Kratochwil Nicole A, Stillhart Cordula, Diack Cheikh, Nagel Sandra, Al Kotbi Nada, Frey Nicolas
Clinical Pharmacology, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Roche Holding AG, Switzerland.
PRA Health Sciences, Groningen, Netherlands.
Br J Clin Pharmacol. 2021 Sep;87(9):3550-3560. doi: 10.1111/bcp.14771. Epub 2021 Mar 10.
RO5459072, a cathepsin-S inhibitor, Biopharmaceutics Classification System class 2 and P-glycoprotein substrate, exhibited complex, nonlinear pharmacokinetics (PK) while fasted that seemed to impact both the absorption and the disposition phases. When given with food, all nonlinearities disappeared. Physiologically based PK (PBPK) modelling attributed those nonlinearities to dose-dependent solubilisation and colonic absorption. The objective of this population PK analysis was to complement the PBPK analysis.
PK profiles in 39 healthy volunteers after first oral dosing (1-600 mg) while fasted or fed in single and multiple ascending dose studies were analysed using population compartmental modelling.
The PK of RO5459072 while fed was characterized by a 1-compartmental PK model with linear absorption and elimination. The nonlinearities while fasted were captured using dose dependent bioavailability and 2 sequential first-order absorption phases: one following drug administration and one occurring 11 hours later and only for doses >10 mg. The bioavailability in the first absorption phase increased between 1 and 10 mg and then decreased with dose, in agreement with in vitro dissolution and solubility studies. The remaining fraction of doses to be absorbed by the second absorption phase was found to have a bioavailability similar to that in the first absorption phase.
The population PK model supported that dissolution- and solubility-limited absorption from the proximal and distal intestine alone explains the nonlinear PK of RO5459072 in fasted state and the linear PK in fed state. This work, together with the PBPK analysis, raised our confidence in the understanding of this complex PK.
RO5459072是一种组织蛋白酶-S抑制剂，属于生物药剂学分类系统2类药物且是P-糖蛋白底物，禁食时表现出复杂的非线性药代动力学（PK），这似乎对吸收和处置阶段均有影响。与食物同服时，所有非线性现象均消失。基于生理的PK（PBPK）模型将这些非线性现象归因于剂量依赖性溶解和结肠吸收。本群体PK分析的目的是补充PBPK分析。
在单次和多次递增剂量研究中，对39名健康志愿者在禁食或进食状态下首次口服给药（1 - 600毫克）后的PK曲线进行群体房室模型分析。
进食状态下RO5459072的PK特征为具有线性吸收和消除的单房室PK模型。禁食时的非线性现象通过剂量依赖性生物利用度和2个连续的一级吸收阶段来描述：一个在给药后出现，另一个在11小时后出现，且仅在剂量>10毫克时出现。第一个吸收阶段的生物利用度在1至10毫克之间增加，然后随剂量降低，这与体外溶出度和溶解度研究结果一致。发现第二个吸收阶段吸收的剩余剂量部分具有与第一个吸收阶段相似的生物利用度。
群体PK模型支持仅近端和远端肠道的溶解和溶解度限制吸收就能解释禁食状态下RO5459072的非线性PK以及进食状态下的线性PK。这项工作与PBPK分析一起，增强了我们对这种复杂PK的理解信心。
