Department of Pharmacy, Fukuoka City Hospital, Fukuoka City Hospital Organization, Local Incorporated Administrative Agency, Fukuoka, Japan.
Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Br J Clin Pharmacol. 2022 Aug;88(8):3819-3828. doi: 10.1111/bcp.15333. Epub 2022 Apr 6.
Theophylline clearance is known to be reduced in patients with chronic liver diseases (CLDs) such as chronic hepatitis (CH) and liver cirrhosis (LC). The Child-Pugh (CP) score is generally used for pharmacokinetic evaluation, whilst a model for end-stage liver disease (MELD) has not yet been fully evaluated. This study aimed to predict theophylline clearance in patients with LC classified based on CP and MELD scores by population pharmacokinetic (PPK) analysis.
PPK analysis included 433 steady-state trough concentrations from 192 Japanese bronchial asthma patients with and without CLDs and was performed using NONMEM. The severity of LC was assessed by CP and MELD scores.
The final CP and MELD models which described apparent theophylline clearance (CL/F) were obtained. The CP model showed that the mean CL/F in patients without CLDs, CH patients and LC patients with CP class A, B and C was 0.0473, 0.0413, 0.0330, 0.0280 and 0.0209 L/h kg , respectively. The MELD model predicted that CL/F in patients without CLDs, CH patients and LC patients with MELD scores of <10, 10-14, 15-19, 20-24 and ≥25 was 0.0472, 0.0413, 0.0324, 0.0268, 0.0230, 0.0197 and 0.0155 L/h kg , respectively.
CL/F in various stages of LC was evaluated, and a change in CL/F was highly dependent on the severity of CLDs in both models. The MELD model provided a more accurate and precise description of theophylline clearance in LC than the CP model, which may be due to the wider dynamic range of the MELD score.
已知茶碱清除率在慢性肝病（CLD）患者中降低，如慢性肝炎（CH）和肝硬化（LC）。Child-Pugh（CP）评分通常用于药代动力学评估，而终末期肝病模型（MELD）尚未得到充分评估。本研究旨在通过群体药代动力学（PPK）分析预测基于 CP 和 MELD 评分的 LC 患者的茶碱清除率。
PPK 分析包括 192 例日本支气管哮喘患者和合并 CLD 患者的 433 个稳态谷浓度，采用 NONMEM 进行分析。LC 的严重程度通过 CP 和 MELD 评分评估。
得到了描述茶碱表观清除率（CL/F）的最终 CP 和 MELD 模型。CP 模型显示，无 CLD 患者、CH 患者和 CP 分级 A、B 和 C 的 LC 患者的平均 CL/F 分别为 0.0473、0.0413、0.0330、0.0280 和 0.0209 L/h/kg。MELD 模型预测，无 CLD 患者、CH 患者和 MELD 评分<10、10-14、15-19、20-24 和≥25 的 LC 患者的 CL/F 分别为 0.0472、0.0413、0.0324、0.0268、0.0230、0.0197 和 0.0155 L/h/kg。
评估了 LC 各个阶段的 CL/F，两种模型中 CL/F 的变化均高度依赖于 CLD 的严重程度。与 CP 模型相比，MELD 模型能更准确和精确地描述 LC 中的茶碱清除率，这可能是由于 MELD 评分的动态范围更广。
