Pharmacokinetics and tolerability of the orally active selective epidermalgrowth factor receptor tyrosine kinase inhibitor ZD1839 in healthy volunteers

Objective: To investigate the pharmacokinetics and tolerability of ZD 1839 (Iressa (TM)). an orally active selective epidermal growth factor receptor- tyrosine kinase inhibitor, in healthy volunteers. Design: Two randomised, d ouble-blind, placebo-controlled, parallel-group studies of pharmacokinetics and tolerability, followed by a nonblind, randomised. 2-period crossover s tudy to assess the effect of food on bioavailability. Setting: Two centres in the UK. Study participants: Healthy male volunteers aged between 18 and 62 years. Interventions: The first study investigated the pharmacokinetics and tolera bility of ascending single oral doses of ZD1839 (1 to 75mg). The second stu dy investigated the pharmacokinetics and tolerability of multiple: doses of ZD1839 (100mg once daily for 3 days). The third study investigated the eff ect of food on the bioavailability of a single 50mg dose of ZD 1839. Outcome measures and results: Peak plasma drug concentrations (C-max) of ZD 1839 occurred between 3 and 7 hours after administration. C-max and area un der the concentration-time curve (AUC) were dose-proportional from 10 to 10 0mg. The terminal elimination half-life (t(1/2 beta)) was 28 hours (range 1 2 to 51 hours). Cmax was reduced by 34% and AUC by 14% by ingestion of food : t(1/2 beta) was not affected. Urinary recovery of ZD1839 was <0.5%. indic ating that this was not a major route of elimination. The pharmacokinetics of ZD1839 during administration of multiple doses could be predicted from d ay 1 values. There were no serious adverse events or withdrawals, and the f requency of adverse events was similar that with placebo. Conclusions: These data support the further clinical investigation of ZD183 9. The elimination half-life suggests that once daily oral administration i s appropriate.