Optimizing the Absorption of Valspodar, a P‐glycoprotein Modulator, Part I: Selecting an Oral Formulation and Exploring its Clinical Pharmacokinetics/Dynamics

Abstract

Valspodar is a cyclosporine D analog used as a chemotherapy adjunct for modifying multidrug resistance. Two studies were sequentially performed to select an optimal oral formulation and to characterize selected aspects of its clinical pharmacokinetics/dynamics. An initial four-way crossover study with 20 volunteers compared the pharmacokinetics of single fasting administrations of 200 mg by intravenous infusion and 600 mg orally as a conventional oral solution, a microemulsion oral solution, and a microemulsion soft gelatin capsule. The two microemulsion dosage forms demonstrated significantly faster and less variable rates of absorption compared with the conventional oral solution. The microemulsion dosage forms were bioequivalent with absolute bioavailability 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 administration after a fat-rich meal. Dose proportionality in area under the curve (AUC) was demonstrated over this dose range. Administration after a fat-rich meal caused a slight time lag until absorption began, a delay in time to reach the peak concentration, and a moderate increase of 24% in AUC. 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 dose levels suggesting that P-glycoprotein inhibition in the biliary canaliculi was maximal even at the lowest dose tested. The microemulsion formulation (oral solution or soft gelatin capsule) represents an improved and less variable oral delivery form providing dose-proportional drug exposure over a clinically relevant dose range.

A Phase I study of infusional vinblastine in combination with the p-glycoprotein antagonist PSC 833 (valspodar)

“…The lower total dose of PSC 833 that was tolerated when the drug was formulated as a microemulsion is consistent with independent studies that found an oral bioavailability nearly double that of the liquid formulation. 21,22 Two patients treated at 5 mg/kg q8h had dose limiting toxicities; however, one of these patients with Grade 4 hyperbilirubinemia accompanied by pruritis was considered to have an idiosyncratic reaction. Thus, after an additional 4 patients were shown to safely tolerate the combination of 4 mg/kg q8h PSC 833 and 0.6 mg/m 2 vinblastine (level 8B), the dose of PSC 833 was increased again to 5 mg/kg q8h (level 9B).…”

Longitudinal assessment of a P-glycoprotein?mediated drug interaction of valspodar on digoxin

“…An influence of digoxin on valspodar pharmacokinetics was not expected because digoxin does not modify the pharmacokinetics of other inhibitors of P‐glycoprotein (quinidine, cyclosporine, and verapamil) and because valspodar is not a substrate of this efflux pump 10 . Therefore the dose regimen of valspodar was derived from those known to be well tolerated in previous studies of healthy subjects 11 . Finally, valspodar is intended for short‐term therapy during each chemotherapy cycle, with a maximum anticipated duration of 5 to 7 days depending on the cancer indication.…”

Development of a liquid chromatography–mass spectrometry (LC/MS) assay method for the quantification of PSC 833 (Valspodar) in rat plasma

“…Previous studies have shown LOQ values in the range of 37.5-75 and 50-100 ng/mL for RIA and HPLC methods of PSC 833 analy- sis, respectively [32,[34][35][36]. The lower level of LOQ for the LC/MS method is an indication for the higher sensitivity of this method compared to the reported RIA and HPLC methods.…”

“…Quantitative analysis of PSC 833 in blood or plasma is usually accomplished through analytical methods based on either RIA [29][30][31][32] or HPLC [33][34][35][36]. Some of the RIA kits are known to detect CyA metabolites especially the major monohydroxylated metabolite (AM9) that also occurs in PSC 833 (M9) [37].…”