Fischer James H, Sarto Gloria E, Hardman Jennifer, Endres Loraine, Jenkins Thomas M, Kilpatrick Sarah J, Jeong Hyunyoung, Geller Stacie, Deyo Kelly, Fischer Patricia A, Rodvold Keith A
Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 833 S Wood Street, Room 164, Chicago, IL, 60612, USA,
Clin Pharmacokinet. 2014 Apr;53(4):373-83. doi: 10.1007/s40262-013-0123-0.
Labetalol is frequently prescribed for the treatment of hypertension during pregnancy; however, the influence of pregnancy on labetalol pharmacokinetics is uncertain, with inconsistent findings reported by previous studies. This study examined the population pharmacokinetics of oral labetalol during and after pregnancy in women receiving labetalol for hypertension.
Data were collected from 57 women receiving the drug for hypertension from the 12th week of pregnancy through 12 weeks postpartum using a prospective, longitudinal design. A sparse sampling strategy guided collection of plasma samples. Samples were assayed for labetalol by high-performance liquid chromatography. Estimation of population pharmacokinetic parameters and covariate effects was performed by nonlinear mixed effects modeling using NONMEM. The final population model was validated by bootstrap analysis and visual predictive check. Simulations were performed with the final model to evaluate the appropriate body weight to guide labetalol dosing.
Lean body weight (LBW) and gestational age, i.e. weeks of pregnancy, were identified as significantly influencing oral clearance (CL/F) of labetalol, with CL/F ranging from 1.4-fold greater than postpartum values at 12 weeks' gestational age to 1.6-fold greater at 40 weeks. Doses adjusted for LBW provide more consistent drug exposure than doses adjusted for total body weight. The apparent volumes of distribution for the central compartment and at steady-state were 1.9-fold higher during pregnancy.
Gestational age and LBW impact the pharmacokinetics of labetalol during pregnancy and have clinical implications for adjusting labetalol doses in these women.
拉贝洛尔常用于治疗妊娠期高血压；然而，妊娠对拉贝洛尔药代动力学的影响尚不确定，既往研究报告的结果并不一致。本研究探讨了接受拉贝洛尔治疗高血压的女性在孕期及产后口服拉贝洛尔的群体药代动力学。
采用前瞻性纵向设计，收集了57名从妊娠第12周开始至产后12周接受该药物治疗高血压的女性的数据。采用稀疏采样策略指导血浆样本的采集。通过高效液相色谱法测定样本中的拉贝洛尔。使用NONMEM通过非线性混合效应模型估计群体药代动力学参数和协变量效应。通过自抽样分析和可视化预测检验对最终群体模型进行验证。使用最终模型进行模拟，以评估指导拉贝洛尔给药的合适体重。
瘦体重（LBW）和孕周（即妊娠周数）被确定为对拉贝洛尔口服清除率（CL/F）有显著影响，CL/F在妊娠12周时比产后值高1.4倍，在妊娠40周时高1.6倍。根据LBW调整的剂量比根据总体重调整的剂量能提供更一致的药物暴露。孕期中央室和稳态时的表观分布容积高出1.9倍。
孕周和LBW会影响孕期拉贝洛尔的药代动力学，对调整这些女性的拉贝洛尔剂量具有临床意义。
