Pharmacokinetics and tolerability of the orally active selective epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in healthy volunteers.
OBJECTIVE
To investigate the pharmacokinetics and tolerability of ZD1839 (Iressa), an orally active selective epidermal growth factor receptor-tyrosine kinase inhibitor, in healthy volunteers.


METHODS
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.


METHODS
Two centres in the UK.


METHODS
Healthy male volunteers aged between 18 and 62 years.


METHODS
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.


RESULTS
Peak plasma drug concentrations (Cmax) of ZD 1839 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 (t1/2beta) was 28 hours (range 12 to 51 hours). Cmax was reduced by 34% and AUC by 14% by ingestion of food; t1/2beta was not affected. Urinary recovery of ZD1839 was <0.5%, indicating that this was not a major route of elimination. The pharmacokinetics of ZD1839 during administration of multiple doses could be predicted from day 1 values. There were no serious adverse events or withdrawals, and the frequency of adverse events was similar that with placebo.


CONCLUSIONS
These data support the further clinical investigation of ZD 1839. The elimination half-life suggests that once daily oral administration is appropriate.
Swaisland
H
H
AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, England. Helen.Swaisland@astrazeneca.com
Laight
A
A
Stafford
L
L
Jones
H
H
Morris
C
C
Dane
A
A
Yates
R
R
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000009:adverse effects* / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib