Population pharmacokinetics and exposure-safety of lipophilic conjugates prodrug DP-VPA in healthy Chinese subjects for dose regime exploring.

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.

Determination of DP-VPA and its active metabolite, VPA, in human plasma, urine, and feces by UPLC-MS/MS: A clinical pharmacokinetics and excretion study.

DP-VPA is a phospholipid prodrug of valproic acid (VPA) that is developed as a potential treatment for epilepsy. To characterize the pharmacokinetics and excretion of DP-VPA, four reliable ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods were validated for quantitation of DP-VPA and its metabolite, VPA, in human plasma, urine, and feces. Protein precipitation and solid-phase extraction (SPE) were used for extraction of C16, C18 homologs of DP-VPA and VPA, respectively, from plasma. Urine and fecal homogenate involving the three analytes were efficiently prepared by methanol precipitation. The determinations of C16 DP-VPA, C18 DP-VPA, and VPA were performed using the positive multiple reaction monitoring (MRM) mode and the negative single ion monitoring (SIM) mode, respectively. The analytes were separated using gradient elution on C8 or phenyl column. Satisfactory results pertaining to selectivity, linearity, matrix effect, accuracy and precision, recovery, stability, dilution integrity, carryover, and incurred sample analysis (ISR) were obtained. The calibration ranges in human plasma were as follows: 0.00200-1.00 µg/mL for C16 DP-VPA, 0.0100-5.00 µg/mL for C18 DP-VPA, and 0.0500-20.0 µg/mL for VPA. The linear ranges in urine and fecal homogenate were 0.00500-2.00 µg/mL and 0.00200-0.800 µg/mL for C16 DP-VPA, 0.00500-2.00 µg/mL and 0.0100-4.00 µg/mL for C18 DP-VPA, and 0.200-80.0 µg/mL for VPA, respectively. The intra- and inter-batch coefficients of variation in three matrices ranged from 1.7% to 12.4% while the accuracy values ranged from 85.4% to 111.7%. The developed methods were successfully applied to determine pharmacokinetics of DP-VPA tablet after a single oral dose of 1200 mg in 12 healthy Chinese subjects under fed condition.