Characterization of contributing factors to variability in morphine clearance through PBPK modeling implemented with OCT1 transporter

Abstract

Morphine shows large interindividual variability in its pharmacokinetics; however, the cause of this has not been fully addressed. The variability in morphine disposition is considered to be due to a combination of pharmacogenetic and physiological determinants related to morphine disposition. We previously reported the effect of organic cation transporter (OCT1) genotype on morphine disposition in pediatric patients. To further explore the underlying mechanisms for variability arising from relevant determinants, including OCT1, a physiologically based pharmacokinetic (PBPK) model of morphine was developed. The PBPK model predicted morphine concentration-time profiles well, in both adults and children. Almost all of the observed morphine clearances in pediatric patients fell within a twofold range of median predicted values for each OCT1 genotype in each age group. This PBPK modeling approach quantitatively demonstrates that OCT1 genotype, age-related growth, and changes in blood flow as important contributors to morphine pharmacokinetic (PK) variability.