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A combined pharmacokinetic model for the hypoxia-targeted prodrug PR-104A in humans, dogs, rats and mice predicts species differences in clearance and toxicity

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Abstract

Background

PR-104 is a phosphate ester that is systemically converted to the corresponding alcohol PR-104A. The latter is activated by nitroreduction in tumours to cytotoxic DNA cross-linking metabolites. Here, we report a population pharmacokinetic (PK) model for PR-104 and PR-104A in non-human species and in humans.

Methods

A compartmental model was used to fit plasma PR-104 and PR-104A concentration–time data after intravenous (i.v.) dosing of humans, Beagle dogs, Sprague–Dawley rats and CD-1 nude mice. Intraperitoneal (i.p.) PR-104 and i.v. PR-104A dosing of mice was also investigated. Protein binding was measured in plasma from each species. Unbound drug clearances and volumes were scaled allometrically.

Results

A two-compartment model described the disposition of PR-104 and PR-104A in all four species. PR-104 was cleared rapidly by first-order (mice, rats, dogs) or mixed-order (humans) metabolism to PR-104A in the central compartment. The estimated unbound human clearance of PR104A was 211 L/h/70 kg, with a steady state unbound volume of 105 L/70 kg. The size equivalent unbound PR-104A clearance was 2.5 times faster in dogs, 0.78 times slower in rats and 0.63 times slower in mice, which may reflect reported species differences in PR-104A O-glucuronidation.

Conclusions

The PK model demonstrates faster size equivalent clearance of PR-104A in dogs and humans than rodents. Dose-limiting myelotoxicity restricts the exposure of PR-104A in humans to approximately 25% of that achievable in mice.

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Notes

  1. Patel K, Foehrenbacher A, Secomb TW, Wilson WR, Hicks KO. A spatially resolved pharmacokinetic/pharmacodynamic model for hypoxic activation and bystander killing by the bioreductive prodrug PR-104. Manuscript in preparation.

  2. Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction corrected visual predictive checks. http://www.go-acop.org/sites/all/assets/webform/PC_VPC_Abstract_ACoP_090715_final.doc.

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Acknowledgments

We thank Proacta Inc. for provision of PR-104 and access to pharmacokinetic and toxicity data for rats, dogs and humans, and MicroConstants Inc. for assay of PR-104 and PR-104A in plasma from these species. The study was supported by grant 08/103 from the Health Research Council of New Zealand and a Fellowship to KP from the Auckland Medical Research Foundation.

William R. Wilson is a founding scientist, stockholder and consultant to Proacta, Inc.

Author information

Authors and Affiliations

  1. Faculty of Medical and Health Sciences, Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland, New Zealand

    Kashyap Patel, Kevin O. Hicks & William R. Wilson

  2. Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand

    Steve S. F. Choy & Nicholas H. G. Holford

  3. Proacta Inc. 9255 Towne Centre Drive, Suite 520, San Diego, CA, 92121-1870, USA

    Teresa J. Melink

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  1. Kashyap Patel
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Correspondence to William R. Wilson.

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Patel, K., Choy, S.S.F., Hicks, K.O. et al. A combined pharmacokinetic model for the hypoxia-targeted prodrug PR-104A in humans, dogs, rats and mice predicts species differences in clearance and toxicity. Cancer Chemother Pharmacol 67, 1145–1155 (2011). https://doi.org/10.1007/s00280-010-1412-z

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  • DOI: https://doi.org/10.1007/s00280-010-1412-z

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