Guanfacine extended release (GXR)—a selective α-2 adrenergic agonist FDA-approved for the treatment of attention-deficit/hyperactivity disorder (ADHD)—has demonstrated efficacy for inattentive and hyperactive/impulsive symptom domains in 2 large trials lasting 8 and 9 weeks.1,2 GXR’s once-daily formulation may increase adherence and deliver consistent control of symptoms across a full day ( Table 1 ).
Table 1
Guanfacine extended release: Fast facts
| Brand name: Intuniv |
| Indication: Attention-deficit/hyperactivity disorder |
| Approval date: September 3, 2009 |
| Availability date: November 2009 |
| Manufacturer: Shire |
| Dosing forms: 1-mg, 2-mg, 3-mg, and 4-mg extended-release tablets |
| Recommended dosage: 0.05 to 0.12 mg/kg once daily |
Clinical implications
GXR exhibits enhancement of noradrenergic pathways through selective direct receptor action in the prefrontal cortex.3 This mechanism of action is different from that of other FDA-approved ADHD medications. GXR can be used alone or in combination with stimulants or atomoxetine for treating complex ADHD, such as cases accompanied by oppositional features and emotional dysregulation or characterized by partial stimulant response.
How it works
Guanfacine—originally developed as an immediate-release (IR) antihypertensive—reduces sympathetic tone, causing centrally mediated vasodilation and reduced heart rate. Although GXR’s mechanism of action in ADHD is not known, the drug is a selective α-2A receptor agonist thought to directly engage postsynaptic receptors in the prefrontal cortex (PFC), an area of the brain believed to play a major role in attentional and organizational functions that preclinical research has linked to ADHD.3
The postsynaptic α-2A receptor is thought to play a central role in the optimal functioning of the PFC as illustrated by the “inverted U hypothesis of PFC activation.”4 In this model, cyclic adenosine monophosphate (cAMP) levels build within the prefrontal cortical neurons and cause specific ion channels—hyperpolarization-activated cyclic nucleotide gated (HCN) channels—to open on dendritic spines of these neurons.5 Activation of HCN channels effectively reduces membrane resistance, cutting off synaptic inputs and disconnecting PFC network connections. Because α-2A receptors are located in proximity to HCN channels, their stimulation by GXR closes HCN channels, inhibits further production of cAMP, and reestablishes synaptic function and the resulting network connectivity.5 Blockade of α-2A receptors by yohimbine reverses this process, eroding network connectivity, and in monkeys has been demonstrated to impair working memory,6 damage inhibition/impulse control, and produce locomotor hyperactivity.
Direct stimulation by GXR of the postsynaptic α-2A receptors is thought to:
- strengthen working memory
- reduce susceptibility to distraction
- improve attention regulation
- improve behavioral inhibition
- enhance impulse control.7
Pharmacokinetics
GXR offers enhanced pharmaceutics relative to IR guanfacine. IR guanfacine exhibits poor absorption characteristics—peak plasma concentration is achieved too rapidly and then declines precipitously, with considerable inter-individual variation.
GXR’s once-daily formulation is implemented by a proprietary enteric-coated sustained release mechanism8 that is meant to:
- control absorption
- provide a broad but flat plasma concentration profile
- reduce inter-individual variation of guanfacine exposure.
Compared with IR guanfacine, GXR exhibits delayed time of maximum concentration (Tmax) and reduced maximum concentration (Cmax). Therapeutic concentrations can be sustained over longer periods with reduced peak-to-trough fluctuation,8 which tends to improve tolerability and symptom control throughout the day. The convenience of once-daily dosing also may increase adherence.
GXR’s pharmacokinetic characteristics do not change with dose, but high-fat meals will increase absorption of the drug—Cmax increases by 75% and area under the plasma concentration time curve increases by 40%. Because GXR primarily is metabolized through cytochrome P450 (CYP) 3A4, CYP3A4 inhibitors such as ketoconazole will increase guanfacine plasma concentrations and elevate the risk of adverse events such as bradycardia, hypotension, and sedation. Conversely, CYP3A4 inducers such as rifampin will significantly reduce total guanfacine exposure. Coadministration of valproic acid with GXR can result in increased valproic acid levels, producing additive CNS side effects.
Efficacy
GXR reduced both inattentive and hyperactive/impulsive symptoms in 2 phase III, forced-dose, parallel-design, randomized, placebo-controlled trials ( Table 2 ). In the first trial,1 345 children age 6 to 17 received placebo or GXR, 2 mg, 3 mg, or 4 mg once daily for 8 weeks. In the second study,2 324 children age 6 to 17 received placebo or GXR, 1 mg, 2 mg, 3 mg, or 4 mg, once daily for 9 weeks; the 1-mg dose was given only to patients weighing <50 kg (<110 lbs).
In both trials, doses were increased in increments of 1 mg/week, and investigators evaluated participants’ ADHD signs and symptoms once a week using the clinician administered and scored ADHD Rating Scale-IV (ADHD-RS-IV). The primary outcome was change in total ADHD-RS-IV score from baseline to endpoint.