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.
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).