An innovative ethosuximide granule formulation designed for pediatric use: Comparative pharmacokinetics, safety, tolerability, and palatability profile versus reference syrup.

Autor: Diezi L; Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland., Dao K; Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland., Jullien V; Inserm U1129, Paris, France., Roussel-Maupetit C; Advicenne Pharma, Nîmes, France., Burton I; Clinbay, Genappe, Belgium., André P; Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland., Bardinet C; Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland., Rothuizen LE; Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland., Chtioui H; Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland., Manso-Silvan MA; Advicenne Pharma, Nîmes, France., Guittet C; Advicenne Pharma, Nîmes, France., Brunner-Ferber F; Brunner Naga, Pfaeffikon, Zürich, Switzerland., Vandenhende F; Clinbay, Genappe, Belgium., Chiron C; Inserm U1129, Paris, France.; Inserm U1141, Paris, France., Granier LA; Advicenne Pharma, Nîmes, France., Buclin T; Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Jazyk: angličtina
Zdroj: Pharmacology research & perspectives [Pharmacol Res Perspect] 2023 Feb; Vol. 11 (1), pp. e01032.
DOI: 10.1002/prp2.1032
Abstrakt: Ethosuximide, the first-line therapy for childhood absence epilepsy, is currently formulated as a syrup (Zarontin®, Pfizer) with a bitter taste and high sugar content, poorly adapted to children, and a ketogenic diet. The collaborative European FP7 project KIEKIDS aimed at developing an innovative sugar-free, tasteless formulation convenient for pediatric use. This dual Phase-I study evaluated two granule formulations based on lipid multiparticulate (LMP) technology. Two panels of 6 healthy adult volunteers underwent a randomized, placebo-controlled, partly blinded, 3-way cross-over trial, comparing ethosuximide granules A or B with placebo granules and syrup at single 10 mg/kg doses. Corresponding plasma pharmacokinetic profiles of ethosuximide were compared, along with palatability, safety, and tolerability. The LMP granule A proved suboptimal due to bitterness and adherence to beaker walls, while the optimized granule B revealed excellent palatability, similar to placebo granules, and low adherence to glass. The relative bioavailability of granules A versus syrup, based on dose-normalized C max and AUC 0-∞ was 93.7% [90% CI: 76.3-115.1] and 96.1% [91.0-101.5], respectively. For granules B it was 87.6% [81.6-94.0] and 92.5% [88.5-96.6], respectively, with slightly delayed t max of 0.75 h [0.5-4.05] compared to syrup 0.5 h [0.3-0.8]. Tolerability visual analog scales revealed a trend for statistically non-significant improvement versus syrup at peak (30 min) for transient dizziness (both granules), fatigue (granules A), and anxiety (granules B). The innovative ethosuximide granule formulation B achieves a suitable profile for pediatric use, being sugar-free, tasteless, bioequivalent, and well-tolerated while enabling precise adjustment to body weight.
(© 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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