PBPK modelling for the evaluation of drug-drug interaction between meropenem and valproic acid.

Aims: The present study aimed to quantitatively investigate the potential drug-drug interaction (DDI) mechanism between meropenem (MEPM) and valproic acid (VPA).

Methods: In the present study, we firstly developed a physiologically based pharmacokinetic (PBPK) model of MEPM and VPA. The verified PBPK model was then used to quantitatively investigate the potential DDI between MEPM and VPA. The effect of genetic polymorphisms of acylpeptide hydrolase (APEH) on DDI was also evaluated.

Results: In our simulation, the plasma concentration of hydrolysate of VPAG decreased to 63% when combined with MEPM. Total plasma concentration of VPA before carbapenem use was 53.61 mg/L, whereas it was 45.42 mg/L during carbapenem use. The inhibition of hydrolysis of VPAG by MEPM alone could not result in a rapid and substantial decrease in the plasma concentration of VPA. Parameter sensitivity analysis showed that the changes of absorption played an important role in the maximum plasma concentration (C_max) of VPA, whereas area under the plasma concentration-time profile (AUC) was more susceptible to elimination changes. In addition, a decrease in APEH activity had little impact on the plasma pharmacokinetics of VPA.

Conclusions: The DDI between MEPM and VPA might be a comprehensive result of multiple factors. On the basis of our simulation, interval medication of MEPM injection and VPA immediate release tablet at 4-6 h timed interval was recommended, or intravenous administration of VPA solution was preferred when combination regimen was necessary in a clinical setting.