Pharmacokinetics and Pharmacodynamics of Immediate-Release Versus Extended-Release Guanfacine in Adult Daily Smokers.

BACKGROUND: Guanfacine is Food and Drug Administration approved for hypertension and attention-deficit hyperactivity disorder and has been used off-label for migraine prophylaxis, heroin withdrawal, and more recently smoking cessation. Previous studies have shown positive effects of 3 mg/d of immediate-release (IR) guanfacine on smoking outcomes, but the dose equivalency of the IR and extended-release (ER) formulations is unknown. PROCEDURES: A within-subject design was used to compare the pharmacokinetics and pharmacodynamics of 3 mg/d of IR, 4 mg/d of ER, and 6 mg/d of ER guanfacine in adult daily smokers (n = 5). Plasma medication levels, vital signs, cigarettes per day, tobacco craving, and adverse events were assessed. Medication was titrated to stable dosing after each laboratory day (3 mg/d IR, then 4 mg/d ER, then 6 mg/d ER). RESULTS: Plasma medication levels did not differ between the 3 mg/d of IR and 4 mg/d of ER doses after 24 hours from last dose and were highest at the 6 mg/d of ER dose (3 mg/d IR: M = 3.40 ng/mL, SE = 0.34 vs 4 mg/d ER: M = 3.46 ng/mL, SE = 0.67 vs 6 mg/d ER: M = 5.92 ng/mL, SE = 1.02). All doses of guanfacine decreased heart rate and blood pressure from baseline. Absolute values of cigarettes per day (6 mg/d ER) and tobacco craving (4 and 6 mg/d ER) were lowest with the ER formulations. Treatment-emergent adverse events were subject rated as minimal to mild, except dry mouth. CONCLUSIONS: We demonstrated similar pharmacokinetic profiles between 3 mg/d of IR guanfacine and 4 mg/d of ER guanfacine, as hypothesized. All doses of guanfacine were well tolerated.

Metabolite profiling of guanfacine in plasma and urine of healthy Japanese subjects after oral administration of guanfacine extended-release tablets.

Guanfacine is used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), metabolite profiling of guanfacine was performed in plasma and urine collected from healthy Japanese adults following repeated oral administration of guanfacine extended-release formulation. Unchanged guanfacine was the most abundant component in both plasma and urine (from the MS signal intensity). In plasma, the M3 metabolite (a sulfate of hydroxy-guanfacine) was the prominent metabolite; the M2 metabolite (a glucuronide of a metabolite formed by monooxidation of guanfacine), 3-hydroxyguanfacine and several types of glucuronide at different positions on guanfacine were also detected. In urine, the M2 metabolite and 3-hydroxyguanfacine were the principal metabolites. From metabolite analysis, the proposed main metabolic pathway of guanfacine is monooxidation on the dichlorobenzyl moiety, followed by glucuronidation or sulfation. A minor pathway is glucuronidation at different positions on guanfacine. As the prominent metabolites in plasma were glucuronide and sulfate of hydroxyguanfacine, which have no associated toxicity concerns, further toxicity studies of the metabolites, for example in animals, were not deemed necessary.

A thorough QT study of guanfacine.

OBJECTIVES: Guanfacine extended- release (GXR) is approved for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. As part of the clinical development of GXR, and to further explore the effect of guanfacine on QT intervals, a thorough QT study of guanfacine was conducted (ClinicalTrials. gov identifier: NCT00672984). METHODS: In this double-blind, 3-period, crossover trial, healthy adults (n = 83) received immediaterelease guanfacine (at therapeutic (4 mg) and supra-therapeutic (8 mg) doses), placebo, and 400 mg moxifloxacin (positive control) in 1 of 6 randomly assigned sequences. Continuous 12-lead electrocardiograms were extracted, and guanfacine plasma concentrations were assessed pre-dose and at intervals up to 24 hours post-dose. QT intervals were corrected using 2 methods: subject-specific (QTcNi) and Fridericia (QTcF). Time-matched analyses examined the largest, baseline-adjusted, drug-placebo difference in QTc intervals. RESULTS: In the QTcNi analysis, the largest 1-sided 95% upper confidence bound (UCB) through hour 12 was 1.94 ms (12 hours postdose). For the 12-hour QTcF analysis, the largest 1-sided 95% UCB was 10.34 ms (12 hours post-supratherapeutic dose), representing the only 1-sided 95% UCB > 10 ms. Following the supra-therapeutic dose, maximum guanfacine plasma concentration was attained at 5.0 hours (median) post-dose. Assay sensitivity was confirmed by moxifloxacin results. Among guanfacine-treated subjects, most treatment-emergent adverse events were mild (78.9%); dry mouth (65.8%) and dizziness (61.8%) were most common. CONCLUSIONS: Neither therapeutic nor supra-therapeutic doses of guanfacine prolonged QT interval after adjusting for heart rate using individualized correction, QTcNi, through 12 hours postdose. Guanfacine does not appear to interfere with cardiac repolarization of the form associated with pro-arrhythmic drugs.

