Comparative preclinical toxicology and pharmacology of isophosphoramide mustard, the active metabolite of ifosfamide.
BACKGROUND
Isophosphoramide mustard (IPM) is the cytotoxic alkylating metabolite of Ifosfamide (IFOS). IPM is being readied for a phase I clinical trial. In the present preclinical study, IPM was evaluated for usage in multidose intravenous (IV) infusion protocols.


METHODS
Mice and dogs received IV IPM daily for 3 days. Single-day dosing-oral and IV-to mice, rats, and monkeys is also reviewed for comparison. Complete toxicology studies were completed in the mice and dogs. For mice, dogs and monkeys, IV pharmacokinetic studies were conducted and compared.


RESULTS
For mice, the LD(10) for the 3-day IV schedule for IPM was calculated to be 119 mg/kg (with 95% confidence limits of 87-134 mg/kg) (combined sexes), and for adult male dogs the maximum tolerated dose (MTD) was 5 mg/kg. Pharmacokinetic studies in mice, dogs and monkeys were compared and projected to human dosing. For dogs that received 10 mg/kg of IPM, T(1/2beta) was 0.99 h, and clearance was constant (1.01 l/h/kg). IPM was detected from 0 h to 1.5 h after the 5 mg/kg dose and from 0 h to 2 h after the 10 mg/kg dose; none was detected after 2 h. The IV MTD in dogs was 5 mg/kg per day for 3 days. Renal tubular necrosis and bone marrow failure were the causes of death. Transient liver, renal and bone marrow toxicity and gastrointestinal dysfunction were seen at low doses (<5 mg/kg) in dogs. In mice (receiving 100 mg/kg IV) plasma concentrations disappeared in less than 1 h (T(1/2alpha) 2 min), with a clearance of 8.44 l/h/kg. For monkeys, the mean T(1/2) was 4.2 h. Median clearance was 1.65 l/h/kg and no IPM was detected 4 h after dosing. No potential IPM metabolites could be detected in any of the studies. In vitro, plasma protein bound 90% of IPM within 5 min of incubation.


CONCLUSIONS
Predictions for human pharmacokinetic parameters and dosing are made from allometric analysis using the above three species. Data predicted an acceptable starting dose of 30 mg/m(2) with a clearance of 39.5 l/h, and a T(1/2) of 1 h 45 min for a 70-kg patient.
Germann
N
N
Service de pharmacology, Centre René Huguenin, 35 rue Dailly, 92210, Saint Cloud, France.
Urien
S
S
Rodgers
Andrew H
AH
Ratterree
Marion
M
Struck
Robert F
RF
Waud
William R
WR
Serota
David G
DG
Bastian
Gerard
G
Jursic
Branko S
BS
Morgan
Lee Roy
LR
D000818:Animals; D004285:Dogs; D005260:Female; D007928:Lethal Dose 50; D008253:Macaca mulatta; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008809:Mice, Inbred C3H; D010752:Phosphoramide Mustards / Q000493:pharmacokinetics / Q000633:toxicity*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
D010752:Phosphoramide Mustards; C027061:isophosphamide mustard