ct of two dose levels of immediate-release guanfacine (4 mg and 8 mg) on the QT interval was eva luated in a double-blind, randomized, placebo- and active-controlled, cross-over study in healthy adults. A dose-dependent decrease in heart rate was observed during the first 12 hours, at time of maximal concentrations. The mean change in heart rate was -13 bpm at 4 mg and -22 bpm at 8 mg. An apparent increase in mean QTc was observed for both doses. However, guanfacine does not appear to interfere with cardiac repolarization of the form associated with pro-arrhythmic drugs. This finding has no known clinical relevance.
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 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 C is 60% lower and AUC 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 5. max0-∞®®®
Table 5: Pharmacokinetic Parameters in Adults
Parameter INTUNIV ®
1 mg once daily
(n=52) Immediate-release
guanfacine
1 mg once daily
(n=12)
C (ng/mL) max
1.0 ± 0.3 2.5 ± 0.6
AUC (ng.h/mL) 0-∞
32 ± 9 56 ± 15
t (h) max
6.0 (4.0 - 8.0) 3.0 (1.5-4.0)
t (h) 1/2
18 ± 4 16 ± 3
Note: Values are mean +/- SD, except for t which is median (range) max
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 C 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 13-17), respectively. These differences are probably attributable to the lower body weight of children compared to adolescents and adults. ®max
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 (C ~75% and AUC ~40%) compared to dosing in a fasted state. ®max
Dose Proportionality
Following administration of INTUNIV in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, C and AUC of guanfacine were proportional to dose. ®max0-∞
Metabolism and Elimination
In vitro studies with human liver microsomes and recombinant CYP’s demonstrated that guanfacine was primaril |
