title: The pharmacokinetics and toxicity of the anthrapyrazole anti-cancer drug CI-941 in the mouse: a guide for rational dose escalation in patients.
abstract: CI-941 is a new synthetic DNA-binding agent selected for phase I clinical evaluation. The drug has broad-spectrum antitumour activity against a number of murine tumours and, in contrast to doxorubicin, is unlikely to induce cardiotoxicity by a free-radical-mediated mechanism. In this study the toxicity and pharmacokinetics of CI-941 were studied in the mouse to enable the implementation of a pharmacokinetically guided dose-escalation strategy in patients. Following a single i.v. bolus injection in mice, CI-941 induced dose-dependent leukopenia. The white blood cell counts were suppressed on day 3 by 18%, 50% and 65% of control, at doses of 10, 15 and 20 mg/kg CI-941, respectively. Other toxicities such as weight loss, alopecia, diarrhoea and convulsions were observed at doses greater than 20 mg/kg. Lethality studies in female Balb-c mice resulted in an LD10 value of 20 mg/kg (95% confidence limits; range, 19-21 mg/kg) and an LD50 value of 22 mg/kg (95% confidence limits; range, 21-23 mg/kg). The pharmacokinetics of CI-941 were studied at four dose levels from 1/10 of the LD10 to the LD10 (20 mg/kg). The drug was rapidly cleared from the plasma (250-400 ml/min per kg) at a rate approaching the cardiac output of mice, displaying triphasic plasma pharmacokinetics. The area under the plasma CI-941 concentration vs time curve (AUC) was linear with respect to the dose, up to and including 15 mg/kg (AUC = 110 microM x min at 15 mg/kg), but became non-linear at 20 mg/kg (AUC = 277 microM x min). Despite 80%-84% plasma protein binding, CI-941 was rapidly and extensively distributed into tissues, especially the kidney. Following i.v. bolus injections at doses of 1.5 and 15 mg/kg, elimination of the parent compound by urinary excretion accounted for 12%-18% of the delivered dose. A phase-I starting dose (based on that equivalent to 1/10 of the LD10 in the mouse) of 5 mg/m2 CI-941 is recommended for single administration schedules. In addition, a pharmacokinetically guided dose-escalation strategy, based on achieving a target AUC of 110 microM x min, is proposed.
authors.affiliation: Drug Development Section, Institute of Cancer Research, Surrey, U.K.
authors.forename: M A
authors.initials: MA
authors.lastname: Graham
authors.forename: D R
authors.initials: DR
authors.lastname: Newell
authors.forename: B J
authors.initials: BJ
authors.lastname: Foster
authors.forename: A H
authors.initials: AH
authors.lastname: Calvert
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D005260:Female; D006321:Heart / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D047069:Pyrazolones; D012640:Seizures / Q000139:chemically induced
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D011720:Pyrazoles; D047069:Pyrazolones; C050637:losoxantrone