Allegaert Karel, Abbasi Mohammad Yaseen, Michelet Robin, Olafuyi Olusola
Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium.
Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
Pharmaceutics. 2022 Sep 16;14(9):1957. doi: 10.3390/pharmaceutics14091957.
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.
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.
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.
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.
低心输出量（LCO）等病理生理变化会影响药代动力学，但与成人相比，其在儿科各年龄段的影响程度可能有所不同。基于生理的药代动力学（PBPK）建模有助于进一步探索。
使用经过验证的丙泊酚模型，通过PBPK平台Simcyp（版本19）模拟LCO对各年龄组丙泊酚清除率的影响。然后测定所有年龄组丙泊酚的肝提取率和肾提取率。随后，在LCO条件下进行手动输注剂量探索，目标是丙泊酚浓度范围为3μg/mL（80 - 125%）。
从新生儿、婴儿、儿童到青少年及成人，肝提取率和肾提取率均升高。随着年龄增长，心输出量降低后清除率的相对变化增加，LCO对新生儿的影响最小。在所有年龄组的正常心输出量和LCO（高达30%）条件下，预测浓度保持在3μg/mL（80 - 125%）范围内。当心输出量降低40 - 50%时，新生儿、婴儿和儿童需要减少15%的剂量，青少年和成人需要减少25%的剂量。
在PBPK驱动下，预计心输出量降低对丙泊酚清除率的影响具有年龄依赖性，且在成人中影响更大。因此，在LCO条件下，丙泊酚需要根据年龄组进行特定剂量的减少。
