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

H. Minami, T. Ohtsu, H. Fujii, T. Igarashi, K. Itoh, N. Uchiyama-Kokubu, T. Aizawa, T. Watanabe, Y. Uda, Yusuke Tanigawara, Y. Sasaki

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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
Publication statusPublished - 2001

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Multiple Drug Resistance
Doxorubicin
P-Glycoprotein
Neutropenia
Biological Assay
Pharmacokinetics
Serum
Granisetron
valspodar
Maximum Tolerated Dose
Hematopoiesis
Ataxia
Drug Resistance
Nausea
Dexamethasone
Inhibitory Concentration 50
Vomiting

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Minami, H., Ohtsu, T., Fujii, H., Igarashi, T., Itoh, K., Uchiyama-Kokubu, N., ... Sasaki, Y. (2001). Phase I study of intravenous PSC-833 and doxorubicin: Reversal of multidrug resistance. Japanese Journal of Cancer Research, 92(2), 220-230.

Phase I study of intravenous PSC-833 and doxorubicin : Reversal of multidrug resistance. / Minami, H.; Ohtsu, T.; Fujii, H.; Igarashi, T.; Itoh, K.; Uchiyama-Kokubu, N.; Aizawa, T.; Watanabe, T.; Uda, Y.; Tanigawara, Yusuke; Sasaki, Y.

In: Japanese Journal of Cancer Research, Vol. 92, No. 2, 2001, p. 220-230.

Research output: Contribution to journalArticle

Minami, H, Ohtsu, T, Fujii, H, Igarashi, T, Itoh, K, Uchiyama-Kokubu, N, Aizawa, T, Watanabe, T, Uda, Y, Tanigawara, Y & Sasaki, Y 2001, 'Phase I study of intravenous PSC-833 and doxorubicin: Reversal of multidrug resistance', Japanese Journal of Cancer Research, vol. 92, no. 2, pp. 220-230.
Minami H, Ohtsu T, Fujii H, Igarashi T, Itoh K, Uchiyama-Kokubu N et al. Phase I study of intravenous PSC-833 and doxorubicin: Reversal of multidrug resistance. Japanese Journal of Cancer Research. 2001;92(2):220-230.
Minami, H. ; Ohtsu, T. ; Fujii, H. ; Igarashi, T. ; Itoh, K. ; Uchiyama-Kokubu, N. ; Aizawa, T. ; Watanabe, T. ; Uda, Y. ; Tanigawara, Yusuke ; Sasaki, Y. / Phase I study of intravenous PSC-833 and doxorubicin : Reversal of multidrug resistance. In: Japanese Journal of Cancer Research. 2001 ; Vol. 92, No. 2. pp. 220-230.
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AU - Itoh, K.

AU - Uchiyama-Kokubu, N.

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