WHAT IS KNOWN AND 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. WHAT IS NEW AND 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.
WHAT IS KNOWN AND 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. WHAT IS NEW AND 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.
Authors: Marie-Rose B S Crombag; Jacobine G C van Doremalen; Julie M Janssen; Hilde Rosing; Jan H M Schellens; Jos H Beijnen; Neeltje Steeghs; Alwin D R Huitema Journal: Br J Clin Pharmacol Date: 2018-09-26 Impact factor: 4.335