Considering Age Variation When Coining Drugs as High Versus Low Hepatic Extraction Ratio

The hepatic extraction ratio (E_H) is commonly considered an “inherent attribute” of drug. It determines the main physiological and biological elements of the system (patient attributes) that are most significant in interindividual variability of clearance. The E_H consists of three age-dependent parameters: fraction of unbound drug in blood (f_u.B), hepatic intrinsic clearance of unbound drug (CL_u.int,H), and hepatic blood flow (Q_H). When the age-effects on these elements are not proportional, a given drug may shift from so-called high extraction status to low extraction. To demonstrate the impact of age-related changes on f_u.B, CL_u.int,H, and Q_H, the E_H of midazolam and two hypothetical drugs with 10-fold higher and 10-fold lower CL_u.int,H than midazolam were investigated in pediatrics based on known ontogeny functions. The E_H was simulated using Simcyp software, version 14. This was then complemented by a comprehensive literature survey to identify the commonly applied covariates in pediatric population pharmacokinetic (PopPK) studies. Midazolam E_H decreased from 0.6 in adults to 0.02 at birth, making its clearance much more susceptible to changes in CL_u.int,H and f_u.B than in adults and reducing the impact of Q_H on clearance. The drug with 10-fold higher CL_u.int,H was categorized as high extraction from 4 days old onward whereas the drug with 10-fold lower CL_u.int,H remained low extraction from birth to adulthood. Approximately 50% of collected PopPK studies (n = 120) did not consider interaction between age and other covariates. Interaction between covariates and age should be considered as part of studies involving younger pediatric patients. The E_H cannot be considered an inherent drug property without considering the effect of age.