"The U.S. Food and Drug Administration today allowed marketing of the first medical device based on brain function to help assess attention-deficit/hyperactivity disorder (ADHD) in children and adolescents 6 to 17 years old. When used as part of "...
Mechanism Of Action
Guanfacine is a selective central alpha2A-adrenergic receptor agonist in that it has a 15-20 times higher affinity for this receptor subtype than for the alpha2B or alpha2C subtypes.
Guanfacine is a known antihypertensive agent. By stimulating central alpha2A-adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate.
In a thorough QT study, the administration of two dose levels of immediate-release guanfacine (4 mg and 8 mg) produced concentrations approximately 2 to 4 times the concentrations observed with the maximum recommended dose of INTUNIV® of 0.12 mg/kg. Guanfacine was not shown to prolong the QTc interval to any clinically relevant extent.
Absorption and Distribution
Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug concentration. After oral administration of INTUNIV® the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD.
Immediate-release guanfacine and INTUNIV® have different pharmacokinetic characteristics; dose substitution on a milligram for milligram basis will result in differences in exposure.
A comparison across studies suggests that the Cmax is 60% lower and AUC0-∞ 43% lower, respectively, for INTUNIV® compared to immediate-release guanfacine. Therefore, the relative bioavailability of INTUNIV® to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults following the administration of INTUNIV® 1 mg once daily and immediate-release guanfacine 1mg once daily are summarized in Table 15.
Table 15: Comparison of Pharmacokinetics: INTUNIV® vs.
Immediate release Guanfacine in Adults
|Parameter||INTUNIV® 1 mg once daily
|Immediate-release guanfacine 1 mg once daily
|Cmax (ng/mL)||1.0 ± 0.3||2.5 ± 0.6|
|AUC0-∞ (ng•h/mL)||32 ± 9||56 ± 15|
|tmax (h)||6.0 (4.0 - 8.0)||3.0 (1.5-4.0)|
|t½ (h)||18 ± 4||16 ± 3|
|Note: Values are mean +/-SD, except for tmax which is median (range)|
Figure 1: Comparison of
Pharmacokinetics: INTUNIV® vs. Immediate-release guanfacine in
Exposure to guanfacine was higher in children (ages 6-12) compared to adolescents (ages 13-17) and adults. After oral administration of multiple doses of INTUNIV® 4 mg, the Cmax was 10 ng/mL compared to 7 ng/mL and the AUC was 162 ng h/mL compared to 116 ng h/mL in children (ages 6-12) and adolescents (ages 1317), respectively. These differences are probably attributable to the lower body weight of children compared to adolescents and adults.
The pharmacokinetics were affected by intake of food when a single dose of INTUNIV® 4 mg was administered with a high-fat breakfast. The mean exposure increased (Cmax ~75% and AUC ~40%) compared to dosing in a fasted state.
Following administration of INTUNIV® in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, Cmax and AUC0∞ of guanfacine were proportional to dose.
Metabolism and Elimination
In vitro studies with human liver microsomes and recombinant CYP's demonstrated that guanfacine was primarily metabolized by CYP3A4. In pooled human hepatic microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5). Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors.
Studies in Specific Populations
The impact of renal impairment on the pharmacokinetics of guanfacine in children was not assessed. In adult patients with impaired renal function, the cumulative urinary excretion of guanfacine and the renal clearance diminished as renal function decreased. In patients on hemodialysis, the dialysis clearance was about 15% of the total clearance. The low dialysis clearance suggests that the hepatic elimination (metabolism) increases as renal function decreases.
The impact of hepatic impairment on PK of guanfacine in children was not assessed. Guanfacine in adults is cleared both by the liver and the kidney, and approximately 50% of the clearance of guanfacine is hepatic [see Hepatic Impairment].
Drug Interaction Studies
Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be affected significantly by CYP3A4 inhibitors or inducers (Figure 2).
Figure 2: Effect of Other Drugs on the
Pharmacokinetics (PK) of INTUNIV®
Guanfacine does not significantly affect exposures of methylphenidate and lisdexamfetamine when coadministered (Figure 3).
Figure 3: Effect of INTUNIV® on the Pharmacokinetics (PK) of Other Drugs
Efficacy of INTUNIV® in the treatment of ADHD was established in children and adolescents (6 to 17 years) in:
- Five short-term, placebo-controlled monotherapy trials (Studies 1, 2, 4, 5, and 6)
- One short-term, placebo-controlled adjunctive trial with psychostimulants (Study 3).
