ABSTRACT
BACKGROUND: The integrase inhibitor dolutegravir and nucleoside analogues abacavir and lamivudine are once-daily treatment options for HIV. This study (NCT01622790) evaluated, first, the bioequivalence (BE) of a fixed-dose combination (FDC) tablet containing dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (dolutegravir/abacavir/lamivudine FDC) vs coadministered dolutegravir 50 mg and abacavir/lamivudine combination tablets (Epzicom) and, second, the effect of food on the dolutegravir/abacavir/lamivudine FDC tablet. METHODS: Study part A (66 healthy subjects) was a single-dose, open-label, randomized, 2-period crossover study to evaluate the BE of the dolutegravir/abacavir/lamivudine FDC tablet and dolutegravir + abacavir/lamivudine tablets in the fasted state. In study part B, 12 subjects from part A received the dolutegravir/abacavir/lamivudine FDC tablet with a high-fat meal. BE and food effect were assessed by analysis of variance to determine the ratio of geometric least squares means and associated 90% confidence intervals for key pharmacokinetic parameters for each of dolutegravir, abacavir, and lamivudine. RESULTS: Sixty-two subjects completed part A. The dolutegravir/abacavir/lamivudine tablet was bioequivalent to the dolutegravir + abacavir/lamivudine tablets; 90% confidence intervals for the geometric least squares mean ratios fell within the 0.8-1.25 BE criteria. The effect of food on the dolutegravir/abacavir/lamivudine FDC tablet was similar to previous food effects observed with the separate formulations. The safety profile was comparable between treatments, with no observed serious or grade 3/4 adverse events. CONCLUSIONS: The BE of the dolutegravir/abacavir/lamivudine FDC tablet was demonstrated; it may be administered without regard to meals.
Subject(s)
Dideoxynucleosides/pharmacokinetics , Food-Drug Interactions , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Lamivudine/pharmacokinetics , Adult , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/blood , Anti-HIV Agents/pharmacokinetics , Cross-Over Studies , Dideoxynucleosides/administration & dosage , Dideoxynucleosides/blood , Dietary Fats , Drug Combinations , Female , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/blood , Humans , Lamivudine/administration & dosage , Lamivudine/blood , Male , Oxazines , Piperazines , Pyridones , Therapeutic Equivalency , Vaginal Creams, Foams, and Jellies , Young AdultABSTRACT
Although the 6 magnitude and pattern of correlation among floral traits (phenotypic integration) is usually conceived as an adaptation for successful pollination and reproduction, studies on the evolution of plant reproductive systems have generally focused on one or a few characters. If evolutionary transitions between reproductive systems involve morphological floral adjustments, changes in the magnitude and pattern of phenotypic integration of floral traits may be expected. In this study, we focused on the evolutionary dynamics of a complex adaptive trait, the extent of reciprocity (reciprocal placement) among sexual organs in a heterostylous species, and explored the associated changes in phenotypic floral integration during the transition from tristyly to distyly. The extent of reciprocity and both the magnitude and pattern of floral integration were characterized in 12 populations of Oxalis alpina representing the tristyly-distyly gradient. Although the extent of reciprocity increased along the tristyly-distyly transition, the flower size diminished. These adjustments did not affect the magnitude, but did affect the pattern, of floral integration. *Changes in the pattern of floral integration suggested that allometric, functional and pleiotropic relationships among floral traits were affected during this evolutionary transition.