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.

Use of ECG restitution (beat-to-beat QT-TQ interval analysis) to assess arrhythmogenic risk of QTc prolongation with guanfacine.

BACKGROUND: Guanfacine (Intuniv) is a centrally active alpha-2A adrenergic agonist for the new indication of attention-deficit/hyperactivity disorder. QTc (QTcF and QTcNi) was prolonged at both therapeutic (4 mg) and supratherapeutic (8 mg) doses of a thorough QT study even though guanfacine has had a safe clinical history of over 3 million prescriptions for the treatment of hypertension. In an attempt to understand this disparity, retrospective evaluation of the continuous ECG data utilized dynamic beat-to-beat and ECG restitution analyses was performed. METHODS: Sixty healthy subjects using 24-hour Holters were examined in a 3-arm, placebo- and positive-controlled, double-blind crossover study for effects on beat-to-beat QT, TQ, and RR intervals. RESULTS: ECG restitution analyses indicated that, at all time points, a disproportionate effect to increase the TQ interval (rest) occurred more in relationship to each QT interval lengthening resulting in a placebo-adjusted reduced QT/TQ ratio of 21% after 4 mg and 31% after 8 mg (both antiarrhythmic responses). Additionally, the percentage of time and magnitude of stress on the heart, as measured by the upper limits of the QT/TQ ratio, were reduced with guanfacine by 22% to 24%. In contrast to guanfacine, moxifloxacin did not show a significant improvement in any restitution parameters but reflected a trend toward proarrhythmia with an increase in the QT/TQ ratio of up to 11%. CONCLUSION: These results indicate that guanfacine causes a stabilizing effect on cardiac restitution that helps reconcile the clinical evidence for a lack of arrhythmia liability despite apparent increases in typical QT/QTc prolongation measures.

Population pharmacokinetic/pharmacodynamic modeling of guanfacine effects on QTc and heart rate in pediatric patients.

Using a previously developed population pharmacokinetic model, an exposure-response (ER) model was successfully developed to describe guanfacine plasma concentrations and changes in heart rate (HR) and the QT interval. Guanfacine exposure was associated with small decreases in HR and a small prolongation of the population-corrected QT (QTcP) interval. Based on the final ER model for effect of guanfacine on HR, the estimated population typical decrease in HR would be 2.3% (2.1-2.7%) of the baseline circadian HR for every 1 ng/mL of guanfacine exposure. A QTcP was developed for the analysis using the sampled population. An effect of sex on baseline-corrected QT (BQTP) was the only covariate effect in the final ER model for QTcP, its inclusion resulting in a typical baseline QTcP estimate that is 9 (5-13) ms higher for females. There was no evidence of QT-RR hysteresis. A linear model was used to relate guanfacine plasma concentrations to QTcP. The typical (95% confidence interval) slope parameter was estimated to be 0.941 (0.62-1.25) ms/ng/mL. The final model predicted an approximate 1-ms increase from baseline for every 1 ng/mL of guanfacine in plasma. The main predictor of QTcP prolongation was guanfacine exposure, which decreased with body weight and increased with dose.

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.

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.

An open-label investigation of the pharmacokinetic profiles of lisdexamfetamine dimesylate and venlafaxine extended-release, administered alone and in combination, in healthy adults.

BACKGROUND: Lisdexamfetamine dimesylate (LDX), a prodrug consisting of d-amphetamine and l-lysine, is being studied in clinical trials of major depressive disorder. Additional drug-drug interaction studies were warranted. OBJECTIVE: This study aimed to describe the pharmacokinetics and safety of LDX and venlafaxine extended-release (VXR), alone or combined. STUDY DESIGN: The study was an open-label, two-arm, single-sequence crossover investigation with randomization to treatment sequence. SETTING AND PARTICIPANTS: The study was conducted at two clinical study centres and included healthy adult males and females (18-45 years of age). INTERVENTION: The study included two single-sequence crossover designs: LDX alone followed by LDX + VXR (Treatment Arm A); and VXR alone followed by VXR + LDX (Treatment Arm B). Drug treatment was initiated on day 1 with once-daily LDX or VXR alone with 15 days' titration to final dose (LDX 30, 50 and 70 mg for 5 days each; VXR 75, 150 and 225 mg for 5 days each). On days 16-30, VXR, titrated to a final dose of 225 mg, or LDX, titrated to a final dose of 70 mg, was coadministered for participants in Treatment Arm A or B, respectively. On days 31-38, VXR doses were tapered. MAIN OUTCOME MEASURES: On days 1-2, 15-16 and 30-31, safety evaluations and blood samples were obtained pre-dose through 24 h post-dose for analysis of LDX, d-amphetamine, venlafaxine (VEN), and O-desmethylvenlafaxine (ODV). Combination treatment was considered bioequivalent to single treatment if 90 % confidence intervals (CIs) for geometric mean ratios (GMRs) of analytes fell within the interval 0.80-1.25 based on maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) from time zero to time of last measurable concentration (AUCτ). Safety assessments included treatment-emergent adverse events (TEAEs), pulse rate and blood pressure (BP), clinical laboratory assessments, and 12-lead electrocardiograms (ECG). RESULTS: Among 80 enrolled subjects, 77 were included in pharmacokinetic and safety analyses. Combination LDX + VXR was bioequivalent to LDX alone, based on exposure to d-amphetamine (GMR [95 % CI], Cmax (ng/mL): 0.97 [0.82, 1.14], AUCτ: 0.95 [0.81, 1.12]). Exposure to VEN with LDX + VXR (vs. VXR alone) was increased (Cmax: 1.10 [0.88, 1.38], AUCτ: 1.13 [0.88, 1.45]) and ODV decreased (Cmax: 0.91 [0.77, 1.06], AUCτ: 0.83 [0.71, 0.96]), whereas composite VEN + ODV was bioequivalent to VXR alone (Cmax: 0.96 [0.84, 1.09], AUCτ: 0.98 [0.85, 1.13]). TEAEs with LDX or LDX + VXR were similar. Maximum mean increases from baseline were: pulse rate, +8.73 to 12.76 beats/min with either treatment alone and +17.67 to 20.85 beats/min with LDX + VXR; systolic BP, +4.32 to 6.56 mmHg with either treatment alone and +12.96 to 13.78 mmHg with LDX + VXR; diastolic BP, +5.39 to 5.74 mmHg with either treatment alone and +12.09 to 12.46 mmHg with LDX + VXR. One participant was withdrawn due to a serious TEAE (presyncope). No unexpected, clinically meaningful trends or changes from baseline in mean laboratory or ECG parameters were observed during the trial. CONCLUSION: In healthy adults, combination LDX + VXR (vs. LDX alone) did not alter exposure to d-amphetamine. Although small changes in exposure to VEN (increased) and ODV (decreased) were seen with combination treatment, total VEN + ODV exposure showed no change (vs. VEN alone). LDX + VXR led to increases in BP and pulse rate, supporting existing recommendations for vital sign monitoring when using these medications.