Studies 1 and 2: Fixed-dose INTUNIV® Monotherapy
Study 1 (301 study) was a double-blind, placebo-controlled, parallel-group, fixed dose study, in which efficacy of once daily dosing with INTUNIV® (2 mg, 3 mg and 4 mg) was evaluated for 5 weeks (n=345) in children and adolescents aged 6-17 years. Study 2 (304 study) was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with INTUNIV® (1 mg, 2 mg, 3 mg and 4 mg) was evaluated for 6 weeks (n=324) in children and adolescents aged 6-17 years. In both studies, randomized patients in 2 mg, 3 mg and 4 mg dose groups were titrated to their target fixed dose, and continued on the same dose until a dose tapering phase started The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. Patients who weighed less than 25 kg were not included in either study.
Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 5 in Study 1 and up to Week 6 in Study 2).
The mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® compared to placebo for Studies 1 and 2. Placebo-adjusted changes from baseline were statistically significant for each of the 2 mg, 3 mg, and 4 mg INTUNIV® randomized treatment groups in both studies, as well as the 1 mg INTUNIV® treatment group that was included only in Study 2 (see Table 16).
Dose-responsive efficacy was evident, particularly when data were examined on a weight-adjusted (mg/kg) basis. When evaluated over the dose range of 0.01-0.17 mg/kg/day, clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg/day. Doses up to 0.12 mg/kg/day were shown to provide additional benefit.
Controlled, monotherapy long-term efficacy studies ( > 15 weeks) have not been conducted.
In the monotherapy trials (Studies 1 and 2), subgroup analyses were performed to identify any differences in response based on gender or age (6-12 vs. 13-17). Analyses of the primary outcome did not suggest any differential responsiveness on the basis of gender. Analyses by age revealed a statistically significant treatment effect only in the 6-12 age subgroup. Due to the relatively small proportion of adolescent patients (ages 13-17) enrolled into these studies (approximately 25%), these data may not have been sufficient to demonstrate efficacy in the adolescent patients. In these studies, patients were randomized to a fixed dose of INTUNIV® rather than optimized by body weight. Therefore, some adolescent patients were randomized to a dose that might have resulted in relatively lower plasma guanfacine concentrations compared to the younger patients. Over half (55%) of the adolescent patients received doses of 0.01-0.04mg/kg. In studies in which systematic pharmacokinetic data were obtained, there was a strong inverse correlation between body weight and plasma guanfacine concentrations.
Table 16: Fixed dose Studies
|Study Number (Age Range)||Treatment Group||Primary Efficacy Measure: ADHD-RS-IV Total Score|
|Mean Baseline Score (SD)||LS Mean Change from Baseline (SE)||Placebo-subtracted Differencea(95% CI)|
|Study 1 (6—17 years)||INTUNIV® 2 mg*||36.1 (9.99)||-15.9 (1.37)||-7.4 (-11.3, -3.5)|
|INTUNIV® 3 mg*||36.8 (8.72)||-16.0 (1.38)||-7.5 (-11.4, -3.6)|
|INTUNIV® 4 mg*||38.4 (9.21)||-18.5 (1.39)||-10.0 (-13.9, -6.1)|
|Placebo||38.1 (9.34)||-8.5 (1.42)||--|
|Study 2 (6—17 years)||INTUNIV® 1 mg*^||41.7 (7.81)||-19.4 (1.69)||-6.8 (-11.3, -2.2)|
|INTUNIV® 2 mg*||39.9 (8.74)||-18.1 (1.60)||-5.4 (-9.9, -0.9)|
|INTUNIV® 3 mg*||39.1 (9.22)||-20.0 (1.64)||-7.3 (-11.8, -2.8)|
|INTUNIV® 4 mg*||40.6 (8.57)||-20.6 (1.60)||-7.9 (-12.3, -3.4)|
|Placebo||39.3 (8.85)||-12.7 (1.60)||--|
|SD : standard deviation; SE: standard error; LS Mean:
least-squares mean; CI: unadjusted confidence interval.
a Difference (drug minus placebo) in least-squares mean change from baseline.
* Doses statistically significantly superior to placebo
.^ The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg.
Study 3: Flexible-dose INTUNIV® as Adjunctive Therapy to Psychostimulants
Study 3 (313 study) was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily optimized dosing (morning or evening) with INTUNIV® (1mg, 2mg, 3mg and 4mg), when co-administered with psychostimulants, was evaluated for 8 weeks, in children and adolescents aged 6-17 years with a diagnosis of ADHD, with a sub-optimal response to stimulants (n=455). Patients were started at the 1 mg INTUNIV® dose level and were titrated weekly over a 5-week dose-optimization period to an optimal INTUNIV® dose not to exceed 4 mg/day based on tolerability and clinical response. The dose was then maintained for a 3-week dose maintenance period before entry to 1 week of dose tapering. Patients took INTUNIV® either in the morning or the evening while maintaining their current dose of psychostimulant treatment given each morning. Allowable psychostimulants in the study were ADDERALL XR®, VYVANSE® , CONCERTA®, FOCALIN XR®, RITALIN LA®, METADATE CD® or FDA-approved generic equivalents.
