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Abstract Details

Physiologically based pharmacokinetic modeling (PBPK) for gaboxadol exposure in children with Angelman syndrome
Child Neurology and Developmental Neurology
P13 - Poster Session 13 (5:30 PM-6:30 PM)
5-012
The objectives of this study were to develop a physiologically based pharmacokinetic modeling (PBPK) for gaboxadol (OV101) and use this model to predict the exposure of gaboxadol in children with Angelman syndrome (AS). 
Gaboxadol is a highly selective orthosteric agonist that activates the δ-containing subunit of extrasynaptic GABAA receptors. In the Phase 2 STARS trial, gaboxadol once daily (QD; 15 mg at bedtime) was demonstrated to be generally safe and well-tolerated. Resulting in a weight-based dose level of 0.13-0.23 mg/kg, gaboxadol QD produced at least minimal improvement in global function. However, gaboxadol PK information is available for adults and adolescents only and a verified PBPK-model is needed to predict exposure in children younger than 12 years of age.
A whole-body PBPK-model was developed from PK information using PK-Sim® and model inputs from various sources, including gaboxadol physicochemical, along with absorption, distribution, metabolism, and excretion (ADME) data, and extant PK information from multiple clinical trials. The PBPK-model was verified by comparing predicted and observed PK information in adult and adolescent patients with AS. Once verified, the model was subsequently used to estimate gaboxadol exposure in 1,000 virtual pediatric patients at various weight bands (age, 0.5-12 years).  
Plasma concentration-time profiles and exposure parameters derived using the PBPK-model were similar to observed actual values in adult and adolescent patients with AS. In virtual pediatric patients weighing between 17-70 kg, predicted Cmax and AUC0-inf values for the above weight-based dose range were 133-151.9 ng/mL and 306.9-483.2 ng·h/mL. 
A gaboxadol PBPK-model, developed and verified in adult and adolescent patients with AS, has been used to predict plasma gaboxadol exposure in pediatric patients. These predicted values will be evaluated using respective exposure levels from actual patients in the ongoing pivotal Phase 3 NEPTUNE trial of gaboxadol in pediatric patients with AS.
Authors/Disclosures

PRESENTER 		No disclosure on file
Tom Parry Tom Parry has received personal compensation for serving as an employee of Ovid Therapeutics Inc. Tom Parry has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boehringer Ingleheim. Tom Parry has received personal compensation in the range of $0-$499 for serving as a Grant Reviewer with NIH.
Amit Rakhit, MD (Ovid Therapeutics) No disclosure on file
No disclosure on file