Development and validation of a simple, sensitive and accurate LC-MS/MS method for the determination of guanfacine, a selective α2A -adrenergicreceptor agonist, in plasma and its application to a pharmacokinetic study.

A simple, practical, accurate and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and fully validated for the quantitation of guanfacine in beagle dog plasma. After protein precipitation by acetonitrile, the analytes were separated on a C18 chromatographic column by methanol and water containing 0.1% (v/v) formic acid with a gradient elution. The subsequent detection utilized a mass spectrometry under positive ion mode with multiple reaction monitoring of guanfacine and enalaprilat (internal standard) at m/z 246.2 → 159.0 and m/z 349.2 → 205.9, respectively. Good linearity was obtained over the concentration range of 0.1-20 ng/mL for guanfacine in dog plasma and the lower limit of quantification of this method was 0.1 ng/mL. The intra- and inter-day precisions were <10.8% relative standard deviation with an accuracy of 92.9-108.4%. The matrix effects ranged from 89.4 to 100.7% and extraction recoveries were >90%. Stability studies showed that both analytes were stable during sample preparation and analysis. The established method was successfully applied to an in vivo pharmacokinetic study in beagle dogs after a single oral dose of 4 mg guanfacine extended-release tablets.

Population pharmacokinetic and exposure-response analyses of guanfacine in Japanese pediatric ADHD patients.

Guanfacine hydrochloride extended-release tablet (GXR) is approved for child and adolescent patients with attention-deficit/hyperactivity disorder (ADHD). The aims of this study were to develop a population pharmacokinetic model of guanfacine after administration of GXR and to evaluate factors influencing the pharmacokinetics of guanfacine in pediatric ADHD patients. A population pharmacokinetic analysis was performed using 3231 plasma concentration data items of guanfacine for pediatric ADHD patients aged 6-17 years obtained from clinical studies in Japan and the US. In addition, the relationship of the ADHD Rating Scale IV (ADHD RS-IV, efficacy endpoint) total score with exposure to guanfacine was assessed for Japanese pediatric ADHD patients. A one-compartment model with first-order absorption and lag time well described the plasma concentration data of guanfacine in pediatric ADHD patients. Body weight was selected as a covariate of apparent total body clearance and apparent volume of distribution. There was no pharmacokinetic difference between Japanese and non-Japanese pediatric ADHD patients. The results suggested a tendency of exposure-dependent reduction in the ADHD RS-IV total score, whereas the reduction was observed even at low plasma exposure levels compared with the placebo group.

Development of Guanfacine Extended-Release Dosing Strategies in Children and Adolescents with ADHD Using a Physiologically Based Pharmacokinetic Model to Predict Drug-Drug Interactions with Moderate CYP3A4 Inhibitors or Inducers.

