Single-dose oral pharmacokinetics of three formulations of thalidomide in healthy male volunteers

Thalidomide was recently approved in the United States for the treatment of erythema nodosum leprosum, a complication of leprosy. The present study de termined the bioequivalence and pharmacokinetics of Celgene's commercial an d clinical trial thalidomide formulations and the Brazilian Tortuga formula tion in an open-label, single-dose, three-way crossover design. Seventeen h ealthy subjects were given 200 mg of thalidomide on three occasions, and bl ood samples were collected over 48 hours. Pharmacokinetic parameters were d etermined using compartmental methods for the two Celgene formulations and using noncompartmental methods for all three formulations. All subjects rep orted adverse events, none of which was serious or unexpected. Celgene form ulations were bioequivalent when comparing C-max, t(max), and AUC. There wa s significant variability in plasma levels from the Tortuga formulation, gi ving a mean profile that was distinctly different from the two Celgene form ulations with a lower C-max value and a longer terminal phase. The lower C- max was probably due to slower absorption. The terminal rate constant for t he Tortuga formulation was significantly less, giving rise to a terminal ha lf-life of 15 hours compared to about 5 to 6 hours for the Celgene formulat ions. Confidence intervals for C-max between the Tortuga and the Celgene fo rmulations were outside the 80% to 125% range, indicating a lack of biocqui valence. Extent of absorption, as measured by AUG(0<--oe) was approximately equal for all three formulations. Terminal half-life for Tortuga was two t o three times longer compared to the Celgene formulations and is clear evid ence for absorption rate limitations. The two Celgene formulations showed s imilar pharmacokinetic parameters with profiles that were best described by a one compartment model with first-order absorption and elimination. The a uthors conclude that Celgene's clinical trial and commercial thalidomide fo rmulations are similar to each other and distinctly different from the Tort uga formulation and that all three formulations exhibited absorption rate-l imited elimination. (C) 1999 the American College of Clinical Pharmacology.