Li Li, Zhang Yan-Yan, Sharma Jyoti, Cartot-Cotton Sylvaine, Crawford Nigel, Macha Sreeraj, Li Yi, Sahi Jasminder
Pharmacokinetics, Dynamics and Metabolism, Sanofi, Shanghai, China.
Pharmacokinetics, Dynamics and Metabolism, Sanofi, Bridgewater, New Jersey, USA.
Br J Clin Pharmacol. 2025 Aug;91(8):2304-2315. doi: 10.1002/bcp.70037. Epub 2025 Mar 11.
Venglustat is an oral glucosylceramide synthase inhibitor under clinical investigation to treat various lysosomal storage diseases. Metabolism is a main pathway for its elimination in humans with CYP3A being the major contributor. This study aims to evaluate effect of CYP3A inhibition (using itraconazole) on venglustat exposure and to develop and validate a physiologically based pharmacokinetic (PBPK) model to assess effects of additional CYP3A inhibitors of varying potencies on venglustat pharmacokinetics.
An open-label, single-sequence, 2-period drug-drug interaction (DDI) study was conducted in healthy subjects with coadministration of multiple twice daily oral doses of 100 mg itraconazole against a single dose of 15 mg venglustat. A minimal PBPK model was developed using available physicochemical, in vitro and in vivo pharmacokinetic data and validated using data from relevant venglustat clinical studies including the itraconazole DDI study. Effects of additional CYP3A inhibitors on venglustat exposure were predicted.
Coadministration with itraconazole increased venglustat area under the concentration-time curve by 2.03-fold (90% confidence interval [90%CI]: 1.81-2.27). Venglustat steady-state area under the concentration-time curve during a dosing interval following coadministration with strong (clarithromycin), moderate (fluconazole) and weak (fluvoxamine and cimetidine; with CYP2D6 inhibition turned off) CYP3A inhibitors is predicted to increase by 1.74- (5th-95th centile, 1.30-2.49), 1.52- (1.23-1.88), 1.08- (1.03-1.15) and 1.08-fold (1.04-1.12), respectively.
The effect of itraconazole on venglustat exposure was quantified clinically, and a minimal PBPK model was successfully developed, validated and applied to assess DDI effect of additional CYP3A inhibitors on venglustat. The results help to further understand the DDI potential with venglustat and will inform dose recommendations with comedications.
文格鲁司他是一种口服葡糖神经酰胺合酶抑制剂，正在进行临床研究以治疗各种溶酶体贮积病。代谢是其在人体内消除的主要途径，细胞色素P450 3A（CYP3A）是主要贡献者。本研究旨在评估CYP3A抑制作用（使用伊曲康唑）对文格鲁司他暴露的影响，并建立和验证基于生理的药代动力学（PBPK）模型，以评估不同效力的其他CYP3A抑制剂对文格鲁司他药代动力学的影响。
在健康受试者中进行了一项开放标签、单序列、两阶段药物相互作用（DDI）研究，每日两次口服多次100mg伊曲康唑与单次15mg文格鲁司他联合给药。使用可用的物理化学、体外和体内药代动力学数据建立了一个最小PBPK模型，并使用来自包括伊曲康唑DDI研究在内的相关文格鲁司他临床研究的数据进行了验证。预测了其他CYP3A抑制剂对文格鲁司他暴露的影响。
与伊曲康唑联合给药使文格鲁司他浓度-时间曲线下面积增加了2.03倍（90%置信区间[90%CI]：1.81-2.27）。预计与强（克拉霉素）、中（氟康唑）和弱（氟伏沙明和西咪替丁；关闭CYP2D6抑制作用）CYP3A抑制剂联合给药后，给药间隔期间文格鲁司他稳态浓度-时间曲线下面积将分别增加1.74倍（第5-95百分位数，1.30-2.49）、1.52倍（1.23-1.88）、1.08倍（1.03-1.15）和1.08倍（1.04-1.12）。
临床上对伊曲康唑对文格鲁司他暴露量的影响进行了量化，并成功建立、验证了最小PBPK模型，并将其应用于评估其他CYP3A抑制剂对文格鲁司他的DDI效应。这些结果有助于进一步了解与文格鲁司他的药物相互作用潜力，并为联合用药的剂量推荐提供依据。
