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Population pharmacokinetics and exposure-safety of lipophilic conjugates prodrug DP-VPA in healthy Chinese subjects for dose regime exploring.
- Source :
-
European Journal of Pharmaceutics & Biopharmaceutics . Jul2023, Vol. 188, p153-160. 8p. - Publication Year :
- 2023
-
Abstract
- [Display omitted] Phospholipid-valproic acid (DP-VPA) is a prodrug for treating epilepsy. The present study explored the pharmacokinetics (PK) and exposure safety of DP-VPA to provide a basis for future studies exploring the safe dosage and therapeutic strategies for epilepsy. The study included a randomized placebo-controlled dose-escalation tolerance evaluation trial and a randomized triple crossover food-effect trial in healthy Chinese volunteers. A population pharmacokinetic (PopPK) model was established to analyze the PK of DP-VPA and active metabolite VPA. The exposure safety was assessed with the adverse drug reaction (ADR) in CNS. The PopPK of DP-VPA and metabolite VPA fitted a two-compartment model coupling one-compartment with Michaelis-Menten metabolite kinetics and first-order elimination. The absorption processes after single oral administration of DP-VPA tablet demonstrated nonlinear characteristics, including 0-order kinetic phase and time-dependent phase fitting Weibull distribution. The final model indicated that the DP-VPA PK was significantly affected by dosage and food. The exposure-safety relationship demonstrated a generalized linear regression; mild/moderate ADRs occurred in some subjects with 600 mg and all subjects with 1500 mg of DP-VPA, and no severe ADRs were reported up to 2400 mg. In conclusion, the study established a PopPK model describing the processing of DP-VPA and VPA in healthy Chinese subjects. DP-VPA showed good tolerance after a single dose of 600–2400 mg with nonlinear PK and was affected by dosage and food. Based on the association between neurological ADRs and higher exposure to DP-VPA by exposure-safety analysis, 900–1200 mg was recommended for subsequent study of safety and clinical effectiveness. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09396411
- Volume :
- 188
- Database :
- Academic Search Index
- Journal :
- European Journal of Pharmaceutics & Biopharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- 164180561
- Full Text :
- https://doi.org/10.1016/j.ejpb.2023.04.023