BACKGROUND: Guanfacine extended-release (GXR) is an orally administered, non-stimulant treatment for children and adolescents with attention-deficit/hyperactivity disorder (ADHD) and is primarily metabolized by the 3A4 isozyme of cytochrome P450 (CYP3A4). The results of clinical pharmacokinetic (PK) studies indicate that guanfacine is sensitive to drug-drug interactions (DDIs) perpetrated by strong inhibitors and inducers of CYP3A4. OBJECTIVE: The aim was to provide guidance on the possible requirement for GXR dose adjustment in children and adolescents with ADHD by predicting DDIs following co-administration with moderate CYP3A4 inhibitors and inducers. METHODS: A physiologically based PK model for GXR orally administered to healthy adults was developed based on physicochemical, in vitro and clinical PK data. The model was validated using clinical PK data for co-administration of GXR with ketoconazole (strong CYP3A4 inhibitor) or rifampicin (strong CYP3A4 inducer). RESULTS: Model predictions indicated that co-administration of GXR with the moderate CYP3A4 inhibitors erythromycin 500 mg three times a day or fluconazole 200 mg daily (q.d.) increased the guanfacine area under the plasma concentration-time curve (AUC) by 2.31-fold or 1.98-fold, respectively, compared with GXR monotherapy. The moderate CYP3A4 inducer efavirenz 400 mg or 600 mg q.d. was predicted to reduce guanfacine AUC to 58 or 33% of its value for GXR monotherapy, respectively. CONCLUSION: Without the requirement for additional clinical studies, the following GXR dose recommendations were developed and approved for US labeling for use in children and adolescents with ADHD: (1) decrease GXR to 50% of the usual target dose when it is co-administered with strong or moderate CYP3A4 inhibitors; (2) consider titrating GXR up to double the usual target dose over 1-2 weeks when it is co-administered with strong or moderate CYP3A4 inducers.

A phase I, randomized, open-label, crossover study of the single-dose pharmacokinetic properties of guanfacine extended-release 1-, 2-, and 4-mg tablets in healthy adults.

BACKGROUND: Guanfacine is an alpha(2)-adrenoreceptor agonist used to treat children and adults with attention-deficit/hyperactivity disorder. An extended-release formulation of guanfacine is currently under development. OBJECTIVE: The objective of this study was to assess the single-dose pharmacokinetic properties and dose proportionality of guanfacine extended-release (GXR) tablets after oral administration in healthy adults. METHODS: This was a Phase I, randomized, open-label, single-dose, crossover trial of GXR 1-, 2-, and 4-mg tablets in healthy adults. In the lead-in period (period 1), subjects received a single GXR 1-mg tablet, and then were randomized to receive single GXR 2- or 4-mg tablets during 4 separate weekly visits. Vital signs were monitored, blood samples were obtained, and subjects underwent electrocardiography (ECG) before dose administration and at regular intervals over 96 hours. The pharmacokinetic parameters of CmaX, AUC(0-t), and AUC(0-infinity) were determined after each dose of GXR in all subjects. Summary statistics for the concentration-time data were analyzed to assess between-dose linearity. An analysis-of-variance model was constructed to test the concentration-time data for dose proportionality. Tolerability was assessed at each visit through the analysis of standard serology tests; urinalysis/drug screen reports; and physical examination, including height and weight measurements; vital-sign data; and ECG findings. RESULTS: The total study enrollment was 52 subjects, including 28 men (53.8%) and 24 (46.2%) women. The subjects had a mean (SD) age of 32.9 (10.3) years (range, 18-54 years) and a mean (SD) body weight of 73.4 (15.7) kg (range, 49.6-120.0 kg). Forty (76.9%) subjects were Hispanic, 7 (13.5%) were white, and 5 (9.6%) were black. Three subjects were discontinued by the study investigators because of noncompliance with study procedures or use of concomitant medications. Forty-nine subjects completed the study. Mean (SD) values for guanfacine plasma concentrations with GXR 1, 2, and 4 mg, respectively, were 0.98 (0.26), 1.57 (0.51), and 3.58 (1.39) ng/mL for C(max); 29.3 (8.84), 54.5 (17.7), and 119.1 (42.3) ng/mL . h(-1) for AUC(0-t); and 32.4 (8.78), 58.0 (18.9), and 124.1 (45.1) ng/mL . h(-1) for AUC(0-infinity) . Mean (SD) t((1/2)) values were 17.5 (3.8), 16.6 (3.8), and 16.7 (4.90) hours for GXR 1, 2, and 4 mg, respectively. The geometric mean ratios for C(max), AUC(0-t), and AUC(0-infinity) were proportional to dose between GXR 1 and 2 mg, 1 and 4 mg, and 2 and 4 mg, except for the increase in C(max) between GXR 1 and 2 mg. All treatment-emergent adverse events (AEs) were assessed as mild or moderate and resolved without treatment with the exception of headache in 3 subjects and 1 case of lower back discomfort, which resolved with therapy. Left rib pain was reported in 1 subject, but it is unknown if it had resolved, since the subject was lost to followup. No subjects withdrew from participation or were discontinued by the study investigators as a result of AEs. The most common treatment-emergent AE, somnolence, occurred in 33 (63.5%) of 52 subjects. All mean vital-sign measurements and mean ECG parameters remained within normal limits after dosing and no marked changes from baseline measurements were noted. Mean values for all test results of hematology and serum chemistry panels were within the reference range at completion of the study, with no significant changes from baseline. CONCLUSIONS: In these 49 healthy adult subjects, the single-dose pharmacokinetic properties of GXR 1-, 2-, and 4-mg tablets appeared to be statistically linear; that is, increases in mean C(max), AUC(0-t), and AUC(0-infinity) of guanfacine were proportional to dose, with the exception of the increase in mean C(max) between GXR 1 and 2 mg. All doses appeared to be well tolerated, with no serious AEs or withdrawal or discontinuation from study participation due to AEs reported.

