A phase I and pharmacologic study of idarubicin, cytarabine, etoposide, and the multidrug resistance protein (MDR1/Pgp) inhibitor PSC-833 in patients with refractory leukemia

Kenneth S. Bauer, Judith E. Karp, Tushar S. Garimella, Suhlan Wu, Ming Tan, Douglas D. Ross

Research output: Contribution to journalArticlepeer-review

Abstract

This study was conducted to define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), and pharmacokinetics of idarubicin when administered with and without the P-glycoprotein inhibitor PSC-833 in combination with cytarabine, and etoposide. Fifteen patients with relapsed and refractory acute leukemia were enrolled and received cytarabine as a 7-day continuous infusion, with etoposide and idarubicin administered for any three consecutive days during the cytarabine infusion. Two hours prior to the second dose of idarubicin, PSC-833 administration was initiated. The pharmacokinetics of idarubicin alone and with PSC-833 was assessed at three idarubicin dose levels (6, 8 and 10 mg/m2). The MTD of idarubicin in this combination was 8 mg/(m 2 day) with a DLT of oral mucositis. The complete remission rate (on an intent-to-treat basis) for this regimen was 33%, with a median duration of 6 months. The clearance of idarubicin was 140 ± 200 and 181 ± 94.3 l/h for idarubicin alone and with PSC-833, respectively. The volume of distribution of the central compartment was 423 ± 443 and 337 ± 394 l for idarubicin alone and in combination with PSC-833, respectively. This combination including PSC-833 was well tolerated. Although a pharmacokinetic interaction might have been expected, PSC-833 did not significantly alter the disposition of idarubicin.

Original languageEnglish (US)
Pages (from-to)263-271
Number of pages9
JournalLeukemia Research
Volume29
Issue number3
DOIs
StatePublished - Mar 2005
Externally publishedYes

Keywords

  • Interaction
  • Multidrug resistance
  • P-glycoprotein
  • Pharmacokinetics
  • Transport proteins

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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