Symptoms of ADHD were evaluated on a weekly basis by clinicians using the ADHD Rating Scale (ADHD-RSIV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week prior to dose tapering for which a valid score was obtained (up to Week 8).
Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® given in combination with a psychostimulant compared to placebo given with a psychostimulant for Study 3, for both morning and evening INTUNIV® dosing (see Table 17). Nearly two-thirds (64.2%) of patients reached optimal doses in the 0.05-0.12 mg/kg/day range.
Studies 4, 5 and 6: Flexible-dose INTUNIV® Monotherapy
Study 4 (314 study) was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily dosing (morning or evening) with INTUNIV® (1mg, 2mg, 3mg, and 4mg) was evaluated for 8 weeks in children aged 6-12 years (n=340).
Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline score at endpoint on the ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 8).
Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® compared to placebo in both AM and PM dosing groups of INTUNIV® (see Table 17).
Study 5 (312 study) was a 15-week, double-blind, randomized, placebo-controlled, dose-optimization study conducted in adolescents aged 13-17 years (n=314) to evaluate the efficacy and safety of INTUNIV® (1-7 mg/day; optimized dose range of 0.05-0.12 mg/kg/day) in the treatment of ADHD as measured by the ADHD Rating Scale-IV (ADHD-RS-IV). Patients receiving INTUNIV® showed statistically significantly greater improvement on the ADHD-RS-IV total score compared with patients receiving placebo (see Table 17).
Study 6 (316 study) was a 12-week (for children aged 6-12) or 15-week (for adolescents aged 13-17), randomized, double-blind, parallel-group, placebo-and active-reference, dose-optimization study conducted in pediatric patients (children and adolescents aged 6-17 years old inclusive) (n=337) to assess the efficacy and safety of once-daily dosing (children: 1-4 mg/day, adolescents: 1-7 mg/day; optimized dose range of 0.05 to 0.12 mg/kg/day) in the treatment of ADHD. INTUNIV® was statistically superior to placebo on symptoms of ADHD in patients 6-17 years as measured by change from baseline in ADHD-RS-IV total scores (see Table 17).
Table 17: Flexible-Dose studies
|Study Number (Age Range)||Treatment Group||Primary Efficacy Measure: ADHD-RS-IV Total Score|
|Mean Baseline Score (SD)||LS Mean Change from Baseline (SE)||Placebo-subtracted Differenceb (95% CI)|
|Study 3a(6—17 years)||INTUNIV® 1—4 mg AM*||37.6 (8.13)||-20.3 (0.97)||-4.5 (-7.5, -1.4)|
|INTUNIV® 1—4 mg PM*||37.0 (7.65)||-21.2 (0.97)||-5.3 (-8.3, -2.3)|
|Placebo||37.7 (7.75)||-15.9 (0.96)||--|
|Study 4 (6—12 years)||INTUNIV® 1—4 mg AM*||41.7 (6.39)||-20.0 (1.23)||-9.4 (-12.8, -6.0)|
|INTUNIV® 1—4 mg PM*||41.6 (6.66)||-20.4 (1.19)||-9.8 (-13.1, -6.4)|
|Placebo||42.9 (6.29)||-10.6 (1.20)||--|
|Study 5 (13—17 years)||INTUNIV® 1—7 mg*||39.9 (5.57)||-24.6 (1.06)||-6.03 (-8.87, -3.19)|
|Placebo||40.0 (6.11)||-18.5 (1.08)|
|Study 6 (6—17 years)||INTUNIV® 1—7 mg*||43.1 (5.47)||-23.89 (1.15)||-8.88 (-11.94, -5.81)|
|Placebo||43.2 (5.60)||-15.01 (1.16)||--|
|SD: standard deviation; SE: standard error; LS Mean:
least-squares mean; CI: unadjusted confidence interval.
a Treatment was given in combination with a psychostimulant.
b Difference (drug minus placebo) in least-squares mean change from baseline.
* Doses statistically significantly superior to placebo.
Last reviewed on RxList: 12/4/2014
This monograph has been modified to include the generic and brand name in many instances.
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