Pharmacokinetics and tolerability of anagrelide hydrochloride in young (18 - 50 years) and elderly (≥ 65 years) patients with essential thrombocythemia.

OBJECTIVE: To ascertain the role of patient age as an influencing factor in the pharmacokinetics of anagrelide and to clarify whether different dosing is required in young (18 - 50 years) vs. elderly (≥ 65 years) patients with essential thrombocythemia (ET). METHOD: This Phase II, multicenter, open-label study compared the pharmacokinetics, pharmacodynamics and tolerability of anagrelide and its active metabolite, 3-hydroxy-anagrelide, in young and elderly patients with ET. Three days prior to pharmacokinetic assessment, patients divided their normal daily anagrelide into a structured twice-daily dosing (BID) schedule. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic analysis over a 12-h dosing interval. Anagrelide and 3-hydroxy-anagrelide plasma concentrations were normalized to a common dose (1 mg BID) to control for dosing differences between patients. Patients were monitored routinely for adverse events (AEs) and vital signs. RESULTS: A total of 24 patients (12 young; 12 elderly) completed the study. The dose-normalized anagrelide maximum observed plasma concentration (Cmax) and area under the plasma concentration vs. time curve over one dosing interval (AUCτ), were higher in elderly patients compared with young patients (Cmax: 3.63 vs. 2.66 ng/ml; p = 0.09, AUCτ: 10.3 vs. 6.4 ng×h/ml; p = 0.01). In contrast, the dose-normalized 3-hydroxy-anagrelide Cmax and AUCτ were lower in the elderly patients when compared with young patients (Cmax: 4.19 vs. 7.26 ng/ml; p = 0.02, AUCτ: 17.4 vs. 27.6 ng×h/ml; p = 0.03). No significant difference was observed in the geometric mean terminal half-life (t1/2) of anagrelide in elderly and young patients (1.4 vs. 1.3 h, respectively; p = 0.38), whereas the geometric mean t1/2 of 3-hydroxy-anagrelide was significantly longer in the elderly patients compared with the young patients (3.5 vs. 2.7 h, respectively; p = 0.01). There were no significant differences in platelet count or vital signs between the age groups. Anagrelide was well tolerated; there were no serious AEs or AEs that led to withdrawal from the study. CONCLUSIONS: To conclude, the differences observed in anagrelide and 3-hydroxy-anagrelide pharmacokinetics do not justify using a different dosing regimen in young vs. elderly patients with ET.

Lisdexamfetamine dimesylate: linear dose-proportionality, low intersubject and intrasubject variability, and safety in an open-label single-dose pharmacokinetic study in healthy adult volunteers.

The pharmacokinetics of lisdexamfetamine dimesylate, a long-acting prodrug stimulant, and its active moiety, d-amphetamine, including dose-proportionality and variability, were assessed in 20 healthy adults. Subjects received a single dose, sequentially, of 50, 100, 150, 200, and 250 mg of lisdexamfetamine dimesylate. Plasma lisdexamfetamine dimesylate and d-amphetamine were measured before dosing and 0.25 to 96 hours postdose. Dose-proportionality and intersubject and intrasubject variability of pharmacokinetic parameters were examined. Safety assessments included adverse events. All 20 subjects received 50 and 100 mg while 18, 12, and 9 subjects received 150, 200, and 250 mg of lisdexamfetamine dimesylate, respectively. Ten subjects were discontinued during the study for prespecified stopping rules (2 consecutive hourly readings of blood pressure: systolic >160 mm Hg or diastolic >100 mm Hg). Mean maximum observed plasma concentration (C(max)) and area under the concentration-time curve from time 0 to infinity (AUC(0-∞)) increased linearly and dose-dependently for d-amphetamine. Median time to C(max) ranged from 4 to 6 hours for d-amphetamine and 1.0 to 1.5 hours for lisdexamfetamine dimesylate. Intersubject and intrasubject variability over doses from 50 to 150 mg was low (<20%) for both C(max) and AUC(0-∞). Adverse events included nausea, dizziness, headache, psychomotor hyperactivity, and dysuria. These findings indicate that the pharmacokinetic parameters of d-amphetamine were dose-proportional and predictable over a wide range of lisdexamfetamine dimesylate doses.