Pharmacokinetics of a guanfacine extended-release formulation in children and adolescents with attention-deficit-hyperactivity disorder.

STUDY OBJECTIVE: To evaluate the single- and multiple-dose pharmacokinetics of an oral extended-release formulation of guanfacine in children and adolescents with a diagnosis of attention-deficit-hyperactivity disorder (ADHD). DESIGN: Phase I-II, open-label, dose-escalation study. SETTING: Clinical study center. PATIENTS: Fourteen children (aged 6-12 yrs) and 14 adolescents (aged 13-17 yrs) with ADHD. INTERVENTION: All patients received guanfacine as a single 2-mg dose on day 1. They received a daily dose of 2 mg on days 9-15, 3 mg on days 16-22, and 4 mg on days 23-29. MEASUREMENTS AND MAIN RESULTS: Blood samples, vital signs, and electrocardiograms (ECGs) were obtained before dosing on day 1 and at intervals over 24 hours, with repeat measurements on days 14 and 28. Guanfacine demonstrated linear pharmacokinetics. Mean plasma concentrations, peak exposure (C(max)), and total or 24-hour exposure (area under the concentration-time curve [AUC](0-infinity) or AUC(0-24), respectively) were as follows in children and adolescents, respectively: after a single 2-mg dose, AUC(0-infinity) was 65.2 +/- 23.9 ng x hour/ml and 47.3 +/- 13.7 ng x hour/ml and C(max) was 2.55 +/- 1.03 ng x ml and 1.69 +/- 0.43 ng/ml after multiple 2-mg doses, AUC(0-24) was 70.0 +/- 28.3 ng x hour/ml and 48.2 +/- 16.1 ng x hour/ml and C(max) was 4.39 +/- 1.66 ng/ml and 2.86 +/- 0.77 ng/ml; and after multiple 4-mg doses, AUC(0-24) was 162 +/- 116 ng x hour/ml and 117 +/- 28.4 ng x hour/ml and C(max) was 10.1 +/- 7.09 ng/ml and 7.01 +/- 1.53 ng/ml. After a single 2-mg dose, half-life was 14.4 +/- 2.39 hours in children and 17.9 +/- 5.77 hours in adolescents. The most frequent treatment-emergent adverse events were somnolence, insomnia, headache, blurred vision, and altered mood. Most were mild to moderate in severity, with the highest frequency associated with the 4-mg doses. Blood pressure, pulse, and ECG reading.hour/ml s were all within normal limits. CONCLUSION: Guanfacine extended-release formulation demonstrated linear pharmacokinetics. Plasma concentrations and concentration-related pharmacokinetic parameters were higher in children than in adolescents. These differences are likely due to heavier body weights in adolescents and young male subjects. No serious adverse events were reported.

Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Guanfacine Extended-Release Formulation in Healthy Japanese and Caucasian Male Adults.

