Optimizing the Absorption of Valspodar, a P‐glycoprotein Modulator, Part II: Quantifying its Pharmacokinetic Variability and Refining the Bioavailability Estimate

Abstract

A randomized, sequential, bioreplication study was performed with 24 healthy volunteers to assess the pharmacokinetic variability of oral and intravenous administrations of valspodar, a multidrug resistance modulator for use as a chemotherapy adjunct. Subjects received 200 mg as a 2-hour intravenous infusion and 400 mg orally as microemulsion soft gelatin capsules each given on two separate occasions. Following replicate intravenous administrations, reproducibility in peak concentration and area-under-the-curve was demonstrated by interoccasion equivalence testing. Low to moderate inter- and intra-subject pharmacokinetic variability were observed with coefficients of variation ranged from 9% to 19%. Absolute bioavailability from the microemulsion formulation was 60%. Replicate oral administrations demonstrated uniform and repeatable absorption with interoccasion equivalence in peak concentration, time to reach the peak concentration, and area-under-the-curve. Coefficients of inter- and intra-subject variation for these parameters ranged from 10% to 20% indicating low to moderate pharmacokinetic variability. When variabilities were compared between the two routes of administration, the absence of differences indicated that the rate and extent of drug absorption from the microemulsion formulation was as uniform and repeatable as by intravenous infusion.

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).…”

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

“…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].…”