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/m2 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 > or =60 ml/min), mildly impaired renal function (creatinine clearance > or =40 to <60 ml/min) and moderately impaired renal function (creatinine clearance >25 to <40 ml/min). For pharmacokinetic analysis plasma sampling was performed during the first course and assayed using a validated liquid chromatographic tandem mass spectrometry assay. Twenty-three patients were entered on the study, of whom 21 received 130 mg/m2 ZD9331 in the first treatment cycle. No relationship was seen between renal impairment and plasma clearance nor with the area under the concentration-time curve of free ZD9331. Increasing renal impairment was associated with a greater incidence of myelosuppression. No predictive relationship between the clearance of free ZD9331 and the degree of renal impairment as determined by creatinine clearance could be assessed. However, data from this trial indicate that increased renal impairment may be associated with greater ZD9331-induced toxicity, particularly myelosuppression, although this cannot be attributed to any alteration in the plasma pharmacokinetics of ZD9331. Therefore, it may be necessary to administer a reduced dose of ZD9331 to patients with impaired renal function.