Effect of valspodar on the pharmacokinetics of unbound paclitaxel.
The aim of this multicenter study was to determine whether valspodar (Amdray; code designation, SDZ PSC 833), a potent P-glycoprotein (P-gp) inhibitor, affects the pharmacokinetics of unbound paclitaxel (Cu). Data were obtained from 31 patients with advanced breast cancer. Thirteen patients were treated with paclitaxel alone (3-h infusion at 175 mg/m2) and another 18 received paclitaxel (3-h infusion at 70 mg/m2) in combination with a 21-day cycle of oral valspodar (5 mg/kg given four times a day) starting 1 day before administration of paclitaxel. Serial blood samples were taken in the first course and Cu in plasma determined using equilibrium dialysis with a [G-3H]paclitaxel tracer. The apparent clearance of Cu was not significantly different between the two groups, with mean +/- standard deviation (+/- SD) values of 230 +/- 56.0 and 202 +/- 49.9 L/h/m2 in the absence and presence of valspodar, respectively (P = 0.17). The volume of Cu distribution was slightly larger in the presence of valspodar (1160 +/- 474 vs. 1620 +/- 552 L/m2; P = 0.025), which contributed to a minor difference in the terminal disposition half-life (6.12 +/- 3.42 vs. 8.50 +/- 2.06 h; P = 0.028). These data indicate that (i) valspodar lacks the significant interaction with paclitaxel observed previously with other P-gp modulators, (ii) the majority of the increased toxicity of the combination does not appear to be attributable to increased levels of Cu, and (iii) provide further evidence of the conjecture that the plasma concentration of paclitaxel may not be an appropriate measure to monitor the impact of P-gp inhibition.
Department of Medical Oncology, Erasmus MC--Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. a.tentije@erasmusmc.nl
Albert J
AJ
ten Tije
Timothy W
TW
Synold
Darcy
D
Spicer
Jaap
J
Verweij
James H
JH
Doroshow
Alex
A
Sparreboom
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000378:metabolism; D003524:Cyclosporins / Q000008:administration & dosage / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D017239:Paclitaxel; C070272:valspodar