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. 2001 Feb;92(2):220–230. doi: 10.1111/j.1349-7006.2001.tb01085.x

Phase I Study of Intravenous PSC‐833 and Doxorubicin: Reversal of Multidrug Resistance

Hironobu Minami 1,✉, Tomoko Ohtsu 1, Hirofumi Fujii 1, Tadahiko Igarashi 1, Kuniaki Itoh 1, Noriko Uchiyama‐Kokubu 2, Tetsushi Aizawa 2, Torn Watanabe 2, Yoshinori Uda 2, Yusuke Tanigawara 3, Yasutsuna Sasaki 1
PMCID: PMC5926698  PMID: 11223552

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.

Keywords: PSC‐833, Doxorubicin, Pharmacokinetics, Pharmacodynamics, Multidrug resistance

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