The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups-An Investigation Using Physiologically Based Pharmacokinetic Modelling

Abstract

Background: pathophysiological changes such as 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, manual infusion 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, and 25% in adolescents and adults.

Conclusions: PBPK-driven, the impact of reduced CO on propofol clearance is predicted to be age-dependent, and proportionally greater in adults. Consequently, age group-specific dose reductions for propofol are required in LCO conditions.

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

Figure 1

Predicted changes in hepatic extraction ratio (E_H) and renal extraction ratio (E_R) with age. Red circle and line: E_H; blue circle and line: E_R; black broken lines: low extraction ratio target (0.3) and high extraction ratio target (0.7). Data points and error bars represent mean and standard deviations of predicted extraction ratios, respectively.

Figure 2

Predicted changes in systemic clearance of propofol under normal or reduced CO conditions. (a) Predicted changes in absolute clearance with age. (b) Predicted changes in absolute clearance with age under reduced CO conditions. (c) Relative percentage changes in systemic clearance under reduced CO conditions with age. Open circles represent individual clearance in virtual subjects. (b) Absolute clearance and (c) relative change in clearance of propofol under reduced cardiac output conditions across age groups. For all Figure 2a–c, black open circle and line, red circles and line, blue squares and line, green triangle and line and brown inverted triangles and line represent clearance under normal, 20%, 30%, 40% and 50%-reduced cardiac reduction, respectively.

Figure 3

Simulated propofol plasma concentrations under various cardiac output conditions. Solid green, red, blue, yellow and black lines represent the predicted mean plasma propofol concentration under 50%, 40%, 30%, 20% and normal cardiac output (CO) conditions, respectively. Dotted green and black lines represent the predicted 95th and 5th percentile of the highest and least predicted mean concentration. The bold black dashed line is plasma concentration achieved at 2 h and the grey shaded area bordered by a thin black dashed line is 80–125% of target plasma concentration achieved at 2 h.

Figure 4

Predicted C_2H concentrations achieved following dosing optimization. Distribution of predicted individual plasma concentrations of propofol at 2 h after start of dosing under 40%-reduced CO conditions (blue plots) and 50%-reduced CO conditions (red plots). The black line is the mean concentration under normal CO conditions and the grey shaded area bordered by a thin black dashed line is the target concentration range. DR: dose reduction.