title: 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.affiliation: Faculty of Medical and Health Sciences, Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Kashyap
authors.initials: K
authors.lastname: Patel
authors.forename: Steve S F
authors.initials: SS
authors.lastname: Choy
authors.forename: Kevin O
authors.initials: KO
authors.lastname: Hicks
authors.forename: Teresa J
authors.initials: TJ
authors.lastname: Melink
authors.forename: Nicholas H G
authors.initials: NH
authors.lastname: Holford
authors.forename: William R
authors.initials: WR
authors.lastname: Wilson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D001798:Blood Proteins / Q000378:metabolism; D015687:Cell Hypoxia; D017321:Clinical Trials, Phase I as Topic; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009588:Nitrogen Mustard Compounds / Q000493:pharmacokinetics* / Q000633:toxicity; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000633:toxicity; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D009588:Nitrogen Mustard Compounds; C524170:PR-104A; D011355:Prodrugs