Cristian Valiante1, Cristina López Bermudo2, Mar Carreño3, Borja Ruiz1, Paula Muñiz1, Marta Forcadell2, Emili González-Pérez2, Valvanera Vozmediano1
1Model Informed Development, CTI, 2Formerly Neuraxpharm Group, 3Clinic Hospital of Barcelona
Introduction & Objectives Midazolam oromucosal solution (MOS) (Buccolam®, Neuraxpharm) 10 mg has been recently approved for the treatment of prolonged, acute convulsive seizures in adults. This study aimed to support the selection of an appropriate adult dose by leveraging exposure matching from pediatric therapeutic doses, a widely accepted approach to extrapolate efficacy data when similar disease progression and response to intervention can be supported. Methods A population pharmacokinetic (PK) model was developed for midazolam (MDZ) and its active metabolite, 1-OH-midazolam (1-OH-MDZ), using data from a single-dose bioavailability study of 15 mg MOS in adults. The model was built in NONMEM® (v7.4.4, Icon Plc) using first-order conditional estimation with interaction (FOCE-I). Several absorption models were explored, with the final model incorporating dual buccal and gastrointestinal absorption pathways for MDZ, a two-compartment disposition model for the parent, linked to a one-compartment model for 1-OH-MDZ. The model was evaluated using standard methods for population modeling. Exposure-matching simulations were performed using a pediatric PK model already available with data from Caucasian and Japanese children (N=74). Age-based virtual pediatric cohorts (total N=3000) were simulated, and adult doses were evaluated based on the combined exposure (AUC) of MDZ and 1-OH-MDZ. Considering the equipotency between parent and metabolite the sum of both active moieties was used to compare the total exposure in adults and pediatrics and select the most appropriate dose in adults based on exposure matching. Results A two-compartment model for parent drug with two different absorption processes, buccal and gastrointestinal, linked to a one-compartment model for metabolite was developed for MDZ and 1-OH-MDZ. In the covariate analysis, body mass index was identified as a significant covariate on the peripheral volume of distribution, body weight on the parent-to-metabolite formation clearance, and age on the metabolite volume of distribution. All covariate effects were incorporated in the model using a power function. After evaluating the model, it was applied for simulations to assess different dosing scenarios and their impact on MDZ and 1-OH-MDZ exposure. A 10 mg MOS dose in adults (=70 years, BMI <34) achieved AUC values (parent + metabolite) comparable to effective pediatric doses. Cmax values aligned with those seen in adolescents (10–18 years). A 15 mg dose resulted in higher AUC but comparable Cmax. Exposures were similar independently on the age, WT or BMI within the studied range. Adults up to 70 years old and with a BMI<34 do not require dose adjustment. Conclusions A 10 mg MOS dose in adults (=70 years, BMI <34) provides systemic exposure consistent with proven pediatric efficacy, supporting its use as the optimal dose for prolonged seizures. Based on the simulations and clinical practice considerations, the 10 mg dose is proposed as the optimal, efficacious and safe dose for MOS to treat adults with prolonged convulsive seizures. These findings align with national guidelines and reinforce the appropriateness of a standardized adult dose. This study played a key role in supporting the regulatory approval of Buccolam® 10 mg for adults in Europe. Official approval of Buccolam® 10 mg prefilled syringes for adults will also help to obviate inappropriate off-label dosing of oromucosal midazolam, as well as the prescription of unsuitable orally administered benzodiazepines for the treatment of acute convulsive seizures in adult patients across Europe. Keywords: midazolam, pharmacokinetics, pediatrics, extrapolation, modeling
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Reference: PAGE 33 (2025) Abstr 11718 [www.page-meeting.org/?abstract=11718]
Poster: Drug/Disease Modelling - Other Topics