Faisal Muhammad, Cawello Willi, Burckhardt Bjoern B, de Hoon Jan, Laer Stephanie
Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Center for Clinical Pharmacology, University Hospitals Leuven/KU Leuven, Leuven, Belgium.
Front Pediatr. 2019 Jul 9;7:281. doi: 10.3389/fped.2019.00281. eCollection 2019.
Enalapril is recommended as the first line of therapy and is proven to improve survival rates for treatment of Pediatric Heart Failure; however, an approved drug and child appropriate dosage formulation is still absent. The present analysis was conducted to perform a detailed model informed population pharmacokinetic analysis of prodrug enalapril and its active metabolite enalaprilat in serum and urine. Further, a model informed dosage form population-pharmacokinetic analysis was conducted to evaluate differences in pharmacokinetics of enalapril and its active metabolite enalaprilat when prodrug was administered to 24 healthy adults in a crossover, two periods, two treatments, phase I clinical trial using child-appropriate orodispersible mini-tablets (ODMT) and reference (Renitec®) dosage formulation. A simultaneous semi-mechanistic population-pharmacokinetic model was developed using NONMEM software, which predicted full profile serum and urine concentrations of enalapril and enalaprilat. First-order conditional estimation with interaction was used for parameter estimation. Transit compartments added using Erlang distribution method to predicted enalapril absorption and enalaprilat formation phases. Normalized body weight was identified as covariate related to enalapril volume of distribution. Visual predictive check (VPC) plots and conducted bootstrap analysis validated the model. The data from the two formulations were pooled for population-pharmacokinetic analysis and covariate effect of the formulation was found on mean transit time (MTT1) of enalapril absorption. In addition, data of each formulation were modeled separately and the estimated parameters of each individual administered both formulations were correlated using paired samples Wilcoxon rank test ( < 0.05 = significant) which also showed only a significant difference ( = 0.03) in MTT1 i.e., 5 min early appearance of enalapril from ODMT compared to reference tablets. No difference in the pharmacokinetics of active enalaprilat was found from the ODMT compared to the reference formulation. The population pharmacokinetic analysis provided detailed information about the pharmacokinetics of enalapril and enalaprilat, which showed that the ODMT formulation might have similar pharmacodynamic response compared to the reference formulation.
依那普利被推荐作为一线治疗药物，且已证实其可提高小儿心力衰竭的治疗存活率；然而，目前仍缺乏经批准的药物及适合儿童的剂型。本分析旨在对前体药物依那普利及其活性代谢产物依那普利拉在血清和尿液中的情况进行详细的模型引导群体药代动力学分析。此外，进行了模型引导剂型群体药代动力学分析，以评估在前体药物以适合儿童的口腔崩解片（ODMT）和参比制剂（Renitec®）剂型，采用交叉、两阶段、两种治疗方案的I期临床试验中给予24名健康成年人时，依那普利及其活性代谢产物依那普利拉的药代动力学差异。使用NONMEM软件建立了一个同步半机制群体药代动力学模型，该模型可预测依那普利和依那普利拉的血清和尿液全时程浓度。采用带交互作用的一阶条件估计法进行参数估计。使用Erlang分布方法添加转运室以预测依那普利的吸收和依那普利拉的形成阶段。确定标准化体重为与依那普利分布容积相关的协变量。视觉预测检查（VPC）图和自抽样分析验证了该模型。将两种剂型的数据合并进行群体药代动力学分析，发现剂型对依那普利吸收的平均转运时间（MTT1）有协变量效应。此外，分别对每种剂型的数据进行建模，并使用配对样本Wilcoxon秩和检验（<0.05为显著）对两种剂型给药的每个个体的估计参数进行相关性分析，结果也仅显示MTT1有显著差异（=0.03），即与参比片剂相比，依那普利从ODMT中出现的时间提前5分钟。与参比制剂相比，ODMT中活性依那普利拉的药代动力学未发现差异。群体药代动力学分析提供了依那普利和依那普利拉药代动力学的详细信息，表明ODMT剂型与参比制剂可能具有相似的药效学反应。