BACKGROUND AND OBJECTIVE: Guanfacine extended-release (guanfacine XR) could be a useful treatment option for children and adolescent patients with attention-deficit/hyperactivity disorder (ADHD). As an initial step in the development in Japan, the pharmacokinetics, safety and tolerability were assessed in healthy Japanese and non-Hispanic Caucasian adults. METHODS: A Phase 1, double-blind, randomized, placebo-controlled, single- and multiple-oral dose escalation study of guanfacine XR was conducted. Healthy Japanese and Caucasian subjects received guanfacine XR 1 mg orally in the morning on Day 1. Following safety assessments, subjects subsequently received guanfacine XR 1 mg (Days 4-8), 2 mg (Days 9-13), 3 mg (Days 14-18), and 4 mg (Days 19-23) once daily, followed by a taper-down period. Single- and multiple-dose pharmacokinetic parameters were estimated based on plasma concentration-time data and urine concentration data of guanfacine by non-compartmental analysis. RESULTS: A total of 30 male subjects (15 Japanese and 15 Caucasian, active:placebo = 12:3) were enrolled. Of those receiving guanfacine XR, 11/12 (91.7%) subjects in each active drug group completed the study. Following multiple doses, the mean area under the plasma concentration-time curves of guanfacine were 9-22% greater for Caucasian subjects than Japanese subjects in the 1-3 mg dose range and 54% greater for the 4 mg. Guanfacine XR was generally well tolerated by both ethnic groups, with most adverse events being mild in both groups. There were no serious or severe adverse events during the study and no adverse events led to withdrawal from the study. CONCLUSIONS: Exposure to guanfacine in Japanese subjects tended to be lower than in Caucasian subjects. Guanfacine XR was generally well tolerated and safety profiles were similar for Japanese and Caucasian subjects.

Guanfacine for the treatment of attention deficit hyperactivity disorder in children and adolescents.

Guanfacine is an α2A-adrenoreceptor agonist currently indicated for the treatment of attention deficit hyperactivity disorder (ADHD). This article reviews the chemistry, pharmacodynamics and pharmacokinetics of guanfacine, as well as the clinical trial literature on guanfacine for the treatment of ADHD in children and adolescents, mainly focusing on the use of guanfacine extended-release (GXR). Six already published prospective randomized controlled trials (RCTs) and one unpublished RCT study were identified for GXR in the treatment of ADHD. All RCTs trials showed superiority over placebo on the primary outcome measure. Guanfacine, especially XR, seems to be an effective and safe treatment option for ADHD in children and adolescents.

Population Pharmacokinetic Modeling of Guanfacine in Pediatric Patients.

INTRODUCTION: The population pharmacokinetics of guanfacine extended release were characterized in pediatric patients aged 6-17 years using NONMEM and evaluated by predictive check and bootstrap. METHODS: Data were described using a one-compartment model. A covariate modeling approach that emphasized parameter estimation rather than stepwise hypothesis testing was implemented. A nonparametric bootstrap procedure and a predictive check method were used to evaluate the final model and parameter estimates. RESULTS: Typical population pharmacokinetic parameters (95 % confidence interval), given the reference covariates (Caucasian, male, age 12 years, weight 50 kg), were 33.1 (30.2-36.4) L/h for apparent clearance (CL/F), 804 (703-900) L for apparent volume of distribution, 0.552 (0.437-0.670) h(-1) for the absorption rate constant, and 0.651 (0.608-0.697) h for absorption lag time. DISCUSSION: The pharmacokinetics of guanfacine are similar in pediatric patients compared with adults when appropriately scaled by patient weight. The main predictor of guanfacine exposure, as determined by a change in CL/F, was weight. Effects of the other covariates (age, sex, and race) on CL/F were estimated with reasonable precision; however, the additional effects of age, sex, and race can be considered to have little to no clinical relevance.

Guanfacine extended release for the treatment of attention-deficit/hyperactivity disorder in children and adolescents.

