Population pharmacokinetics of erlotinib in Japanese patients with advanced non-small cell lung cancer.
OBJECTIVE
This study aimed to elucidate the pharmacokinetics of erlotinib in Japanese patients with advanced non-small cell lung cancer (NSCLC) and to investigate the relationship between erlotinib exposure and the occurrence of interstitial lung disease (ILD)-like events.


METHODS
Population pharmacokinetics analysis was performed using nonlinear mixed-effects modelling software (NONMEM) based on 348 plasma samples from 97 patients obtained in two phase II clinical studies. Individual empirical Bayesian estimates (EBEs) of apparent oral clearance (CL/F) and Cmax were compared between the patients who developed and did not develop ILD-like events.


RESULTS
A 1-compartment model with first-order absorption and first-order elimination was used to describe the plasma concentrations of erlotinib. The estimated population pharmacokinetics parameters were as follows: 4·71 L/h for CL/F, 163 L for apparent volume of distribution (Vc /F) and 1·97 h(-1) for absorption rate constant (Ka ). Total bilirubin (TBIL) and alpha 1-acid glycoprotein (AGP) were identified as statistically significant covariates for CL/F. No differences in CL/F and Cmax were observed between the patients with ILD-like events and those without ILD-like events.


CONCLUSIONS
A population pharmacokinetics model of erlotinib was developed and validated in Japanese patients. There was no relationship between exposure of erlotinib before the occurrence of ILD-like events and the occurrence of ILD-like events when erlotinib was administered at the same dosage. The high plasma concentration of erlotinib reported in patients after the onset of ILD-like events may be explained by CL/F decrease which occurs along with increasing levels of AGP which was identified as a covariate for CL/F.
Clinical Research Planning Department, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan.
Y
Y
Emoto-Yamamoto
S
S
Iida
T
T
Kawanishi
M
M
Fukuoka
D000328:Adult; D000368:Aged; D044466:Asian People; D001499:Bayes Theorem; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D000069347:Erlotinib Hydrochloride / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use
D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride
advanced non-small cell lung cancer; erlotinib; interstitial lung disease; nonlinear mixed-effects modelling; population pharmacokinetics