Pharmacokinetics and safety of Padsevonil in healthy Chinese subjects and comparison of two sampling methods for Padsevonil quantification

X.-Y. Li, C. Hu, X.-H. Zhu, Y. Wang, S.-Q. Shu, Z. Luo

Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital, Sichuan University, Chengdu, Sichuan, China. luozhu720@163.com

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• Pharmacology

OBJECTIVE: Padsevonil (PSL) is a novel antiepileptic drug candidate that inhibits seizure activity in both presynaptic and postsynaptic ways. The pharmacokinetic (PK) profiles and volumetric absorptive microsampling (VAMS) application of PSL in the Chinese population are limited. The objectives of this study were to evaluate the PK profile of PSL and its 2 metabolites, the safety of PSL, and compare the PK profile of PSL from samples collected using the VAMS technique with that of conventional venous samples in healthy Chinese subjects.

SUBJECTS AND METHODS: In this randomized, double-blind, placebo-controlled single-dose study, the participants received either 200 mg PSL or placebo. Blood samples for the PK variables were collected using both the traditional venous method and the VAMS Mitra® technique at the scheduled time points. The PK parameters of PSL and 2 metabolites were calculated, and the concentration agreement of VAMS and venous samples were also evaluated.

RESULTS: A total of 14 subjects were enrolled. The concentration-time profile of PSL showed rapid absorption with a median tmax of 1.25 h (range: 0.5 to 3.0), followed by an apparent biphasic disposition. For PSL, the geometric means of AUC(0-t), AUC, Cmax, and t1/2 were 6,573 h*ng/mL, 6,588 h*ng/mL, 1,387 ng/mL, and 5.275 h, respectively. The geometric mean body weight-normalized AUC(0-t), AUC, and Cmax were 5,712 h*ng/mL, 5,725 h*ng/mL, and 1,205 ng/mL, respectively. The AUC(0-t), AUC, Cmax of PSL and metabolites in VAMS-dried blood were all lower than those in plasma. The Passing-Bablok regression showed that the PSL and metabolite concentrations obtained by VAMS analysis were comparable to those obtained by plasma at some time points. The most frequently reported treatment-emergent adverse events (TEAEs) were somnolence and dizziness. There were no serious TEAEs, severe TEAEs, discontinuations due to TEAEs, or deaths reported during this study. No clinically significant laboratory, vital signs, electrocardiograph (ECG), or physical examination results were reported.

CONCLUSIONS: PSL has a favorable PK profile after single-dose oral administration and good safety properties in healthy Chinese volunteers. The regression analysis results of VAMS and plasma indicated that the application of VAMS for therapeutic drug monitoring in novel antiepileptic drug development is promising and needs further validation.

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