Using Simcyp Simulator to Determine DDI Liability of Guanfacine in Children
Guanfacine (Intuniv® XR) extended release (GXR) is an orally administered, selective alpha2A-adrenergic receptor agonist, non-stimulant treatment for children and adolescents with attention deficit/hyperactivity disorder (ADHD). Guanfacine is primarily metabolized by the CYP3A4 enzyme. Thus, it was important to evaluate the drug-drug interaction (DDI) liability perpetrated by strong inhibitors and inducers of CYP3A4. Using data from clinical pharmacokinetics (PK) studies in which GXR was administered as a monotherapy, or co-administered with strong CYP3A4 inhibitors or inducers, physiologically-based pharmacokinetic (PBPK) modeling using the Simcyp Simulator was employed for DDI evaluation.
Based on these predictions using Simcyp, dosing recommendations for GXR were approved by the US FDA without the need to conduct further clinical studies, which is beneficial for both patients and the sponsor with obtaining access to GXR more quickly.
The dosing recommendations on the label are to (1) decrease GXR to 50% of the usual target dose when it is co-administered with strong or moderate CYP3A4 inhibitors and (2) consider titrating GXR up to double the usual target dosage over 1–2 weeks when it is co-administered with strong or moderate CYP3A4 inducers. As pharmacological treatment of ADHD may be needed for extended periods, healthcare providers should periodically re-evaluate the long-term use of GXR and adjust weight-based dosage as needed. The majority of children and adolescents reach optimal doses in the 0.05-0.12 mg/kg/day range. Doses above 4 mg/day have not been evaluated in children (ages 6-12 years) and above 7 mg/day have not been evaluated in adolescents (ages 13-17 years).
ADHD is a common childhood diagnosis. The average age of diagnosis for ADHD is 8 years and 10 years for attention deficit disorder.