INTRODUCTION: Guanfacine extended release (GXR) is a selective α(2A)-adrenoreceptor agonist originally developed as an antihypertensive agent and now FDA approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) as monotherapy and as adjunctive to psychostimulants in children and adolescents 6-17 years old. AREAS COVERED: Search of the PubMed and PsycInfo databases from 1990 to 2014 using the search term 'guanfacine'. Studies selected for review were either controlled or open trials of guanfacine or GXR. Shire Pharmaceuticals, Inc. was contacted and supplied a synopsis of all available ADHD studies on GXR for review. EXPERT OPINION: GXR is an evidence-based treatment for ADHD in children and adolescents. Because this compound has a smaller effect size than psychostimulants for the symptoms of ADHD, it is generally considered a second-line treatment after the psychostimulants or in combination with psychostimulants. Evidence for efficacy is more robust in children than for adolescents. Because of its pharmacodynamic actions in prefrontal cortex, GXR shows considerable promise for other behavioral conditions frequently comorbid with ADHD and potential promise for emotional and behavioral dysregulation secondary to traumatic stress.

Pharmacokinetics and pharmacodynamics of guanfacine extended release in adolescents aged 13-17 years with attention-deficit/hyperactivity disorder.

The safety and efficacy of guanfacine extended release (up to 4 mg/day) for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents aged 6-17 years is well documented. Data suggest that weight-adjusted doses of guanfacine extended release >0.08 mg/kg but ≤0.12 mg/kg, if tolerated, may provide additional clinical benefits. For many adolescents, such dosing would exceed 4 mg/day, the highest approved dose. This open-label multicenter study evaluated the safety, tolerability, and steady-state pharmacokinetics of guanfacine extended release at escalated forced doses ≤9 mg/day in adolescents (N = 31) aged 13-17 years with ADHD. Following doses of approximately 0.12 mg/kg, the highest weight group (>70-90 kg) exhibited lower mean clearance at steady-state than the lowest weight group (≥30-50 kg). Consistent with its known antihypertensive effects, guanfacine extended release was associated with dose-dependent decreases in blood pressure (BP) and heart rate (HR). The physiologic response of increased BP upon standing was blunted in a dose-related manner while the physiologic response of increased HR upon standing was not substantively affected. The most common treatment-emergent adverse events were somnolence, dizziness, and sinus bradycardia. These results, and those from prior studies, support further examination of the efficacy and safety of higher weight-adjusted doses of guanfacine extended release for ADHD.

Pharmacokinetics of coadministration of guanfacine extended release and methylphenidate extended release.

BACKGROUND: α2-Adrenoceptor agonists are used adjunctively to psychostimulants in treating attention-deficit/hyperactivity disorder (ADHD) when psychostimulants alone do not sufficiently reduce symptoms. However, data on the pharmacokinetic profiles and safety of combination treatments in ADHD are needed. OBJECTIVE: The primary objective of this study was to evaluate the pharmacokinetic profiles of guanfacine extended release (GXR) and methylphenidate hydrochloride (MPH) extended release, alone and in combination. STUDY DESIGN: This was an open-label, randomized, three-period crossover, drug-drug interaction study. SETTING: The study was conducted at a single clinical research center. PARTICIPANTS: Thirty-eight healthy adults were randomized in this study. INTERVENTIONS: Subjects were administered single oral doses of GXR (Intuniv(®); Shire Development LLC, Wayne, PA, USA) 4 mg, MPH (Concerta(®); McNeil Pediatrics, Titusville, NJ, USA) 36 mg, or GXR and MPH combined. MAIN OUTCOME MEASURES: Guanfacine, dexmethylphenidate (d-MPH), and l-methylphenidate (l-MPH) levels were measured with blood samples collected predose and up to 72 h postdose. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms (ECGs). RESULTS: Thirty-five subjects completed the study. Analyses of the 90 % confidence intervals (CIs) for the geometric mean ratios of the maximum plasma concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUC∞) values for guanfacine and d-MPH following administration of GXR or MPH alone or combined met strict bioequivalence criteria (90 % CIs within the interval of 0.80-1.25). Overall, combining GXR and MPH did not alter the pharmacokinetic parameters of either medication. Sixteen subjects (42.1 %) had at least one TEAE. The most commonly reported TEAEs included headache and dizziness following GXR, MPH, and GXR and MPH combined. Two subjects had clinically significant abnormalities in ECG results following coadministration: both events were mild and resolved the same day. CONCLUSIONS: In this short-term, open-label study of healthy adults, coadministration of GXR and MPH did not result in significant pharmacokinetic drug-drug interactions. No unique TEAEs were observed with coadministration of GXR and MPH compared with either treatment alone.

