DEVELOPMENT OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL TO PREDICT PLASMA AND BRAIN EXPOSURE FOLLOWING ADMINISTRATION OF VALPROIC ACID AND CLOBAZAM IN COMBINATION TREATMENT REGIMEN FOR DRAVET SYNDROME IN CHILDREN

Abstract Background Combination of valproic acid and clobazam is considered as a first-line option for Dravet syndrome (Wirrell and Nabbout, 2019). Therapeutic trough plasma concentration of valproic acid has been reported in the literature to be 50-100 mg/mL (Damegunta, 2014), and for clobazam between 30-300 ng/mL (de Leon, Spina and Diaz, 2013). A PBPK model to predict concentration-time data of valproic acid and clobazam in combination has not been established yet. Having such a model could be clinically useful for predicting the exposures of these drugs and forecasting clinical outcome. Aims And Objectives (1) Develop a PBPK model to simulate concentration-time profile for valproic acid oral solution and clobazam oral suspension in a combined regimen in children aged 1-10 years old in order to optimize the dose that could result in a clinical trough concentration. (2) Apply a PBPK model to predict the concentration in the brain following administration. Methods A PBPK model was developed for valproic acid and clobazam in adults by a bottom-up approach and validated. The model was further developed for a pediatric population by modifying anatomical parameters by age. The model was then applied for simulating concentration-time profile of each drug in children aged 1, 5 and 10 years old. Valproic acid was started at 5 mg/kg every 12 hours and weekly escalated by 10 mg/kg/day until reaching 20 mg/kg every 12 hours, meanwhile clobazam was initiated at 0.05 mg/kg every 12 hours and weekly titrated to a maintenance dose of 0.3 mg/kg/day every 12 hours. The code to explain drug-drug interaction was incorporated for simulation. Results The model was successfully developed and validated. Simulation showed that the concentration in the brain of both drugs were lower than in plasma. The predicted plasma trough concentration in population aged 1, 5 and 10 years old was 80, 100, 115 mg/mL and 315, 400, 480 ng/mL for valproic acid and clobazam, respectively, when each drug was given alone. Clobazam increased by 1.5-3% (320, 415, 490 ng/mL), when co-administered with valproic acid. To reach the lowest therapeutic range of 50 mg/mL, valproic acid dose 12.5, 10 and 9 mg/kg every 12 hour may be required for children aged 1, 5 and 10 years old, respectively. For clobazam, the dose higher than 0.3 mg/kg every 12 hours tended to result in trough concentration above 300 ng/mL. Discussion And Conclusion An age-adjusted PBPK model worked well to predict the concentration-time profile following both single and multiple dosing of valproic acid and clobazam in pediatric population. It was also able to predict the concentration in other organs including the brain, which is the target organ, to determine the correlation to plasma concentration. Drug-drug interaction, inhibition on clobazam metabolism, can be observed from simulation but it is not clinically relevant. To conclude, this study presents a pioneer PBPK model developed for predicting valproic acid and clobazam in combination regimen. This model could predict trough concentration and could be potentially useful for optimizing the dose to reach a desired clinical trough concentration. References 1.Wirrell, E.C. and Nabbout, R. (2019). Recent Advances in the Drug Treatment of Dravet Syndrome. CNS Drugs. doi:https://doi.org/10.1007/s40263-019-00666-8. 2.Damegunta, S. (2014). Time matters!: When is the right time to estimate serum valproic acid levels? Indian Journal of Psychological Medicine, 36(3), p.349. doi:https://doi.org/10.4103/0253-7176.135402. 3.de Leon, J., Spina, E. and Diaz, F.J. (2013). Clobazam Therapeutic Drug Monitoring. Therapeutic Drug Monitoring, 35(1), pp.30–47. doi:https://doi.org/10.1097/ftd.0b013e31827ada88.