the tablet formulation resulted in more consistent lopinavir and ritonavir exposures within and across studies and across meal conditions. The diminished food effect and decreased variability of the tablet are likely to result in more consistent lopinavir and ritonavir exposures, minimizing the likelihood of extreme high or low values compared with the SGC.

This article is available online at http://dmd.aspetjournals.org ABSTRACT:1-Aminobenzotriazole (ABT) has been extensively used as a nonspecific inhibitor of cytochromes P450 (P450s) in animals for mechanistic studies, and antipyrine (AP) has been used as a probe for hepatic oxidative metabolic capacity determination in vivo. The method of use of ABT has been variable from lab to lab due largely to unknown pharmacokinetics of ABT itself and incomplete information on various P450s inhibited. The oral pharmacokinetic profiles of ABT were generated in rats, dogs, and monkeys in the dose range of 5 to 200 mg/kg. The results showed that after single oral doses of 50 mg/kg in rats, and 20 mg/kg in dogs and monkeys, the plasma concentrations were high and were sustained for over 24 h. In vitro, inhibition of various expressed P450s upon 30-min preincubation with ABT (0-500 M) showed that CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A4 were inhibited in a dose-dependent manner. The intravenous pharmacokinetics of AP also was affected in a dose-dependent manner in all species, treated 2 h earlier with ABT. Thus, the plasma clearance of AP was inhibited by 88% in rats pretreated with 50 mg/kg ABT and 96% in dogs and 83% in monkeys pretreated with 20 mg/kg ABT. Based on these data in rats, dogs, and monkeys, and the established safety profile of ABT in rats dosed up to 100 mg/kg, a pretreatment at 2 h with a single oral dose of ABT at 100 mg/kg in rats (providing 93% inhibition) and 20 mg/kg in dogs and monkeys effectively inhibited the clearance of the probe compound. ABT1 has been extensively used as a nonspecific inhibitor of cytochromes P450 in animals for mechanistic studies (Mico et al., 1988;Huijzer et al., 1989;Mugford and Tarloff, 1995;Su et al., 1998;Constan et al., 1999;Marczylo and Ioannides, 1999). The method of use of ABT has been quite variable from lab to lab, for example, single versus multiple dosing of animals prior to the test compound, p.o. versus i.v. route of administration, different pretreatment times, and different dose levels. Moreover, the pharmacokinetics of ABT in different species have not been reported. Also there is incomplete information in the literature on the inhibition of P450s by ABT (Knickle and Bend, 1992;Su et al., 1998;Di Re et al., 1999). To provide a guideline for the pretreatment regimen of ABT, 1) single dose oral pharmacokinetic studies were conducted in rats, dogs, and monkeys at several dose levels; 2) in vitro inhibition of various recombinant P450s by ABT was determined; and 3) the effect of selected doses of ABT on the intravenous pharmacokinetics of antipyrine, a probe for measuring efficiency of hepatic oxidative metabolism, was determined. The results from these studies are described in this report. Materials and MethodsABT and antipyrine (AP) were obtained from Sigma-Aldrich (St. Louis, MO). Single oral dose pharmacokinetics of ABT, in 0.5% aqueous methylcellulose, were studied in fasted male Sprague-Dawley rats at 10, 50, and 200 mg/kg (n Ն 3) and in Beagle dogs and Cynomolus m...

This study compared the gastrointestinal (GI) absorption characteristics and absolute bioavailability of fenofibric acid and fenofibrate (which is converted to fenofibric acid in vivo) in healthy volunteers. Treatments were delivered to the proximal small bowel, distal small bowel, and colon using a site-specific delivery system (Enterion capsule) and to the stomach by oral administration of equimolar doses. Serial blood samples were collected for 120 hours postdose and assayed for plasma fenofibric acid concentrations. The absolute bioavailability of each treatment was determined relative to 50 mg of fenofibric acid administered intravenously. Plasma exposure to fenofibric acid following fenofibric acid administration was approximately 1.5 times higher than that following fenofibrate administration for delivery to the proximal and distal small bowel and following oral administration, and it was approximately 5 times higher following colon delivery. The absolute bioavailability in the stomach, proximal small bowel, distal small bowel, and colon was approximately 81%, 88%, 84%, and 78%, respectively, for fenofibric acid and 69%, 73%, 66%, and 22%, respectively, for fenofibrate (P < .0001 and P = .033 for fenofibric acid vs fenofibrate in the colon and distal small bowel, respectively). In conclusion, fenofibric acid is well absorbed throughout the GI tract and has greater bioavailability than fenofibrate in all GI regions.

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