Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups - an Investigation using Physiologically based Pharmacokinetic Modelling

Version 1 : Received: 5 August 2022 / Approved: 8 August 2022 / Online: 8 August 2022 (06:12:36 CEST)

A peer-reviewed article of this Preprint also exists.

Allegaert, K.; Abbasi, M.Y.; Michelet, R.; Olafuyi, O. The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups—An Investigation Using Physiologically Based Pharmacokinetic Modelling. Pharmaceutics 2022, 14, 1957. Allegaert, K.; Abbasi, M.Y.; Michelet, R.; Olafuyi, O. The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups—An Investigation Using Physiologically Based Pharmacokinetic Modelling. Pharmaceutics 2022, 14, 1957.

Journal reference: Pharmaceutics 2022, 14, 1957
DOI: 10.3390/pharmaceutics14091957

Abstract

Background: pathophysiological changes like low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used to simulate the impact of LCO on propofol clearance across age groups using the PBPK platform, Simcyp® (version 19). The hepatic and renal extraction ratio of propofol was then determined in all age groups. Subsequently, dose explorations were conducted under LCO conditions, targeting a 3 µg/mL (80-125%) propofol concentration range. Results: Both hepatic and renal extraction ratios increased from neonates, infants, children to adolescents and adults. The relative change in clearance following CO reductions increased with age, with the least impact of LCO in neonates. The predicted concentration remained within the 3 µg/mL (80-125%) range under normal CO and LCO (up to 30%) conditions in all age groups. When CO was reduced by 40-50%, a dose reduction of 15% is warranted in neonates, infants and children, 25% in adolescents and adults. Conclusions: PBPK driven, the impact of reduced CO on propofol clearance is predicted to be age-dependent, proportionally greater in adults. Consequently, age group specific dose reductions for propofol are required in LCO conditions.

Keywords

physiologically based pharmacokinetic modelling; propofol; low cardiac output; pharmacokinetics; neonate; developmental pharmacology; asphyxia; hypothermia; pediatrics; pharmacokinetics

Subject

MEDICINE & PHARMACOLOGY, Pharmacology & Toxicology

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