Technology evaluation: Valspodar, Novartis AG.

Valspodar (PSC-833) is a derivative of cyclosporin but devoid of the immunosuppressive and nephrotoxic properties seen in cyclosporin A. It exhibited high affinity binding to Mdr1 P-glycoprotein (P-gp) and demonstrated multidrug resistance-reversing activity superior to cyclosporin A and verapamil both in vitro and in vivo. Preclinical and phase I/II clinical data have indicated that plasma levels of PSC-833 with multidrug resistance-reversing activities are achievable. Potent inhibition of intestinal, hepatobiliary and blood-brain barrier P-gp function has been demonstrated. Since valspodar is also a substrate of cytochrome P450 3A (CYP3A), dual interactions of this compound with P-gp and CYP3A are the basis for the pharmacokinetic interactions seen in preclinical and clinical studies. A new formulation of the drug has recently been developed with better oral bioavailability (60%) and less interindividual variability. The toxicity profiles of valspodar are acceptable and dose-limited by transient and reversible cerebellar ataxia. It has shown multidrug resistance-modulating activities towards acute myeloid leukemia, multiple myeloma and ovarian cancer in phase I/II clinical trials. Phase III studies with respect to these three diseases are ongoing.