Anisa Khan (1), Alessandro Di Deo (1), Oscar Della Pasqua (1)
(1) Clinical Pharmacology & Therapeutics, University College London, United Kingdom
Objectives: Epilepsy is a chronic disorder affecting 50 million people worldwide, including 450,000 children(1-5). Cenobamate (CNB) has been approved for treating focal-onset seizures (FOS) in adults and is under evaluation for primary generalized tonic-clonic (PGTC) seizures. It has shown remarkable efficacy as adjunct therapy with once-daily doses up to 200mg/day following a titration period(6,7). Whilst CNB is not approved for children, its mechanism illustrates the feasibility of extrapolation principles thereby reducing the time required to approve novel therapies for paediatrics. Although clinical trials rely on empirical dosing, it has been shown that antiepileptic drugs have comparable efficacy in adults and children, and that seizure type and mechanism is a more robust approach to dose rationale. However, despite the evolving guidelines and understanding of age-related changes in disease and drug disposition, the European Medicines Agency’s paediatric investigation plan relies on empirical evidence, without considering extrapolating data from adults to children(8). Thus, this study aimed to establish the dose rationale for CNB in children (2–18 years old) using extrapolation principles and explore the feasibility of an optimised dosing regimen.
Method: A nonlinear mixed-effects modelling approach was used alongside simulation and extrapolation principles to predict the pharmacokinetics (PK) of CNB in children, assuming comparable exposure-response relationships between adults and paediatric subjects with FOS and PGTC seizures. The only available PK and PKPD models published by the FDA were used for these analyses(7). Age and weight-related changes in the PK were described using allometry and the effect of co-medication drug metabolism was considered. The dosing rationale assumes that CNS penetration is similar to adults, despite variations in clinical presentation of seizures. Median AUC0-24, Css and Cmax estimates in adults were a target for dosing regimen selection. Simulation scenarios were then implemented considering various regimens (i.e., fixed, weight-banded and mg/kg doses) to identify doses exhibiting comparable exposure in both populations. Scenarios included typical adults weighing 70–75kg, whereas children were stratified by weight bands (15–25, 25–30, 30–40, and 40–50kg).
To demonstrate how matching exposure correlates with efficacy, a Poisson (count) model was used to predict treatment response, accounting for differences due to the placebo effect in children.
Results: Median AUC0-24 (90% CI) estimates corresponding to maintenance doses of 100, 200, and 400mg in adults were 151.2(85.4–273.7), 352.4(196.2–634.9), and 811.2(456.4–1544.0) µg/mL.h, respectively. The recommended doses to achieve target AUC0-24 values are as follows: ≤25kg: 37.5, 87.5, and 175mg; 25–30kg: 50, 112.5, and 225mg; 30-40kg: 62.5, 125, and 250mg; and 40-50kg: 75, 150, and 300mg. The effect of drug-drug interaction was not affected by varying body weight.
Conclusion: This study represents the first attempt to illustrate the feasibility of using a model-based approach to optimize CNB dosing for children with FOS and PGTC seizures. Although prospective data is required to confirm PKPD relationships across populations, our analysis highlights the importance of four weight bands in children to achieve the desired target exposure. This approach expedites CNB access for paediatric patients through extrapolation and facilitates assessing placebo effect differences without a control group.
References:
(1) J. I. Sirven, ‘Epilepsy: A Spectrum Disorder’, Cold Spring Harb Perspect Med, vol. 5, no. 9, p. a022848, 2015, doi: 10.1101/CSHPERSPECT.A022848.
(2) H. Bhasin and S. Sharma, ‘The New International League Against Epilepsy (ILAE) 2017 Classification of Seizures and Epilepsy: What Pediatricians Need to Know!’, Indian J Pediatr, vol. 86, no. 7, pp. 569–571, Jul. 2019, doi: 10.1007/S12098-019-02910-X/FIGURES/2.
(3) A. Singh, ‘Cenobamate for treatment-resistant focal seizures: current evidence and place in therapy’, https://doi.org/10.1177/11795735211070209, vol. 14, p. 117957352110702, Mar. 2022, doi: 10.1177/11795735211070209.
(4) K. M. Fiest et al., ‘Prevalence and incidence of epilepsy’, Neurology, vol. 88, no. 3, pp. 296–303, Jan. 2017, doi: 10.1212/WNL.0000000000003509.
(5)WHO, ‘Epilepsy’, 2023. https://www.who.int/news-room/fact-sheets/detail/epilepsy (accessed Jun. 08, 2023).
(6)CHMP, ‘Committee for Medicinal Products for Human Use (CHMP) Assessment report’, 2021, Accessed: Jun. 08, 2023. [Online]. Available: www.ema.europa.eu/contact
(7) FDA, ‘CENTER FOR DRUG EVALUATION AND RESEARCH’, 2019.
(8) EMA, ‘European Medicines Agency decision P/0300/2021 of 13 August 2021 on the acceptance of a modification of an agreed paediatric investigation plan for cenobamate (ONTOZRY), (EMEA-002563-PIP02-19-M01)’, 2021, Accessed: Aug. 21, 2023. [Online]. Available: www.ema.europa.eu/contact
Reference: PAGE 32 (2024) Abstr 11245 [www.page-meeting.org/?abstract=11245]
Poster: Clinical Applications