Modeling and simulation of the exposure–response and dropout pattern of guanfacine extended-release in pediatric patients with ADHD

William Knebel, Jim Rogers, Dan Polhamus, James Ermer, Marc R. Gastonguay

Guanfacine extended-release (GXR) is a selective α2A-adrenergic receptor agonist approved in the United States for once-daily administration for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents ages 6-17 years old either as monotherapy or adjunctive to stimulant medications. This analysis integrates exposure-response, placebo, and dropout data from 10 clinical trials that used GXR in adolescents and children with ADHD. In these trials, the ADHD Rating Scale-IV (ADHD RS-IV) score was collected longitudinally within patients over the course of 6-13 weeks. Non-linear mixed effects models were developed and used to describe the exposure-response of the GXR and placebo time course. The OpenBUGS program was utilized to describe the dropout time course across the trials. Placebo time course was best described by an inverse Bateman function with a 3-group mixture model that allowed for the onset and offset of the placebo response. Dropout time modeling indicated a missing at random mechanism for dropouts which was best described by a Weibull distribution with an estimated percentage of non-dropout patients. A linear exposure-response model with an adolescent effect on maximum slope (SLPmax), and a time delay for reaching SLPmax, provided the best description of the GXR exposure-response time course. The GXR exposure-response model indicated that the typical (95 % confidence interval) decrease in ADHD RS-IV score from the placebo-response trajectory would be 37.1 % (32.2, 42.0 %) per 0.1 mg/kg of GXR exposure. There was little noticeable difference between the exposure-response in adolescents and children or across ADHD subtypes.