Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Synthetic anticholinergics, quaternary ammonium compounds ATC code: A03AB02

Mechanism of action

Rybrila is a synthetic muscarinic anticholinergic agent that binds competitively to the muscarinic acetylcholine receptor. Like other anticholinergic (antimuscarinic) agents, it inhibits the action of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation.
These peripheral cholinergic receptors are present in the autonomic effector cells of smooth muscle, cardiac muscle, the sinoatrial node, the
atrioventricular node, exocrine glands and, to a limited degree, in the autonomic ganglia.
Thus, it diminishes the volume and free acidity of gastric secretions and controls excessive pharyngeal, tracheal, and bronchial secretions.

Aside from differences in the CNS actions, the spectrum of pharmacological actions by Rybrila is qualitatively similar to that of the naturally occurring alkaloids atropine and scopolamine, but differs with regard to duration and intensity. Within the peripheral nervous system, Rybrila acts as a potent competitive antagonist at muscarinic receptors and attenuates physiological processes regulated by the parasympathetic nervous system, including predictable actions within the respiratory tract, gastrointestinal system, and heart. The highly polar quaternary ammonium group of Rybrila limits its passage across lipid membranes, such as the blood-brain barrier.

Pharmacodynamic effects

In common with other anticholinergics, Rybrila has gastrointestinal, genitourinary, cardiovascular, respiratory, and ophthalmic effects. Due to its limited passage across lipid membranes, CNS effects such as drowsiness are unlikely. Specific known effects of Rybrila include dryness of the mouth, reduced bronchial secretions, dilation of pupils with loss of accommodation, photophobia, flushing, inhibition of sweating, transient bradycardia followed by tachycardia with palpitations and arrhythmias, urinary urgency and retention, reduced gastrointestinal motility and tone.

Clinical efficacy and safety

The medicinal use of Rybrila for its anticholinergic effects is well- established. Studies published in the scientific literature demonstrate reduction in gastric secretions and acidity, and delayed gastric emptying by Rybrila in peptic ulcer patients. Some efficacy of Rybrila as monotherapy was shown in peptic ulcer healing, recurrence rate of duodenal ulcer, chronic gastric ulcer, duodenal ulcer, peptic ulcer, gastrointestinal disorders and acid-peptic disease.
Published studies of Rybrila in adults as add-on therapy with antacids in the treatment of peptic ulcer also demonstrate some efficacy.

Glycopyrronium competitively inhibits cholinergic muscarinic receptors in salivary glands and other peripheral tissues, thus indirectly reducing the rate of salivation. Glycopyrronium has little effect on cholinergic stimuli at nicotinic acetylcholine receptors, on structures innervated by postganglionic cholinergic neurons, and on smooth muscles that respond to acetylcholine but have no cholinergic innervation. Peripheral antimuscarinic effects that are produced as the dose increases are: decreased production of secretions from the salivary, bronchial and sweat glands; dilatation of the pupils (mydriasis) and paralysis of accommodation (cyclopegia); increased heart rate; inhibition of micturition and reduction in gastrointestinal tone; inhibition of gastric acid secretion.
Placebo controlled efficacy data includes patients with a treatment duration of 8 weeks. There is no placebo or comparator controlled data beyond 8 weeks.
Zeller et al 2012a evaluated the efficacy of Rybrila oral solution (1 mg/5 mL) in managing problem drooling associated with cerebral palsy and other neurologic conditions. Thirty-eight patients aged 3–23 years weighing at least 27 lb (12.2 kg) with severe drooling (clothing damp 5–7 days/week) were randomized to eight-weeks treatment with glycopyrronium (n = 20), 20-100 μg/kg (not exceeding 3 mg in total) three times a day, or matching placebo (n =
18). The first four weeks were an individual titration period in fixed steps depending on response followed by 4-weeks maintenance treatment. Primary efficacy endpoint was responder rate, defined as percentage showing ≥3-point improvement on the modified Teacher's Drooling Scale (mTDS). The primary analysis population was revised to only comprise patients with an age of 3 -16 years which rendered 19 patients in the glycopyrrolate oral solution group an 17 in the placebo group. Responder rate was defined as at least a 3-point improvement in modified Teacher's Drooling Scale (mTDS).
Responder rate at week 8        At least a 3-point              Mean improvements in mTDS improvement in mTDS
Glycopyrronium                  14 of 19 patients (73.7%)       3.94 points (SD: 1.95; 95%; CI: 2.97–4.91)
Placebo                         3 of 17 patients (17.6%)        0.71 points (SD: 2.14; 95% CI: –0.43–
1.84) p value                         p = 0.0011                      p <0.0001 

