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

The hepatic extraction ratio (EH) 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 (CLu.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), CLu.int,H, and Q(H), the E-H of midazolam and two hypothetical drugs with 10-fold higher and 10-fold lower CLu.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 CLu.int, H and f(u). B than in adults and reducing the impact of Q(H) on clearance. The drug with 10-fold higher C-Lu.int,C-H was categorized as high extraction from 4 days old onward whereas the drug with 10-fold lower CLu.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.