A phase I/II study of infusional vinblastine with the P-glycoprotein antagonist valspodar (PSC 833) in renal cell carcinoma.
OBJECTIVE
P-glycoprotein (Pgp) inhibitors have been under clinical evaluation for drug resistance reversal for over a decade. Valspodar (PSC 833) inhibits Pgp-mediated efflux but delays drug clearance, requiring reduction of anticancer drug dosage. We designed an infusional schedule for valspodar and vinblastine to mimic infusional vinblastine alone. The study was designed to determine the maximally tolerated dose of vinblastine, while attempting to understand the pharmacokinetic interactions between vinblastine and valspodar and to determine the response rate in patients with metastatic renal cell cancer.


METHODS
Thirty-nine patients received continuous infusion valspodar and vinblastine. Vinblastine was administered for 3 days to compensate for the expected delay in clearance and the required dose reduction. Valspodar was administered initially at a dose of 10 mg/kg/d; the dose of vinblastine varied.


RESULTS
The maximum-tolerated dose of vinblastine was 1.3 mg/m(2)/d. As suggested previously, serum valspodar concentrations exceeded those needed for Pgp inhibition. Consequently, the dose of valspodar was reduced to 5 mg/kg, allowing a vinblastine dose of 2.1 mg/m(2)/d to be administered. Pharmacodynamic studies demonstrated continued inhibition of Pgp at lower valspodar doses by functional assay in Pgp-expressing CD56+ cells and by (99m)Tc-sestamibi imaging. A 15-fold range in cytochrome p450 activity was observed, as measured by midazolam clearance. No major responses were observed.


CONCLUSIONS
These results suggest that the pharmacokinetic impact of cytochrome P450 inhibition by valspodar can be reduced although not eliminated, while preserving Pgp inhibition, thus separating the pharmacokinetic and pharmacodynamic activities of valspodar.
Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. sebates@helix.nih.gov
Susan E
SE
Bates
Susan
S
Bakke
Min
M
Kang
Robert W
RW
Robey
Suoping
S
Zhai
Paul
P
Thambi
Clara C
CC
Chen
Sheela
S
Patil
Tom
T
Smith
Seth M
SM
Steinberg
Maria
M
Merino
Barry
B
Goldspiel
Beverly
B
Meadows
Wilfred D
WD
Stein
Peter
P
Choyke
Frank
F
Balis
William D
WD
Figg
Tito
T
Fojo
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000293:Adolescent; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003248:Constipation / Q000139:chemically induced; D003524:Cyclosporins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D003524:Cyclosporins; D014747:Vinblastine; C070272:valspodar