Clinical pharmacology of intravenous paracetamol in perinatal medicine

Abstract

Clinical pharmacology aims to predict drug-related effects based on compound and population specific pharmacokinetics (PK, concentration-time), and pharmacodynamics (PD, concentration-effect). Consequently, dosing needs to be based on the physiological characteristics of the individual patient. Pregnancy and early infancy hereby warrant focused assessment. The specific characteristics of both subpopulations will be illustrated based on observations on intravenous (iv) paracetamol PK and PD collected in these specific populations. At delivery, there is a significant higher paracetamol clearance (+ 45%, L/h) when compared to non-pregnant observations. This higher clearance is in part explained by a proportional increase in oxidative metabolite production, but mainly an increase in glucuronidation. When focusing on PD, an association between maternal paracetamol exposure and atopy in infancy and fetal gastroshizis has been reported. In early infancy, paracetamol clearance is significantly lower and mainly depends on size (weight 0.75), while also the distribution volume is higher (L/kg). Reports on hepatic tolerance, haemodynamic stability and impact of body temperature have been published while the concentration effect profile for analgesia seems to be similar between neonates and children. Similar to maternal exposure, there are reports on the association with atopy. Studies on the use of paracetamol to close the patent ductus arteriosus are ongoing. At least, these observations provide evidence on the need to study commonly administered anesthetics in such specific subpopulations with specific focus on both population specific PK and PD to further improve patient tailored pharmacotherapy.

Keywords: Pregnancy, Newborn, Intravenous paracetamol, Pharmacokinetics

Core tip: Although urgently needed to further improve patient tailored pharmacotherapy, data on the clinical pharmacology in pregnant women and young infants are limited, even for commonly used drugs like paracetamol. We summarize the available observations on both pharmacokinetics and pharmacodynamics of intravenous paracetamol in pregnant women and early infancy to illustrate the relevance of subpopulation specific observations. This includes differences in metabolic routes of elimination, in (side) effects (e.g., analgesia, hypotension, atopy) and in potential indications (patent ductus arteriosus).