Mechanism of Action
Glycopyrrolate is a competitive inhibitor of acetylcholine receptors that are located on certain peripheral tissues, including salivary glands. Glycopyrrolate indirectly reduces the rate of salivation by preventing the stimulation of these receptors.
Glycopyrrolate inhibits the action of acetylcholine on salivary glands thereby reducing the extent of salivation.
In a parallel study of children (n=6 per group) aged 7-14 years undergoing intraocular surgery receiving either intravenous (IV) or oral glycopyrrolate as a premedication, the mean absolute bioavailability of glycopyrrolate tablets was low (approximately 3%) and highly variable among subjects (range 1.3 to 13.3%). A similar pattern of low and variable relative bioavailability is seen in adults.
Analysis of population pharmacokinetic data from normal adults and children with cerebral palsy associated chronic moderate to severe drooling failed to demonstrate linear pharmacokinetics across the dose range. In the same analysis, population estimates of the apparent oral clearance (scaled by weight in children and adults) ranged from 5.28 ~ 38.95 L/hr/kg for healthy adults and 8.07 ~ 25.65 L/hr/kg for patients with cerebral palsy, a reflection of the low and highly variable oral bioavailability of glycopyrrolate.
Absorption of CUVPOSA (fasting) was compared to that of a marketed glycopyrrolate oral tablet. The Cmax after oral solution administration was 23% lower compared to tablet administration and the AUC0-inf was 28% lower after oral solution administration. Mean Cmax after oral solution administration in the fasting state was 0.318 ng/mL, and mean AUC0-24 was 1.74 ng.hr/mL. Mean time to maximum plasma concentration for CUVPOSA was 3.1 hours, and mean plasma half-life was 3.0 hours.
In healthy adults, a high fat meal was shown to significantly affect the absorption of glycopyrrolate oral solution (10 mL, 1 mg/5 mL). The mean Cmax under fed high fat meal conditions was approximately 74% lower than the Cmax observed under fasting conditions. Similarly, mean AUC0-T was reduced by about 78% by the high fat meal compared with the fasting AUC0-T. A high fat meal markedly reduces the oral bioavailability of CUVPOSA. Therefore, CUVPOSA should be dosed at least one hour before or two hours after meals. Pharmacokinetic results (mean ± SD) are described in Table 3.
Table 3: Pharmacokinetic Parameters (mean±SD) for
CUVPOSA, Fasting and Fed, in Healthy Adults
|Cmax (ng/mL)||Tmax (hrs)||AUC0-T (ng•hr/mL)||AUC0-Inf (ng•hr/mL)||T½ (hrs)|
|Fasting (n=37)||0.318 ± 0.190||3.10 ± 1.08||1.74 ± 1.07||1.81 ± 1.09||3.0 ± 1.2|
|Fed (n=36)||0.084 ± 0.081||2.60 ± 1.12||0.38 ± 0.14||0.46 ± 0.13*||3.2 ±1.1*|
After IV administration, glycopyrrolate has a mean volume of distribution in children aged 1 to 14 years of approximately 1.3 to 1.8 L/kg, with a range from 0.7 to 3.9 L/kg. In adults aged 60-75 years, the volume of distribution was lower (0.42 L/kg +/- 0.22).
In adult patients who underwent surgery for cholelithiasis and were given a single IV dose of tritiated glycopyrrolate, approximately 85% of total radioactivity was excreted in urine and < 5% was present in T-tube drainage of bile. In both urine and bile, > 80% of the radioactivity corresponded to unchanged drug. These data suggest a small proportion of IV glycopyrrolate is excreted as one or more metabolites.
Approximately 65-80% of an IV glycopyrrolate dose was eliminated unchanged in urine in adults. In two studies, after IV administration to pediatric patients ages 1-14 years, mean clearance values ranged from 1.01- 1.41 L/kg/hr (range 0.32 – 2.22 L/kg/hr). In adults, IV clearance values were 0.54 ± 0.14 L/kg/hr.
The estimated apparent clearance of glycopyrrolate from a population pharmacokinetic analysis (scaled by weight in children and adults) of oral and IV data was found to be 13.2 L/hr/Kg or 92 7L/hr for a typical 70 kg subject. In the same population based analysis, gender was not identified as having an effect on either glycopyrrolate clearance or systemic exposure.
Population pharmacokinetic evaluation of adults and children administered IV or oral glycopyrrolate identified no effect of gender on glycopyrrolate clearance or systemic exposure.
The pharmacokinetics of glycopyrrolate by race has not been characterized.
Glycopyrrolate pharmacokinetics have not been characterized in the elderly.
In one study, glycopyrrolate 4 mcg/kg was administered intravenously in uremic patients undergoing renal transplantation surgery. Mean AUC (10.6 mcg•h/L), mean plasma clearance (0.43 L/hr/kg) and mean 3-hour urinary excretion (0.7%) for glycopyrrolate were significantly different than those of control patients (3.73 μg•h/L, 1.14 L/hr/kg, and 50%, respectively). These results suggest that elimination of glycopyrrolate is severely impaired in patients with renal failure.
Glycopyrrolate is largely renally eliminated. The pharmacokinetics of glycopyrrolate has not been evaluated in patients with hepatic impairment.
CUVPOSA was evaluated in a multi-center, randomized, double-blind, placebo-controlled, parallel, eight-week study for the control of pathologic drooling in children (Study 1). The study enrolled 38 subjects aged 3-23 years; thirty-six subjects were aged 3-16 years and two patients were greater than 16 years. The subjects were male or female, weighed at least 13 kg (27 lbs), and had cerebral palsy, mental retardation, or another neurologic condition associated with problem drooling defined as drooling in the absence of treatment so that clothing became damp on most days (approximately five to seven days per week). Subjects were randomized in a 1:1 fashion to receive CUVPOSA or placebo. Doses of study medication were titrated over a 4-week period to optimal response beginning at 0.02 mg/kg given three times a day increasing doses in increments of approximately 0.02 mg/kg three times per day every 5-7 days, not to exceed the lesser of approximately 0.1 mg/kg three times per day or 3 mg three times per day.
Subjects were evaluated on the 9-point modified Teacher's Drooling Scale (mTDS), which is presented below. The mTDS evaluations were recorded by parents/caregivers 3 times daily approximately two hours post-dose on evaluation days during pre-treatment baseline and at Weeks 2, 4, 6 and 8 of therapy.
Modified Teacher's Drooling Scale
1 = Dry: never drools
2 = Mild: only the lips are wet; occasionally
3 = Mild: only the lips are wet; frequently
4 = Moderate: wet on lips and chin; occasionally
5 = Moderate: wet on the lips and chin; frequently
6 = Severe: drools to the extent that clothing becomes damp; occasionally
7 = Severe: drools to the extent that clothing becomes damp; frequently
8 = Profuse: clothing, hands, tray and objects become wet; occasionally
9 = Profuse: clothing, hands, tray and objects become wet; frequently
Responders were defined as subjects with at least a 3-point reduction in mean daily mTDS scores from baseline to Week 8. Table 4 presents the proportion of responders at Week 8 and Figure 1 presents mean mTDS values from baseline through Week 8.
Table 4: Percentage of Responders at Week 8
|15/20 (75%)||2/18 (11%)|
Figure 1: Mean (± 2 Standard
Errors) mTDS Scores
Last reviewed on RxList: 6/3/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Cuvposa Information
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