Department of Mathematics and Applied Mathematics, University of Johannesburggrid.412988.e, Johannesburg, South Africa.
Antimicrob Agents Chemother. 2022 Sep 20;66(9):e0027422. doi: 10.1128/aac.00274-22. Epub 2022 Jul 19.
Physiologically based pharmacokinetic (PBPK) models have gained in popularity in the last decade in both drug development and regulatory science. PBPK models differ from classical pharmacokinetic models in that they include specific compartments for tissues involved in exposure, toxicity, biotransformation, and clearance processes connected by blood flow. This study aimed to address the gaps between the mathematics and pharmacology framework observed in the literature. These gaps included nonconserved systems of equations and compartment concentration that were not biologically relatable to the tissues of interest. The resulting system of nonlinear differential equations is solved numerically with various methods for benchmarking and comparison. Furthermore, a sensitivity analysis of all parameters were conducted to elucidate the critical parameters of the model. The resulting model was fit to clinical data as a performance benchmark. The clinical data captured the second line of antiretroviral treatment, lopinavir and ritonavir. The model and clinical data correlate well for coadministration of lopinavir/ritonavir with rifampin. Drug-drug interaction was captured between lopinavir and rifampin. This article provides conclusions about the suitability of physiologically based pharmacokinetic models for the prediction of drug-drug interaction and antiretroviral and anti-TB pharmacokinetics.
在过去十年中，生理药代动力学（PBPK）模型在药物开发和监管科学中越来越受欢迎。PBPK 模型与经典药代动力学模型的不同之处在于，它们包括与暴露、毒性、生物转化和清除过程相关的组织的特定隔室，这些隔室通过血流连接。本研究旨在解决文献中观察到的数学和药理学框架之间的差距。这些差距包括非守恒方程组和与感兴趣的组织没有生物学相关性的隔室浓度。由此产生的非线性微分方程系统使用各种方法进行数值求解，以进行基准测试和比较。此外，对所有参数进行了敏感性分析，以阐明模型的关键参数。将所得模型拟合到临床数据中作为性能基准。该临床数据捕捉了抗逆转录病毒治疗的二线药物洛匹那韦和利托那韦。洛匹那韦/利托那韦与利福平联合给药时，模型和临床数据相关性良好。洛匹那韦和利福平之间存在药物相互作用。本文就生理药代动力学模型在预测药物相互作用以及抗逆转录病毒和抗结核药物药代动力学方面的适用性得出了结论。
