A Re-evaluation and Validation of Ontogeny Functions for Cytochrome P450 1A2 and 3A4 Based on In Vivo Data

Abstract

Current cytochrome P450 (CYP) 1A2 and 3A4 ontogeny profiles, which are derived mainly from in vitro studies and incorporated in paediatric physiologically based pharmacokinetic models, have been reported to under-predict the in vivo clearances of some model substrates in neonates and infants. We report ontogeny functions for these enzymes as paediatric to adult relative intrinsic clearance per mg of hepatic microsomal protein, based on the deconvolution of in vivo pharmacokinetic data and by accounting for the impact of known clinical condition on hepatic unbound intrinsic clearance for caffeine and theophylline as markers of CYP1A2 activity and for midazolam as a marker of CYP3A4 activity. The function for CYP1A2 describes an increase in relative intrinsic metabolic clearance from birth to 3years followed by a decrease to adult values. The function for CYP3A4 describes a continuous rise in relative intrinsic metabolic clearance, reaching the adult value at about 1.3years of age. The new models were validated by showing improved predictions of the systemic clearances of ropivacaine (major CYP1A2 substrate; minor CYP3A4 substrate) and alfentanil (major CYP3A4 substrate) compared with those using a previous ontogeny function based on in vitro data (alfentanil: mean squared prediction error 3.0 vs. 6.8; ropivacaine: mean squared prediction error 2.3 vs.14.2). When implementing enzyme ontogeny functions, it is important to consider potential confounding factors (e.g. disease) that may affect the physiological conditions of the patient and, hence, the prediction of net in vivo clearance.