RESUMEN

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.

Asunto(s)

Conducta del Adolescente/efectos de los fármacos , Agonistas de Receptores Adrenérgicos alfa 2/farmacocinética , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Guanfacina/farmacocinética , Adolescente , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Agonistas de Receptores Adrenérgicos alfa 2/efectos adversos , Agonistas de Receptores Adrenérgicos alfa 2/química , Factores de Edad , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Presión Sanguínea/efectos de los fármacos , Preparaciones de Acción Retardada , Femenino , Florida , Guanfacina/administración & dosificación , Guanfacina/efectos adversos , Guanfacina/química , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Resultado del Tratamiento

RESUMEN

BACKGROUND: Pharmacokinetic and safety data on stimulants in older adults are limited. The objective of this study was to characterize the pharmacokinetics of lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, in older adults. METHODS: In this two-period crossover trial, healthy adults (n = 47) stratified by age (55-64, 65-74, and ≥ 75 years) and gender received randomized, double-blind, single doses of LDX 50 mg or placebo. Baseline creatinine clearance, d-amphetamine and intact LDX pharmacokinetics, and safety were assessed. RESULTS: Mean (±standard deviation) baseline creatinine clearance in participants aged 55-64, 65-74, and ≥ 75 years was 102.5 ± 26.1, 105.3 ± 23.1, and 94.9 ± 27.3 mL per minute, respectively. In the groups aged 55-64, 65-74, and ≥ 75 years, the mean maximum plasma d-amphetamine concentration in men was 44.2 ± 11.1, 47.7 ± 7.0, and 53.4 ± 19.4 ng/mL, respectively; area under the concentration time curve from time 0 extrapolated to infinity (AUC(0-inf)) was 915.0 ± 164.9, 1123.0 ± 227.0, and 1325.0 ± 464.4 nghour/mL; median time to reach peak plasma concentration was 4.5, 3.5, and 5.5 hours; in women, mean maximum plasma d-amphetamine concentration was 51.0 ± 6.7, 50.2 ± 6.8, and 64.3 ± 12.1 ng/mL, AUC(0-inf) was 1034.5 ± 154.6, 988.4 ± 80.5, and 1347.8 ± 198.9 ng hour/mL, and median time to reach peak plasma concentration was 3.5, 4.1, and 5.5 hours, respectively. d-Amphetamine clearance was unrelated to baseline creatinine clearance. Five participants aged 55-64 years reported treatment-emergent adverse events (versus one each aged 65-74 and ≥ 75 years), and as did six women (versus one man). No trends in blood pressure or pulse changes were seen with LDX according to age. In participants aged 55-64, 65-74, and ≥ 75 years, the mean change from time-matched baseline pulse ranged from -5.0 to 14.7, -4.3 to 9.5, and -3.0 to 14.7 beats per minute; for systolic blood pressure, from -3.9 to 18.5 mmHg, -2.1 to 14.5 mmHg, and -5.9 to 16.0 mmHg; for diastolic blood pressure from -2.5 to 8.3 mmHg, from -0.8 to 9.4 mmHg, and -0.6 to 9.5 mmHg. Vital sign changes were similar between men and women. CONCLUSION: Clearance of d-amphetamine decreased with age and was unrelated to creatinine clearance. No trends in pulse or blood pressure changes with LDX were seen according to age. The safety profile of LDX was consistent with prior observations in younger adult study participants.