Out of the Pipeline p Guanfacine extended release for ADHD Floyd R. Sallee, MD, PhD uanfacine extended release (GXR)— Table 1 α Once-daily a selective -2 adrenergic agonist Guanfacine extended release: GFDA-approved for the treatment formulation may of attention-defi cit/hyperactivity disor- Fast facts improve adherence der (ADHD)—has demonstrated effi cacy Brand name: Intuniv and control for inattentive and hyperactive/impulsive Indication: Attention-defi cit/hyperactivity symptoms across disorder symptom domains in 2 large trials lasting® Dowden Health Media a full day 8 and 9 weeks.1,2 GXR’s once-daily formu- Approval date: September 3, 2009 lation may increase adherence and deliver Availability date: November 2009 consistent control of symptomsCopyright across a For personalManufacturer: use Shire only full day (Table 1). Dosing forms: 1-mg, 2-mg, 3-mg, and 4-mg extended-release tablets Recommended dosage: 0.05 to 0.12 mg/kg Clinical implications once daily GXR exhibits enhancement of noradren- ergic pathways through selective direct receptor action in the prefrontal cortex.3 brain believed to play a major role in at- This mechanism of action is different from tentional and organizational functions that that of other FDA-approved ADHD medi- preclinical research has linked to ADHD.3 cations. GXR can be used alone or in com- The postsynaptic α-2A receptor is bination with stimulants or atomoxetine thought to play a central role in the opti- for treating complex ADHD, such as cases mal functioning of the PFC as illustrated accompanied by oppositional features and by the “inverted U hypothesis of PFC ac- emotional dysregulation or characterized tivation.”4 In this model, cyclic adenos- by partial stimulant response. ine monophosphate (cAMP) levels build within the prefrontal cortical neurons and cause specifi c ion channels—hyper- How it works polarization-activated cyclic nucleotide Guanfacine—originally developed as an gated (HCN) channels—to open on den- immediate-release (IR) antihypertensive— dritic spines of these neurons.5 Activa- reduces sympathetic tone, causing cen- tion of HCN channels effectively reduces trally mediated vasodilation and reduced membrane resistance, cutting off synaptic heart rate. Although GXR’s mechanism of inputs and disconnecting PFC network action in ADHD is not known, the drug is a connections. Because α-2A receptors are selective α-2A receptor agonist thought to directly engage postsynaptic receptors in Dr. Sallee is professor, department of psychiatry, University of Current Psychiatry the prefrontal cortex (PFC), an area of the Cincinnati College of Medicine, Cincinnati, OH. Vol. 9, No. 1 49 For mass reproduction, content licensing and permissions contact Dowden Health Media. 49_CPSY0110 49 12/16/09 11:50:12 AM Out of the Pipeline Table 2 Randomized, controlled trials supporting GXR’s eff ectiveness for treating ADHD symptoms Study Subjects GXR dosages Results Biederman et al, 20087; 345 ADHD patients 2, 3, or 4 mg given GXR was associated phase III, forced-dose age 6 to 17 once daily for 8 weeks with significantly lower parallel-design ADHD-RS-IV score compared with placebo (-16.7 vs -8.9) Sallee et al, 20098; 324 ADHD patients 1,* 2, 3, or 4 mg given GXR was associated phase III, forced-dose age 6 to 17 once daily for 9 weeks with significantly lower parallel-design ADHD-RS-IV score compared with placebo (-19.6 vs -12.2) Clinical Point Connor et al, 20099; 217 complex ADHD Starting dose 1 mg/d, GXR was associated collateral study patients age 6 to 12 titrated to a maximum with significantly lower GXR provides a with oppositional of 4 mg/d for a total of scores on CPRS-R:L broad but fl at symptoms 8 weeks oppositional subscale (-10.9 vs -6.8) and concentration profi le ADHD-RS-IV (-23.8 vs -11.4) compared with placebo *1-mg dose was given only to subjects weighing <50 kg (<110 lbs) ADHD: attention-defi cit/hyperactivity disorder; ADHD-RS-IV: Attention-Defi cit/Hyperactivity Disorder Rating Scale-IV; CPRS-R:L: Conners’ Parent Rating Scale-Revised: Long Form; GXR: guanfacine extended release located in proximity to HCN channels, GXR’s once-daily formulation is imple- their stimulation by GXR closes HCN mented by a proprietary enteric-coated sus- channels, inhibits further production of tained release mechanism8 that is meant to: cAMP, and reestablishes synaptic function • control absorption and the resulting network connectivity.5 • provide a broad but fl at plasma con- Blockade of α-2A receptors by yohimbine centration profi le reverses this process, eroding network • reduce inter-individual variation of connectivity, and in monkeys has been guanfacine exposure. demonstrated to impair working memo- Compared with IR guanfacine, GXR ry,6 damage inhibition/impulse control, exhibits delayed time of maximum con- and produce locomotor hyperactivity. centration (Tmax) and reduced maximum Direct stimulation by GXR of the post- concentration (Cmax). Therapeutic con- synaptic α-2A receptors is thought to: centrations can be sustained over longer • strengthen working memory periods with reduced peak-to-trough fl uc- • reduce susceptibility to distraction tuation,8 which tends to improve tolerabil- • improve attention regulation ity and symptom control throughout the • improve behavioral inhibition day. The convenience of once-daily dosing • enhance impulse control.7 also may increase adherence. GXR’s pharmacokinetic characteristics do not change with dose, but high-fat meals Pharmacokinetics will increase absorption of the drug—Cmax GXR offers enhanced pharmaceutics rela- increases by 75% and area under the plasma tive to IR guanfacine. IR guanfacine exhib- concentration time curve increases by 40%. its poor absorption characteristics—peak Because GXR primarily is metabolized plasma concentration is achieved too rap- through cytochrome P450 (CYP) 3A4, CY- idly and then declines precipitously, with P3A4 inhibitors such as ketoconazole will Current Psychiatry 50 January 2010 considerable inter-individual variation. increase guanfacine plasma concentrations 50_CPSY0110 50 12/16/09 11:50:17 AM Out of the Pipeline Figure Incidence of somnolence, sedation, and fatigue in study patients receiving GXR with or without psychostimulants 60 All subjects GXR monotherapy 50 GXR and psychostimulants 40 30 Incidence (%) 20 Clinical Point 10 In 2 trials, patients 0 experienced Somnolence, Somnolence Sedation Fatigue sedation, or fatigue events signifi cant improvements in In an open-label continuation study of 259 patients treated with guanfacine extended release (GXR), ADHD-RS-IV score somnolence, sedation, or fatigue was reported by 49% of subjects overall, 59% of those who received GXR monotherapy, and 11% of those given GXR with a psychostimulant. 1 to 2 weeks after starting GXR GXR: guanfacine extended release Source: Reprinted with permission from Sallee FR, Lyne A, Wigal T, et al. Long-term safety and effi cacy of guanfacine extended release in children and adolescents with attention-defi cit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2009;19(3):215-226 and elevate the risk of adverse events such increments of 1 mg/week, and investiga- as bradycardia, hypotension, and sedation. tors evaluated participants’ ADHD signs Conversely, CYP3A4 inducers such as ri- and symptoms once a week using the clini- fampin will signifi cantly reduce total guan- cian administered and scored ADHD Rat- facine exposure. Coadministration of val- ing Scale-IV (ADHD-RS-IV). The primary proic acid with GXR can result in increased outcome was change in total ADHD-RS-IV valproic acid levels, producing additive score from baseline to endpoint. CNS side effects. In both trials, patients taking GXR dem- onstrated statistically signifi cant improve- ments in ADHD-RS-IV score starting 1 to Effi cacy 2 weeks after they began receiving once- GXR reduced both inattentive and hyper- daily GXR: active/impulsive symptoms in 2 phase III, • In the fi rst trial, the mean reduction in forced-dose, parallel-design, randomized, ADHD-RS-IV total score at endpoint was placebo-controlled trials (Table 2). In the –16.7 for GXR compared with –8.9 for pla- fi rst trial,1 345 children age 6 to 17 received cebo (P < .0001). placebo or GXR, 2 mg, 3 mg, or 4 mg once • In the second, the reduction was –19.6 daily for 8 weeks. In the second study,2 324 for GXR and –12.2 for placebo (P = .004). children age 6 to 17 received placebo or Placebo-adjusted least squares mean GXR, 1 mg, 2 mg, 3 mg, or 4 mg, once daily changes from baseline were statistically for 9 weeks; the 1-mg dose was given only signifi cant for all GXR doses in the ran- to patients weighing <50 kg (<110 lbs). domized treatment groups in both studies. Current Psychiatry In both trials, doses were increased in Secondary effi cacy outcome measures Vol. 9, No. 1 51 continued on page 58 51_CPSY0110 51 12/16/09 11:50:21 AM Out of the Pipeline INVEGA® (paliperidone) Extended-Release Tablets Overall, of the total number of subjects in schizophrenia clinical studies of continued from page 51 INVEGA® (n = 1796), including those who received INVEGA® or placebo, 125 (7.0%) were 65 years of age and older and 22 (1.2%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these included the Conners’ Parent Rating Scale-Revised: subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but Short Form (CPRS-R) and the Conners’ Teacher Rat- greater sensitivity of some older individuals cannot be ruled out. ing Scale-Revised: Short Form (CTRS-R). This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with moderate to severe renal impairment [see Clinical Signifi cant improvements were seen on both Pharmacology (12.3) in full PI], who should be given reduced doses.