Zhao Qiaolin, Naume Marie Mostue, de Winter Brenda C M, Krag Thomas, Haslund-Krog Sissel Sundell, Revsbech Karoline Lolk, Vissing John, Holst Helle, Møller Morten Hylander, Hornsyld Tessa Munkeboe, Dunø Morten, Hoei-Hansen Christina Engel, Born Alfred Peter, Jensen Per Bo, Ørngreen Mette Cathrine
Department of Hospital Pharmacy, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
Rotterdam Clinical Pharmacometrics Group, Rotterdam, the Netherlands.
Br J Clin Pharmacol. 2025 Jul;91(7):2045-2056. doi: 10.1002/bcp.70028. Epub 2025 Mar 4.
The aim of the study was to investigate whether differences in paracetamol pharmacokinetics (PK) between spinal muscular atrophy (SMA) patients and healthy controls (HC) could be attributed to specific clinical covariates.
Nonlinear mixed-effects modelling (NONMEM 7.4) was used to develop a population PK model, explore covariates for paracetamol and its metabolites and perform simulations.
With body weight as allometric scaling in the model, SMA disease resulted in a 58% (95% confidence interval [CI]: 20%-130%) increase in the volume of distribution for paracetamol and its metabolites compared to healthy controls. Decreased plasma myoglobin and plasma bilirubin concentrations, seen in SMA patients, resulted in a higher paracetamol leftover clearance (SMA, median: 13.30 L/h/70 kg, 95% CI: 9.14-18.29%; HC, median: 4.05 L/h/70 kg, 95% CI: 3.38-8.83%) and a shift from slower sulfate formation clearance (SMA, median: 8.78 L/h/70 kg, 95% CI: 7.22-9.61%; HC, median: 9.30 L/h/70 kg, 95% CI: 8.42-10.15%) and faster oxidative metabolites elimination clearance (SMA, median: 3.74 L/h/70 kg, 95% CI: 3.31-4.72%; HC, median: 3.25 L/h/70 kg, 95% CI: 2.87-3.92%). Simulations revealed that in SMA patients, higher bodyweight was associated with increased exposure to paracetamol and its metabolites.
The differences in PK between SMA patients and healthy controls could be explained by body weight and the disease itself. SMA patients should be dosed cautiously, ensuring doses do not exceed the recommended body weight adjusted limit.
本研究旨在调查脊髓性肌萎缩症（SMA）患者与健康对照者（HC）之间对乙酰氨基酚药代动力学（PK）的差异是否可归因于特定的临床协变量。
采用非线性混合效应建模（NONMEM 7.4）建立群体PK模型，探索对乙酰氨基酚及其代谢物的协变量并进行模拟。
在模型中以体重作为异速生长标度，与健康对照者相比，SMA疾病导致对乙酰氨基酚及其代谢物的分布容积增加58%（95%置信区间[CI]：20%-130%）。SMA患者血浆肌红蛋白和血浆胆红素浓度降低，导致对乙酰氨基酚剩余清除率更高（SMA，中位数：13.30 L/h/70 kg，95% CI：9.14-18.29%；HC，中位数：4.05 L/h/70 kg，95% CI：3.38-8.83%），并从较慢的硫酸盐形成清除率（SMA，中位数：8.78 L/h/70 kg，95% CI：7.22-9.61%；HC，中位数：9.30 L/h/70 kg，95% CI：8.42-10.15%）转变为较快的氧化代谢物消除清除率（SMA，中位数：3.74 L/h/70 kg，95% CI：3.31-4.72%；HC，中位数：3.25 L/h/70 kg，95% CI：2.87-3.92%）。模拟显示，在SMA患者中，较高的体重与对乙酰氨基酚及其代谢物的暴露增加有关。
SMA患者与健康对照者之间PK的差异可以通过体重和疾病本身来解释。SMA患者应谨慎给药，确保剂量不超过推荐的体重调整限值。
