Abstract
Hepatic extraction ratio (EH) is commonly considered as 'an inherent attribute' of drug. It determines the main physiological and biological elements of the system (patient attributes) which are most significant in inter-individual variability of clearance. EH consists of three age-dependent parameters: fraction of unbound drug in blood (fuB), hepatic intrinsic clearance of unbound drug (CLuint,H) and hepatic blood flow (QH). When 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 fuB, CLuint,H and QH, EH of midazolam and two hypothetical drugs with 10-fold higher and 10-fold lower CLuint,H than midazolam were investigated in paediatrics based on known ontogeny functions. EH was simulated using Simcyp V14. This was then complemented by a comprehensive literature survey to identify commonly applied covariates in paediatric population pharmacokinetic (PopPK) studies. Midazolam EH decreased from 0.6 in adults to 0.02 at birth, making its clearance much more susceptible to changes in CLuint,H and fuB than adults and reducing impact of QH on clearance. The drug with 10-fold higher CLuint,H was categorised as high extraction from 4 days old onwards, whilst the drug with 10-fold lower CLuint,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 young paediatric patients. EH cannot be considered as an inherent drug property without considering the effect of age.
- The American Society for Pharmacology and Experimental Therapeutics