Haemophilia PK & ADME, Haemophilia Research, Global Research, Novo Nordisk A/S, Maaloev, Denmark; Department of Veterinary Clinical Sciences, University of Copenhagen, Frederiksberg, Denmark.
Quantitative Clinical Pharmacology, Novo Nordisk A/S, Soeborg, Denmark.
Eur J Pharm Sci. 2018 Mar 30;115:196-203. doi: 10.1016/j.ejps.2018.01.035. Epub 2018 Jan 31.
Various experimental animal models are used in haemophilia research, however, little is known about how well the different species predict pharmacokinetic (PK) profiles in haemophilia patients. The aim of the current study was to describe the plasma concentration-time profile of recombinant activated factor VII (rFVIIa) and recombinant factor VIII (rFVIII) in several experimental animal models using population PK modelling, and apply a simulation-based approach to evaluate how well the developed animal population PK models predict human PK. PK models were developed for rFVIIa and rFVIII in mice, rats, monkeys, and dogs using nonlinear mixed-effects modelling, accounting for inter-individual variability, nonlinear kinetics and covariate effects. Three scaling principles were applied to predict human PK: proportional scaling to body weight from single species, scaling with fixed theory-based allometric exponents from single species, and allometric interspecies scaling with estimated allometric coefficients and exponents. The plasma concentration-time profile of rFVIIa and rFVIII in mice, rats, monkeys and dogs were accurately described by the developed species-specific PK models, accounting for nonlinear kinetics and gender-specific difference in clearance for rFVIII. The predictive performance of the animal population PK models of rFVIIa and rFVIII revealed significant species-variation. The developed PK models of rFVIIa and rFVIII in monkeys and dogs along with allometric interspecies scaling revealed high predictive performance for human PK, and may promote rational decision-making in future first-in-human trials for rFVIIa and rFVIII variants.
多种实验动物模型被用于血友病研究，然而，对于不同物种在多大程度上可以预测血友病患者的药代动力学（PK）特征，人们知之甚少。本研究旨在使用群体 PK 模型描述重组激活因子 VII（rFVIIa）和重组因子 VIII（rFVIII）在几种实验动物模型中的血浆浓度-时间曲线，并采用基于模拟的方法评估所开发的动物群体 PK 模型在多大程度上可以预测人体 PK。使用非线性混合效应模型为 rFVIIa 和 rFVIII 在小鼠、大鼠、猴子和犬中开发 PK 模型，以解释个体间差异、非线性动力学和协变量效应。应用了三种缩放原理来预测人体 PK：从单一物种按比例缩放至体重、从单一物种按固定理论的异速指数缩放、以及基于估计的异速系数和指数的种间异速缩放。所开发的特定物种 PK 模型能够准确描述 rFVIIa 和 rFVIII 在小鼠、大鼠、猴子和犬中的血浆浓度-时间曲线，解释了 rFVIII 清除率的非线性动力学和性别特异性差异。rFVIIa 和 rFVIII 的动物群体 PK 模型的预测性能显示出显著的物种差异。开发的猴子和犬中 rFVIIa 和 rFVIII 的 PK 模型以及基于种间异速缩放的模型显示出对人体 PK 的高预测性能，可能会促进未来 rFVIIa 和 rFVIII 变体的首次人体试验中的合理决策。
