title: Pharmacokinetics of TH-302: a hypoxically activated prodrug of bromo-isophosphoramide mustard in mice, rats, dogs and monkeys.
abstract: OBJECTIVE
  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/m(2) and 34.3 l/m(2), 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/m(2), 23.5 l/m(2) and 47 min).
  
  
  CONCLUSIONS
  TH-302 exhibited good safety, efficacy and pharmacokinetic properties in nonclinical species, translating into favorable properties in humans.
authors.affiliation: Department of Nonclinical and Clinical Pharmacology, Threshold Pharmaceuticals, Inc., 170 Harbor Way, Suite 300, South San Francisco, CA, 94080, USA. djung@thresholdpharm.com
authors.forename: Donald
authors.initials: D
authors.lastname: Jung
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Hailong
authors.initials: H
authors.lastname: Jiao
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Cai
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Duan
authors.forename: M
authors.initials: M
authors.lastname: Matteucci
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D006207:Half-Life; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D015394:Molecular Structure; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D010752:Phosphoramide Mustards / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D011237:Predictive Value of Tests; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; D011355:Prodrugs; C552526:TH 302; C027061:isophosphamide mustard