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.
Tai
H L
HL
Roche Pharmaceuticals, Neurobiology Research, 3410 Hillview Avenue, Paulo Alto, CA 94304, USA. ezra.tai@roche.com
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D001709:Biotechnology; D003524:Cyclosporins / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D009101:Multiple Myeloma / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; C070272:valspodar