Medical physiology and drug disposition in special populations: from compound specific observations to physiology based pharmacokinetics

摘要

The general pharmacokinetic principles of disposition and elimination of exogenous compounds apply, irrespective of population specific characteristics. However, perinatal characteristics like pregnancy or early infancy warrant a focussed approach because important alterations in physiology (either pregnancy or maturation, age-related changes) affect drug disposition in a clinical relevant way. During pregnancy, there are changes in distribution volume due to changes in body composition, in metabolic activity affecting drug metabolism and in renal elimination (GFR, tubular) capacity. In early neonatal life, maturational changes in drug disposition are most prominent Almost all phase I and phase II metabolic processes display ontogeny in an iso-enzyme specific pattern while renal elimination clearance in early life is low. The link between pregnancy related changes in medical physiology and changes in drug disposition will be illustrated based on aspects of cefazolin disposition during pregnancy while the complex interaction between maturation, genetic polymorphisms and renal elimination in early life will be illustrated based on tramadol observations in early life. We hereby aim to stress the relevance to link medical physiology with clinical pharmacology through physiology based models in order to improve predictability of clinical pharmacology in these specific populations. Beyond the anecdotal observations, patterns related to medical physiology are unveiled.