Phase I study of intravenous PSC-833 and doxorubicin: Reversal of multidrug resistance

Hironobu Minami, Tomoko Ohtsu, Hirofumi Fujii, Tadahiko Igarashi, Kuniaki Itoh, Noriko Uchiyama-Kokubu, Tetsushi Aizawa, Torn Watanabe, Yoshinori Uda, Yusuke Tanigawara, Yasutsuna Sasaki

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

PSC-833 reverses multidrug resistance by P-glycoprotein at concentrations ≤1000 ng/ml. A phase I study of PSC-833 and doxorubicin was conducted to determine the maximum tolerated dose and to investigate pharmacokinetics. PSC-833 was intravenously infused as a 2-h loading dose (LD) and a subsequent 24-h continuous dose (CD). Doxorubicin was infused over 5 min, 1 h after the LD. The starting dose was 1 mg/kg for both LD and CD with 30 mg/m2 doxorubicin; these dosages were increased to 2 and 10 mg/kg and 50 mg/m2, respectively. Thirty-one patients were treated. Nausea/ vomiting was controllable with granisetron and dexamethasone. Neutropenia and ataxia were dose limiting. Steady-state concentrations of PSC-833 > 1000 ng/ml were achieved at a 2 mg/kg LD and a 10 mg/kg CD. Ex-vivo bioassay revealed that activity in serum for reversing multidrug resistance was achieved in all patients; IC50 of P-glycoprotein expressing 8226/Dox6 in patients' serum was decreased from 5.9 to 1.3 μg/ml (P<0.0001) by PSC-833 administration. Doxorubicin clearance was 24.3±13.7 (mean±SD) liter/h/m2, which was lower than the 49.0±16.9 liter/h/m2 without PSC-833 (P<0.0001). The relationship between doxorubicin exposure and neutropenia did not differ between patients treated and not treated with PSC-833. The recommended phase II dose of PSC-833 was 2 and 10 mg/kg for LD and CD, respectively, which achieved a sufficient concentration in serum to reverse drug resistance, as confirmed by bioassay. The dose of doxorubicin should be reduced to 40 mg/m2, not because of the pharmacodynamic interaction between PSC-833 and doxorubicin affecting hematopoiesis, but because of pharmacokinetic interaction.

Original languageEnglish
Pages (from-to)220-230
Number of pages11
JournalJapanese Journal of Cancer Research
Volume92
Issue number2
DOIs
Publication statusPublished - 2001

Keywords

  • Doxurubicin
  • Multidrug resistance
  • PSC-833
  • Pharmacodynamics
  • Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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