Pharmacokinetics of coadministered guanfacine extended release and lisdexamfetamine dimesylate.

BACKGROUND: In clinical practice, α2-adrenoceptor agonists have been adjunctively administered with psychostimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD). Two studies have examined the adjunctive use of guanfacine extended release (GXR, Intuniv®; Shire Development LLC, Wayne, PA, USA) with psychostimulants in children and adolescents with a suboptimal response to psychostimulant treatment. However, the potential for pharmacokinetic drug-drug interactions (DDIs) between GXR and lisdexamfetamine dimesylate (LDX, Vyvanse®; Shire US LLC, Wayne, PA, USA) has not been thoroughly evaluated. OBJECTIVE: The primary objective of this study was to examine the pharmacokinetics of GXR 4 mg and LDX 50 mg given as single doses alone and in combination. STUDY DESIGN: This was an open-label, randomized, three-period crossover, DDI study. SETTING: The study was conducted in a single clinical research center. PARTICIPANTS: Forty-two healthy adults were randomized in this study. INTERVENTIONS: Subjects were administered single oral doses of GXR 4 mg, LDX 50 mg, or GXR and LDX in combination. MAIN OUTCOME MEASURES: Blood samples collected predose and up to 72 h postdose assessed guanfacine, LDX, and d-amphetamine levels. Bioequivalence was defined as the 90% confidence intervals (CIs) of the geometric mean ratios of the area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) and maximum plasma concentration (Cmax) falling within the bioequivalence reference interval (0.80-1.25). Safety measures included adverse events, vital signs, and electrocardiograms (ECGs). RESULTS: Forty subjects completed the study. Following administration of LDX alone or in combination with GXR, the statistical comparisons of the AUC0-∞ and Cmax of d-amphetamine fell entirely within the reference interval. For guanfacine, the 90% CI of the geometric mean ratio of AUC∞ for the two treatments was within the bioequivalence criteria, but for Cmax the upper bound of the 90% CI exceeded the standard range for bioequivalence by 7%. This relatively small change is unlikely to be clinically meaningful. Treatment-emergent adverse events (TEAEs) were reported by 42.9% of subjects; the most commonly reported TEAEs included dizziness (5.0, 7.3, and 7.3%) and headache (7.5, 4.9, and 7.3%) following administration of GXR, LDX, and GXR and LDX in combination, respectively. Clinically significant ECG abnormalities occurred in one subject following administration of LDX and in one subject following coadministration of GXR and LDX. CONCLUSIONS: In healthy adults, coadministration of GXR and LDX did not result in a clinically meaningful pharmacokinetic DDI compared with either treatment alone. No unique TEAEs were observed with coadministration of GXR and LDX compared with either treatment alone.

Guanfacine ER for the treatment of adolescent attention-deficit/hyperactivity disorder.

INTRODUCTION: Guanfacine extended release (GXR) is an alpha 1A noradrenergic agonist that has been approved by the FDA for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) as a monotherapy, and as an adjunctive therapy to stimulants for the treatment of ADHD in children and adolescents age 6 - 17. AREAS COVERED: PubMed, the Ovid Medline database, and the PsycInfo database were searched using the term 'guanfacine'. Results were then limited to criteria such as English and human, from 1990 through December 2011. The resulting yield from the comprehensive literature search was 4391 articles. The titles and abstracts of all articles were reviewed. Studies were selected for full-text review based upon their place in the hierarchy of evidence (e.g., randomized controlled trials), relevance and quality of individual studies, and generalizability to clinical practice. The search was augmented by further search of article reference lists. A total of 15 articles were selected for full-text examination. EXPERT OPINION: Due to the absence of positive evidence for the efficacy of GXR for monotherapy in adolescents, clinicians should be guarded in the use of GXR for monotherapy in adolescents with ADHD. The use of GXR has considerable promise as an adjunct to stimulants for other behavioral conditions associated with ADHD.

Metabolic, toxicological, and safety considerations for drugs used to treat ADHD.

