DOSE PREDICTION OF STIRIPENTOL AND CANNABIDIOL (CBD) IN COMBINATION TREATMENT REGIMEN FOR EPILEPSY BASED ON AN AVERAGE CONCENTRATION AT THE STEADY STATE (CAV,SS) USING A PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL IN AGE- VARYING PATIENTS
Authors: Jaisupa *Nattapon , Birgersson Sofia , Ashton Michael 
Published: February 2025

Abstract

Background
Polypharmacy is considered as a mainstay for epilepsy treatment. Combining CBD to stiripentol- containing regimen could be one option for the treatment. The therapeutic range of each drug in term of drug concentration ratio is important as it could reflect the different types of combinations, whether it exercises synergistic, additive or antagonistic effect. However, the appropriate concentration ratio between stiripentol and CBD is not currently known. As these drugs possess complicated pharmacokinetic profiles and interacts to each other through their metabolism, having a pharmacokinetic tool to predict the concentration in the brain could be helpful for dose optimization. PBPK models are useful tools for drug-drug interaction studies and especially for drugs excercising the effect in the brain.

Aims and Objectives
To optimize doses of CBD and stiripentol in age-varying patients. To apply a validated PBPK model to predict average concentration at the steady state (Cav,ss) and Cav,ss ratio between stiripentol and CBD (stiripentol/CBD).

Method
A validated PBPK model developed for CBD (in house data not yet published) together with a validated PBPK model developed for stiripentol (Ogungbenro and Aarons, 2014; Peigné et al., 2014; Wang et al., 2022) were combined. The predicted concentration-time profiles of each drug in the brain and plasma were simulated among age-varying population after these drugs were administered and titrated until reaching the recommended maximum dose (50 mg/kg/day for stiripentol and 20 mg/kg/day for CBD). Concentration- and time-dependent inhibition on CYP450 enzymes responsible for stiripentol and CBD metabolism were incorporated for simulation to explain drug-drug interaction. The Cav,ss and Cav,ss ratio were then calculated and compared.

Results
Predicted exposures of both CBD and stiripentol when in combination tended to directly correlate to age when the same weight-adjusted dose was administered. An increase in exposure of approximately 5-10% of each drug in combination were observed compared to those when administered alone. Predicted plasma concentration of both drugs was lower than that in the brain. The predicted Cav,ss ratio in the brain were approximately 45-50:1 and 12-15:1 for the total and unbound concentration, respectively. In contrast to stiripentol, increasing the CBD dose from 20 to 40 mg/kg/day resulted in the increased exposures by approximately 30%.

Discussion And Conclusion
This was a study employing a PBPK model for predicting CBD and stiripentol Cav,ss in a combination regimen in order to optimize the dose. The exposures of stiripentol and CBD increase non-linearly due to a saturated clearance (May et al., 2012) and limited absorption (Research, n.d.), respectively. Simulation implied that higher dose may be required for children in order to reach the comparable exposure as observed in adults. Very high value of predicted Cav,ss ratio was observed meaning that stiripentol concentration was largely higher than that of CBD although the approximately equal doses were given. In conclusion, increasing antiseizure drug dose to improve clinical response without pharmacokinetic considerations may not be sufficient. Adjusting CBD dose to obtain higher exposure than stiripentol may be less feasible if that was an appropriate ratio. Other approaches should be considered.

References
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2.Peigné, S., Rey, E., Le Guern, M.-E., Dulac, O.,Chiron, C., Pons, G. and Jullien, V. (2014). Reassessment of stiripentol pharmacokinetics in healthy adult volunteers. Epilepsy Research, 108(5), pp.909–916. doi:https://doi.org/10.1016/j.eplepsyres.2014.03.009.
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