Effects of impaired renal function on the pharmacokinetics and toxicity of i.v. ZD9331, a novel non-polyglutamated thymidylate synthase inhibitor, in adult patients with solid tumors

ZD9331 is a potent thymidylate synthase inhibitor. Renal and hepatic clearances were found to be important routes of elimination. The objectives of this pharmacologic trial were to investigate the effect of renal impairment on the pharmacokinetics of ZD9331, to study the toxicity profile and to document any antitumor effects of ZD9331 when administered i.v. to patients with different degrees of renal impairment. Patients were treated with ZD9331 130 mg/m(2) given as an i.v. infusion on day 1 of a 4-week cycle to allow full pharmacokinetic assessment. Subsequent cycles involved the administration of ZD9331 on days 1 and 8, every 3 weeks. Patients were stratified according to their renal function assessed by the creatinine clearance: normal renal function (creatinine clearance greater than or equal to 60 ml/min), mildly impaired renal function (creatinine clearance greater than or equal to40 to 25 to