Bioequivalence studies of a new valproic acid delayed-release capsule and divalproex sodium delayed-release tablet.

OBJECTIVE: The study examined relative bioavailability of a novel valproic acid (VPA) delayed-release (DR) soft gelatin capsule formulation to divalproex sodium DR tablet under fasting conditions and the effect of food on the bioavailability of the VPA DR soft gelatin capsule. METHOD: This open-label, randomized three-way crossover study enrolled 36 healthy non-smoking adult volunteers. Treatments included a single 500 mg divalproex sodium DR tablet, fasting; a single 500 mg VPA DR soft gelatin capsule, fasting; and, a single 500 mg VPA DR soft gelatin capsule 500 mg, non-fasting. Analysis of variance was performed on the pharmacokinetic parameters. The ratio of geometric means and corresponding 90% confidence intervals (CI) were calculated on ln-transformed data for the area under the serum concentration-time curve (mug-hr/mL) from time zero to the time of the last quantifiable concentration (t) (AUC(0-t)), AUC(0-infinity) and maximum plasma concentration (C(max)). Bioequivalence was shown when 90% CIs were within the 80-125% range. RESULTS: All subjects completed the study. The 90% CIs of VPA DR soft gelatin capsules compared to divalproex sodium DR tablets were within the 80-125% limits for AUC(0-t), AUC(0-infinity), and C(max). The time of maximum or peak concentration (T(max)) of VPA DR soft gelatin capsules was 2.3 hours versus 3.7 hours with divalproex sodium DR tablets. AUC(0-t) and AUC(0-infinity) of VPA soft gelatin capsules were not affected in the non-fasting condition, but T(max) occurred at 6.1 hours compared to 2.3 hours fasting. Eight subjects experienced a total of 10 adverse events; none were serious. CONCLUSION: The VPA DR soft gelatin capsule formulation was shown to be bioequivalent to divalproex sodium DR tablet and no serious adverse events occurred. Because this was not a multiple-dose study, however, direct comparisons in chronic dosing were not possible. Administration with food affected rate but not extent of absorption of the VPA DR soft gelatin capsules, but comparisons with the reference product were not conducted under non-fasting conditions.

Identification of phenylisoxazolines as novel and viable antibacterial agents active against Gram-positive pathogens.

A new and promising group of antibacterial agents, collectively known as the oxazolidinones and exemplified by linezolid (PNU-100766, marketed as Zyvox), have recently emerged as important new therapeutic agents for the treatment of infections caused by Gram-positive bacteria. Because of their significance, extensive synthetic investigations into the structure-activity relationships of the oxazolidinones have been conducted at Pharmacia. One facet of this research effort has focused on the identification of bioisosteric replacements for the usual oxazolidinone A-ring. In this paper we describe studies leading to the identification of antibacterial agents incorporating a novel isoxazoline A-ring surrogate. In a gratifying result, the initial isoxazoline analogue prepared was found to exhibit in vitro antibacterial activity approaching that of the corresponding oxazolidinone progenitor. The synthesis and antibacterial activity profile of a preliminary series of isoxazoline analogues incorporating either a C-C or N-C linkage between their B- and C-rings will be presented. Many of the analogues exhibited interesting levels of antibacterial activity. The piperazine derivative 54 displayed especially promising in vitro activity and in vivo efficacy comparable to the activity and efficacy of linezolid.