Guanfacine - How It Works

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Guanfacine is a central alpha 2A -adrenergic receptor agonist.

Guanfacine is not a central nervous system (CNS) stimulant.

The mechanism of action of guanfacine in ADHD is not known. molecular-structure.jpg 12.2 Pharmacodynamics Guanfacine is a selective central alpha 2A -adrenergic receptor agonist in that it has a 15 to 20 times higher affinity for this receptor subtype than for the alpha 2B or alpha 2C subtypes.

Guanfacine is a known antihypertensive agent.

By stimulating central alpha 2A -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 guanfacine extended-release tablets of 0.12 mg/kg.

Guanfacine was not shown to prolong the QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics Absorption and Distribution Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug concentration.

After oral administration of guanfacine extended-release tablets the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD.

Immediate-release guanfacine and guanfacine extended-release tablets have different pharmacokinetic characteristics; dose substitution on a milligram per milligram basis will result in differences in exposure.

A comparison across studies suggests that the C max is 60% lower and AUC 0-∞ 43% lower, respectively, for guanfacine extended-release tablets compared to immediate-release guanfacine.

Therefore, the relative bioavailability of guanfacine extended-release tablets to immediate-release guanfacine is 58%.

The mean pharmacokinetic parameters in adults following the administration of guanfacine extended-release tablets 1 mg once daily and immediate-release guanfacine 1 mg once daily are summarized in Table 15 .

Table 15: Comparison of Pharmacokinetics: Guanfacine Extended-Release Tablets vs.

Immediate release Guanfacine in Adults Note: Values are mean +/- SD, except for t max which is median (range) Parameter Guanfacine Extended-Release Tablets 1 mg once daily (n=52) Immediate-release guanfacine 1 mg once daily (n=12) C max (ng/mL) 1.0 ± 0.3 2.5 ± 0.6 AUC 0-∞ (ng∙h/mL) 32 ± 9 56 ± 15 t max (h) 6.0 (4.0 - 8.0) 3.0 (1.5-4.0) t ½ (h) 18 ± 4 16 ± 3 Figure 1: Comparison of Pharmacokinetics: Guanfacine Extended-Release Tablets vs.

Immediate-release guanfacine in Adults Exposure to guanfacine was higher in children (ages 6 to 12) compared to adolescents (ages 13 to 17) and adults.

After oral administration of multiple doses of guanfacine extended-release tablets 4 mg, the C max 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 to 12) and adolescents (ages 13 to 17), 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 guanfacine extended-release tablets 4 mg was administered with a high-fat breakfast.