Clinical pharmacokinetics of the anthrapyrazole CI-941: factors compromising the implementation of a pharmacokinetically guided dose escalation scheme.
The pharmacokinetics of the anthrapyrazole CI-941 has been investigated in conjunction with the Phase I evaluation of the drug with the intent of applying a pharmacokinetically guided dose escalation strategy. A starting dose of 5 mg/m2 was chosen, based on one-tenth the 10% lethal dose in mice. Due to the steep dose lethality relationship and nonlinear pharmacokinetics in mice, a target area under the CI-941 plasma concentration x time curve (AUC) of 110 microM x min (i.e., 40% of the mouse 10% lethal dose AUC) was chosen. This AUC was achieved in mice at 40 mg/m2. A total of 37 patients received 74 courses of CI-941 (5 to 55 mg/m2), with 26 patients consenting to pharmacokinetic monitoring. CI-941 was rapidly cleared from plasma, and a triexponential open model could be fitted to the data (t1/2 alpha = 7.6 +/- 2 min, t1/2 beta = 65 +/- 27 min, t1/2 zeta = 21 +/- 9 h). CI-941 was subjected to only limited urinary elimination, accounting for 5.2 +/- 2.8% of the administered dose. Wide interpatient variability in plasma CI-941 clearance at the starting dose and subsequent doses precluded the implementation of a pharmacokinetically guided dose escalation scheme, and the dose was escalated in 5-mg/m2 increments until the maximally tolerated dose was achieved. A number of investigations were performed to study potential reasons for variability in CI-941 clearance. However, CI-941 plasma protein binding (95 +/- 1%) and measures of pretreatment renal (51Cr-EDTA clearance), hepatic (plasma alanine transaminase and alkaline phosphatase levels), or cardiac function (left ventricular ejection fractions) did not relate strongly to CI-941 clearance. In patients treated at 40 mg/m2, the AUC values (156 to 415 microM x min) approximated or exceeded the target AUC. Fifty mg/m2 was the Phase II recommended dose. Further prospective studies are warranted to assess the utility of pharmacokinetically guided dose escalation strategies and to determine whether or not the variability encountered in clearance is unique to CI-941.
Graham
M A
MA
Drug Development Section, Royal Marsden Hospital, Sutton, Surrey, England.
Newell
D R
DR
Foster
B J
BJ
Gumbrell
L A
LA
Jenns
K E
KE
Calvert
A H
AH
D000880:Anthraquinones / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D004341:Drug Evaluation; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D008657:Metabolic Clearance Rate; D009369:Neoplasms / Q000188:drug therapy*; D009961:Orosomucoid / Q000378:metabolism; D011485:Protein Binding; D011720:Pyrazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D047069:Pyrazolones; D012044:Regression Analysis; D014018:Tissue Distribution
D000880:Anthraquinones; D000970:Antineoplastic Agents; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D009961:Orosomucoid; D011720:Pyrazoles; D047069:Pyrazolones; C050637:losoxantrone