Physiologically based pharmacokinetic model of valproic acid using PK-sim

Background: Valproic acid (VPA) is one of the highly prescribed first-line agents for epilepsy. VPA levels are monitored to maintain at appropriate levels. Physiologically based pharmacokinetic modeling (PBPK) is a useful tool for a mechanistic understanding of pharmacokinetics (PKs) of drugs. Objectives: The objective is to develop a PBPK model for VPA using an opensource software platform like PK-Sim with a potential for dosage regimen optimization in epileptic patients. It was also planned to predict the impact of meropenem on the PKs of VPA. Methodology: Anonymized data of Indian epileptic patients with VPA levels were obtained from a prior study from our department. Data necessary for building a PBPK model were obtained from the literature. Pk-Sim® software was used to build and validate a PBPK model for VPA and also to understand its interaction with meropenem. Results: The PBPK model of valproate was successfully developed and validated. The predicted concentration-time profiles for VPA at steadystate were in a comparable range as other published studies. The drug interaction model showed the impact of meropenem on the PKs of valproate. Conclusion: The developed valproate PBPK model has potential application in dose optimization in epileptic patients and helps to assess the drug interaction with meropenem. The potential use of meropenem as a treatment for VPA toxicity or overdose was also predicted.