A Systematic Review of Population Pharmacokinetics of Valproic Acid

Summary

Aims

Population pharmacokinetics is an essential tool that helps guiding individualized dosing regimens. The aims of this systematic review are to provide knowledge concerning population pharmacokinetics of valproic acid (VPA) and to identify factors influencing VPA pharmacokinetic variability.

Methods

Pubmed and Embase databases were systematically searched from inception to June, 2017. Relevant articles from reference lists were also included. All population pharmacokinetic studies of VPA conducted in human and employed nonlinear mixed effect modeling approach were included in this review.

Results

Twenty six studies were included in this review. Most studies characterized VPA pharmacokinetics as a one-compartment model. Three studies reported a two-compartment model. Body weight, dose and age were significant predictors for VPA volume of distribution (V_d). The estimated V_d for one-compartment models ranged from 8.4 to 23.3 L. For two-compartment models, peripheral volumes of distribution ranged from 4.08 to 42.1 L. Frequently reported significant predictors for VPA clearance (CL_VPA) included body weight, VPA dose, concomitant medications, gender, and age. The estimated CL_VPA ranged from 0.206 to 1.154 L/h and the inter-individual variability ranged from 13.40 to 35.90%. Two studies reported population pharmacokinetics-pharmacodynamics of VPA in patients with epilepsy. Seventeen studies evaluated the performance of their final models.

Conclusions

Significant predictors influencing VPA pharmacokinetics as well as model methodologies were highlighted in this review. For clinical application, CL_VPA could be predicted using body weight, VPA dose, concomitant medications, gender or age. For future research, there is knowledge gap regarding population pharmacokinetics-pharmacodynamics of VPA in population other than epilepsy.

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