INTRODUCTION: Pharmacotherapy is frequently used to treat symptoms of attention-deficit/hyperactivity disorder (ADHD), the most common neurobehavioral disorder of childhood. The typically prescribed agents for ADHD have varying durations of effect and degrees of efficacy. The broad range of pharmacological treatments available allows for both single and combination therapies for achieving optimal therapeutic effects. Metabolic, toxicological, and safety information are critical for an informed evaluation of the risk/benefit considerations in prescribing practices. AREAS COVERED: This article focuses on the medications with current FDA approval for use in the treatment of ADHD in pediatric and adult populations. This review covers the stimulants (amphetamine and methylphenidate) and non-stimulants (atomoxetine, clonidine extended release, and guanfacine extended release) used to treat ADHD and presents an overview of their respective metabolic, toxicological, and safety features. A literature search and review of the relevant medications were carried out using the PubMed database up to November 2011. EXPERT OPINION: New trends in study design based on drug profiles include the use of adjuvant therapies and the inclusion of patients with comorbidities. The recent expansion of inclusion/exclusion criteria in pediatric clinical trials of ADHD allows for a more rigorous analysis of associated benefits and risks with the use of adjuvant therapy.

Guanfacine extended release as adjunctive therapy to psychostimulants in children and adolescents with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder associated with a wide range of impairments. Psychostimulants are generally first-line pharmacotherapy, but symptom improvement is suboptimal in some patients. In these patients, clinicians frequently use a combination of psychostimulants and nonscheduled medications to manage ADHD, although published evidence supporting this practice was relatively scarce until recently.Guanfacine extended release (GXR), a selective alpha2A-adrenoceptor agonist, is approved as a monotherapy and adjunctive therapy to psychostimulant medications for ADHD in patients 6-17 years of age. Drug-drug interaction studies have demonstrated that the adjunctive administration of GXR with a long-acting methylphenidate preparation or lisdexamfetamine dimesylate did not change exposure to the active components of either medication in a clinically meaningful way compared with either treatment alone.Data supporting the potential efficacy of GXR adjunctive to psychostimulants were preliminarily observed in a 9-week, open-label, dose-escalation study and subsequent extension study (≤ 24 months) in subjects aged 6-17 years with suboptimal control of ADHD symptoms on psychostimulant monotherapy. In a subsequent 9-week, randomized, double-blind, placebocontrolled study of subjects aged 6-17 years with suboptimal response to a long-acting, extendedrelease, oral psychostimulant, adjunctive GXR (administered in the morning or evening) was associated with significantly greater symptom reduction than placebo and psychostimulant (ADHD Rating Scale IV [ADHD-RS-IV] total score, placebo-adjusted least squares mean reductions: GXR AM, -4.5, P = 0.002; GXR PM, -5.3, P < 0.001, based on Dunnett's test). Across multiple studies, the safety and tolerability profile of GXR administered adjunctively to psychostimulants has been consistent with the known profiles of each medication. Additional studies should further explore the role of adjunctive GXR in clinical practice to help identify those patients most likely to benefit from such therapy.

Guanfacine extended-release for attention-deficit/hyperactivity disorder (ADHD).

IMPORTANCE OF THE FIELD: Guanfacine extended-release (GXR) is a non-stimulant approved in the US for treatment of attention deficit/hyperactivity disorder (ADHD). GXR is a 'first in class' α(2A)-adrenoceptor agonist reformulated to optimize efficacy. GXR enters a rapidly growing but crowded ADHD market as an alternative not only to psychostimulants but also to atomoxetine. AREAS COVERED IN THIS REVIEW: Pharmacodynamics, pharmacokinetics, clinical efficacy and safety of GXR are covered based on a literature review (MEDLINE and EMBASE) from 1980 to 2010. Two large pivotal controlled trials are reviewed along with companion safety studies over 24 months. Collateral studies in ADHD children with oppositional symptoms and combination use of GXR in psychostimulant partial-responders are featured. WHAT THE READER WILL GAIN: Novel aspects of apparent GXR mechanism of action may complement existing treatments. Study evidence indicates that GXR is a well-tolerated and effective treatment for children and adolescents with ADHD, and appears efficacious to reduce oppositional symptoms in children with these complicating features. The GXR safety database reflects mild and asymptomatic decreases in both blood pressure and heart rate throughout, with most adverse events being somnolence-related and time-limited. TAKE HOME MESSAGE: This review of GXR will allow the reader to determine the place for GXR in the ADHD treatment landscape.