OPTIMIZING THE ABSORPTION OF VALSPODAR, A P-GLYCOPROTEIN MODULATOR .1. SELECTING AN ORAL FORMULATION AND EXPLORING ITS CLINICAL PHARMACOKINETICS DYNAMICS/

Valspodar is a cyclosporine D analog used as a chemotherapy adjunct fo r modifying multidrug resistance. Two studies were sequentially perfor med to select an optimal oral formulation and to characterize selected aspects of its clinical pharmacokinetics/dynamics. An initial four-wa y crossover study with 20 volunteers compared the pharmacokinetics of single fasting administrations of 200 mg by intravenous infusion and 6 00 mg orally as a conventional oral solution, a microemulsion oral sol ution, and a microemulsion soft gelatin capsule. The two microemulsion dosage forms demonstrated significantly faster and less variable rate s of absorption compared with the conventional oral solution. The micr oemulsion dosage forms were bioequivalent with absolute bioavailabilit y nearly double that of the conventional oral solution. Based on these results, the microemulsion capsule was further investigated in a four -way randomized crossover study with 24 volunteers who received single fasting administrations of 200, 400, and 600 mg and a 400-mg administ ration after a fat-rich meal. Dose proportionality in area under the c urve (AUC) was demonstrated over this dose range. Administration after a fat-rich meal caused a slight time lag until absorption began, a de lay in time to reach the peak concentration, and a moderate increase o f 24 % in A UC. Serial determinations of total bilirubin were explored as a potential pharmacodynamic marker for P-glycoprotein inhibition. A similar magnitude of reversible hyperbilirubinemia was seen at all d ose levels suggesting that P-glycoprotein inhibition in the biliary ca naliculi was maximal even at the lowest dose tested. The microemulsion formulation (oral solution or soft gelatin capsule) represents an imp roved and less variable oral delivery form providing dose-proportional drug exposure over a clinically relevant dose range.