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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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.
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.
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.
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.
KeywordsHypoxia-activated prodrugs Nitrogen mustards Pharmacokinetics PR-104 Allometry
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.
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