Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA.
Br J Clin Pharmacol. 2022 Feb;88(4):1441-1451. doi: 10.1111/bcp.15018. Epub 2021 Aug 26.
Physiologically based pharmacokinetic (PBPK) models have been previously developed for betamethasone and buprenorphine for pregnant women. The goal of this work was to replicate and reassess these models using data from recently completed studies.
Betamethasone and buprenorphine PBPK models were developed in Simcyp V19 based on prior publications using V17 and V15. Ability to replicate models was verified by comparing predictions in V19 to those previously published. Once replication was verified, models were reassessed by comparing predictions to observed data from additional studies in pregnant women. Model performance was based upon visual inspection of concentration vs. time profiles, and comparison of pharmacokinetic parameters. Models were deemed reproducible if parameter estimates were within 10% of previously reported values. External validations were considered acceptable if the predicted area under the concentration-time curve (AUC) and peak plasma concentration fell within 2-fold of the observed.
The betamethasone model was successfully replicated using Simcyp V19, with ratios of reported (V17) to reproduced (V19) peak plasma concentration of 0.98-1.04 and AUC of 0.95-1.07. The model-predicted AUC ratios ranged from 0.98-1.79 compared to external data. The previously published buprenorphine PBPK model was not reproducible, as we predicted intravenous clearance of 70% that reported previously (both in Simcyp V15).
While high interstudy variability was observed in the newly available clinical data, the PBPK model sufficiently predicted changes in betamethasone exposure across gestation. Model reproducibility and reassessment with external data are important for the advancement of the discipline. PBPK modelling publications should contain sufficient detail and clarity to enable reproducibility.
先前已经为孕妇建立了倍他米松和丁丙诺啡的基于生理学的药代动力学（PBPK）模型。本研究的目的是使用最近完成的研究数据复制和重新评估这些模型。
基于先前在 V17 和 V15 版本中发表的研究成果，在 Simcyp V19 中开发了倍他米松和丁丙诺啡的 PBPK 模型。通过比较 V19 中的预测值与之前发表的值，验证了模型的复制能力。验证复制后，通过将预测值与来自孕妇的其他研究中的观察数据进行比较，重新评估了模型。基于浓度-时间曲线的直观检查和药代动力学参数的比较来评估模型性能。如果参数估计值在之前报告的值的 10%以内，则认为模型可重现。如果预测的浓度-时间曲线下面积（AUC）和血浆峰浓度与观察值相差在 2 倍以内，则认为外部验证是可接受的。
成功地使用 Simcyp V19 复制了倍他米松模型，报告的（V17）与重现的（V19）峰值血浆浓度的比值为 0.98-1.04，AUC 的比值为 0.95-1.07。模型预测的 AUC 比值范围为 0.98-1.79，与外部数据相比。先前发表的丁丙诺啡 PBPK 模型不可重现，因为我们预测静脉清除率为 70%，而先前在 Simcyp V15 中报告的为 70%。
虽然新获得的临床数据显示出高度的研究间变异性，但 PBPK 模型充分预测了倍他米松暴露在妊娠期间的变化。模型的重现性和使用外部数据进行重新评估对于该学科的发展很重要。PBPK 建模出版物应包含足够的详细信息和清晰度，以实现可重现性。
