Pharmacokinetic study of infusional valspodar

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.
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				S. E. Bates, S. Bakke, M. Kang, R. W. Robey, S. Zhai, P. Thambi, C. C. Chen, S. Patil, T. Smith, S. M. Steinberg, et al. A Phase I/II Study of Infusional Vinblastine with the P-Glycoprotein Antagonist Valspodar (PSC 833) in Renal Cell Carcinoma Clin. Cancer Res., July 15, 2004; 10(14): 4724 - 4733. [Abstract] [Full Text] [PDF]