Pharmacokinetics and Tolerability of the Orally Active Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 in Healthy Volunteers

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Abstract
Objective: To investigate the pharmacokinetics and tolerability of ZD1839 (Iressa™), an orally active selective epidermal growth factor receptor-tyrosine kinase inhibitor, in healthy volunteers. Design: Two randomised, double-blind, placebo-controlled, parallel-group studies of pharmacokinetics and tolerability, followed by a nonblind, randomised, 2-period crossover study 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 tolerability of ascending single oral doses of ZD1839 (1 to 75mg). The second study investigated the pharmacokinetics and tolerability of multiple doses of ZD1839 (100mg once daily for 3 days). The third study investigated the effect of food on the bioavailability of a single 50mg dose of ZD1839. Outcome measures and results: Peak plasma drug concentrations (Cmax) of ZD1839 occurred between 3 and 7 hours after administration. Cmax and area under the concentration-time curve (AUC) were dose-proportional from 10 to 100mg. The terminal elimination half-life (t1/2β) was 28 hours (range 12 to 51 hours). Cmax was reduced by 34% and AUC by 14% by ingestion of food; t1/2β was not affected. Urinary recovery of ZD1839 was Conclusions: These data support the further clinical investigation of ZD1839. The elimination half-life suggests that once daily oral administration is appropriate.