title: Pharmacokinetic study of infusional valspodar.
abstract: The pharmacokinetics of valspodar (PSC 833), a selective second-generation P-glycoprotein modulator, was evaluated as part of a Phase I study to modulate paclitaxel therapy in 15 patients with refractory malignancies. Valspodar was given intravenously at 1.42 mg/kg/h for 2 hours, followed by a 27-hour continuous infusion at 0.42 mg/kg/h. Serial blood samples were obtained after intravenous infusion of valspodar and paclitaxel. Valspodar disposition was best described by a linear two-compartment model. The median (range) valspodar clearance was 0.40 ml/min/kg (0.07-1.40 ml/min/kg). The 20-fold interpatient variability in valspodar clearance was not correlated with age, body weight, orgender but might be associated with coadministered medications that were metabolized via cytochrome P450 3A-mediated elimination. Valspodar whole-blood concentrations were maintained above the target threshold of 1000 ng/ml for a median of 32 hours. The pharmacokinetic model generated from this study allows for application in future studies to optimize the use of valspodar.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110-1093, USA.
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Ma
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.forename: Peter
authors.initials: P
authors.lastname: Westervelt
authors.forename: Paula M
authors.initials: PM
authors.lastname: Fracasso
mesh_terms: D000328:Adult; D000368:Aged; D003524:Cyclosporins / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D018709:Statistics, Nonparametric
chemical_list: D003524:Cyclosporins; C070272:valspodar