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Pharmacokinetics of TH-302: a hypoxically activated prodrug of bromo-isophosphoramide mustard in mice, rats, dogs and monkeys

Cancer Chemotherapy and Pharmacology volume 69, pages 643–654 (2012)Cite this article

Abstract

Purpose

To characterize the pharmacokinetics of the prodrug, TH-302, and its active metabolite, bromo-IPM (Br-IPM), in nonclinical species.

Methods

TH-302 was administered in single oral, intraperitoneal and intravenous bolus doses to mice, rats, dogs and monkeys as well as in acute and chronic safety studies in rats and dogs as a 30-min intravenous infusion given once a week for 3 weeks. Assessments were made using liquid chromatography–tandem mass spectrometry.

Results

TH-302 was extensively distributed with high systemic clearance exceeding hepatic plasma flow in all species studied, resulting in half-lives ranging between 8 min (mice) and over 4 h (rats). In rats, TH-302 exhibited linear kinetics following intravenous administration and good oral bioavailability. In acute and chronic safety studies, there was no accumulation of TH-302 following once weekly dosing for 3 weeks in the rat and dog. Br-IPM plasma concentrations were a small fraction of the TH-302 plasma concentrations with significantly smaller percentages present in dogs than in rats. Allometric scaling predicted that the systemic clearance and steady-state volume of distribution in humans would be 38.8 l/h/m2 and 34.3 l/m2, respectively, resulting in a terminal elimination half-life of about 36 min. These values were similar to those observed in patients with solid tumors (27.1 l/h/m2, 23.5 l/m2 and 47 min).

Conclusions

TH-302 exhibited good safety, efficacy and pharmacokinetic properties in nonclinical species, translating into favorable properties in humans.

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Affiliations

  1. Department of Nonclinical and Clinical Pharmacology, Threshold Pharmaceuticals, Inc., 170 Harbor Way, Suite 300, South San Francisco, CA, 94080, USA

    Donald Jung & Lin Lin

  2. Department of Medicinal Chemistry, Threshold Pharmaceuticals, Inc., South San Francisco, CA, USA

    Hailong Jiao, Xiaohong Cai, Jian-Xin Duan & M. Matteucci

Authors
  1. Donald Jung
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  2. Lin Lin
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  3. Hailong Jiao
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  4. Xiaohong Cai
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  5. Jian-Xin Duan
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  6. M. Matteucci
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Corresponding author

Correspondence to Donald Jung.

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Jung, D., Lin, L., Jiao, H. et al. Pharmacokinetics of TH-302: a hypoxically activated prodrug of bromo-isophosphoramide mustard in mice, rats, dogs and monkeys. Cancer Chemother Pharmacol 69, 643–654 (2012). https://doi.org/10.1007/s00280-011-1741-6

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  • DOI: https://doi.org/10.1007/s00280-011-1741-6

Keywords

  • Pharmacokinetics
  • TH-302
  • Prodrug
  • Bromo-isophosphoramide mustard