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

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.

• Authors: Kashyap Patel, Steve S F Choy, Kevin O Hicks, Teresa J Melink, Nicholas H G Holford, William R Wilson
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 67 Issue 5 Pg. 1145-55 (May 2011) ISSN: 1432-0843 [Electronic] Germany
• PMID: 20683596 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Blood Proteins
• Nitrogen Mustard Compounds
• PR-104A
• Prodrugs

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics, toxicity)
• Blood Proteins (metabolism)
• Cell Hypoxia
• Clinical Trials, Phase I as Topic
• Dogs
• Female
• Humans
• Male
• Mice
• Mice, Nude
• Models, Biological
• Nitrogen Mustard Compounds (pharmacokinetics, toxicity)
• Prodrugs (pharmacokinetics, toxicity)
• Protein Binding
• Rats
• Rats, Sprague-Dawley
• Species Specificity