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.