State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences (ICMS), University of Macau, Macau, China.
Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
Pharm Res. 2023 Jul;40(7):1765-1775. doi: 10.1007/s11095-023-03523-y. Epub 2023 May 4.
Labetalol has an irreplaceable role in treating Hypertensive disorders of pregnancy (HDP), a common disease during pregnancy with a prevalence of 5.2-8.2%. However, there were big differences in dosage regimens between various guidelines.
A physiologically-based pharmacokinetics (PBPK) model was established and validated to evaluate the existing oral dosage regimens, and to compare the difference in plasma concentration between pregnant and non-pregnant women.
First, non-pregnant woman models with specific plasma clearance or enzymatic metabolism (UGT1A1, UGT2B7, CYP2C19) were established and validated. For CYP2C19, slow, intermediate, and rapid metabolic phenotypes were considered. Then, a pregnant model with proper structure and parameters adjustment was established and validated against the multiple oral administration data.
The predicted labetalol exposure captured the experimental data well. The following simulations with criteria lowering 15 mmHg blood pressure (corresponding to around 108 ng/ml plasma labetalol) found that the maximum daily dosage in the Chinese guideline may be insufficient for some severe HDP patients. Moreover, similar predicted steady-state trough plasma concentration was found between the maximum daily dosage in the American College of Obstetricians and Gynecologists (ACOG) guideline, 800 mg Q8h and a regimen of 200 mg Q6h. Simulations comparing non-pregnant and pregnant women found that the difference in labetalol exposure highly depended on the CYP2C19 metabolic phenotype.
In summary, this work initially established a PBPK model for multiple oral administration of labetalol for pregnant women. This PBPK model may lead to personalized labetalol medication in the future.
拉贝洛尔在治疗妊娠期高血压疾病（HDP）中具有不可替代的作用，HDP 是一种常见的妊娠疾病，患病率为 5.2-8.2%。然而，不同指南中的剂量方案存在很大差异。
建立并验证一个基于生理学的药代动力学（PBPK）模型，以评估现有的口服剂量方案，并比较妊娠妇女与非妊娠妇女之间的血浆浓度差异。
首先，建立并验证了具有特定血浆清除率或酶代谢（UGT1A1、UGT2B7、CYP2C19）的非妊娠妇女模型。对于 CYP2C19，考虑了慢代谢、中代谢和快代谢表型。然后，建立并验证了一个合适结构和参数调整的妊娠模型，以对抗多次口服给药数据。
预测的拉贝洛尔暴露情况很好地捕捉到了实验数据。随后根据降低 15mmHg 血压（相当于约 108ng/ml 血浆拉贝洛尔）的标准进行模拟，发现中国指南中的最大日剂量可能对一些严重的 HDP 患者不足。此外，还发现美国妇产科医师学会（ACOG）指南中的最大日剂量 800mg Q8h 与 200mg Q6h 方案之间，稳态谷浓度的预测值相似。模拟比较非妊娠和妊娠妇女发现，拉贝洛尔暴露的差异高度依赖于 CYP2C19 的代谢表型。
总之，本工作初步建立了用于妊娠妇女多次口服拉贝洛尔的 PBPK 模型。该 PBPK 模型未来可能会导致拉贝洛尔的个体化用药。