In addition, 84% of physicians and 100% of parents/caregivers regarded glycopyrrolate as worthwhile compared with 41% and 56%, respectively, for placebo (p≤0.014). Most frequently reported treatment-emergent adverse events (glycopyrrolate vs placebo) were dry mouth, constipation, vomiting and nasal congestion.
The safety and efficacy of glycopyrronium have been studied in an open labelled study with no control group over a 24-week period in children aged 3 to 18 years. At the week 24/exit visit, 52.3% (95% confidence interval 43.7–60.9) of patients (n=130) had an at least three- point decrease in mTDS from baseline and were classified as responders to treatment with oral glycopyrrolate solution. The adverse event profile was consistent with the one seen with anticholinergics (see section 4.4 and 4.8).
The incidence of expected adverse events is dose-related. Therefore, dose is to be titrated to achieve an optimal balance of effectiveness with minimal anticholinergic associated adverse events.

There is no safety data available beyond 24 weeks treatment duration, therefore the treatment duration should be kept as short as possible.

Pharmacokinetic Properties

5.2       Pharmacokinetic properties

Absorption
Rybrila is poorly absorbed from the gastrointestinal tract. Rybrila has low oral bioavailability; a mean of approximately 3% is found in plasma.

Mean absolute oral bioavailability of glycopyrronium comparing a single 50 µg/kg oral dose and a single 5 µg/kg i.v. dose was low at approximately 3% (range 1.3–13.3%) in children aged 7–14 years undergoing intraocular surgery (n = 6) due to the medicinal product's low lipid solubility. Data from sparse PK sampling in children suggests dose proportional PK.

Rybrila produces low plasma concentrations (Cmax 0.318 ± 0.190 ng/ml) lasting up to 12 hours.

Food effect data indicate that the mean Cmax under fed high fat meal conditions is about 74% lower than the Cmax observed under fasting conditions.

Distribution
The bioavailability of oral glycopyrronium in children was between that of adults under fed and fasted conditions. Co-administration with food results in a marked decrease in systemic glycopyrronium exposure.
In adults, distribution of glycopyrronium was rapid following a single 6 µg/kg i.v. dose; distribution half-life was 2.2 ± 1.3 minutes. Following administration of 3H-labelled glycopyrronium more than 90% of the radiolabel disappeared from the plasma in 5 minutes, and almost 100% within 30 minutes, reflecting rapid distribution. Analyses of population pharmacokinetic data from healthy adults and children with cerebral palsy-associated chronic moderate to severe drooling who received glycopyrronium (route of administration and dosages not specified) did not demonstrate linear pharmacokinetics of the medicinal product.
The volume of distribution, 0.64 ± 0.29 L/kg in adults is similar to that of total body water.
Volume of distribution is somewhat higher in the paediatric population(s), in the range 1.31 to 1.83 L/kg.
The PK of glycopyrronium has been shown to be essentially independent of age in children in the age range 0.19 – 14 years administered a 5 µg/kg i.v. single-dose. In most paediatric subjects, plasma glycopyrronium vs. time plots are reported to show a triexponential curve; adults generally show a biexponential curve. Modest changes in volume of distribution (Vss) and clearance (Cl) have been observed in children between 1 and 3 years of age, leading to a statistically significant shorter elimination half-life (t½, z) than that observed in younger (<1 year of age; p = 0.037) or older (>3 years of age; p = 0.042) groups.
In a study in healthy adults, a 2000 µg single dose of Rybrila resulted in an AUC of 2.39 µg.h/L (fasted). An AUC0-6 h of 8.64 µg.h/L was observed after 6 µg/kg i.v.
glycopyrronium.
Based upon theoretical physicochemical considerations, the quaternary ammonium compound glycopyrronium would be expected to have low central bioavailability; no glycopyrronium was detectable in the CSF of anaesthetised surgical patients or patients undergoing caesarean section following a 6 – 8 µg/kg i.v. dose. In the paediatric population 5 µg/kg i.v.
glycopyrronium has low central bioavailability, except in the case where the blood brain barrier has been compromised (e.g. a shunt infection).
The primary route of elimination of glycopyrronium is via renal excretion, mainly as unchanged medicinal product. Approximately 65% of an i.v. dose is renally excreted within the first 24 hours. A small proportion (~5%) is eliminated in the bile.
The elimination half-life of glycopyrronium appears to be dependent on route of administration being 0.83 ± 0.27 hours after i.v. administration, 75 minutes after i.m.
administration and in the region of 2.5 - 4 h after oral (solution) administration, though again this was highly variable. That the latter two half-lives, and especially that for oral administration, are longer than for i.v. administration probably reflects the complex absorption and distribution of glycopyrronium by each route. It is possible that prolonged absorption after oral administration translates into elimination being faster than absorption (known as flip-flop kinetics, characterized by Ka < Ke).
The total body clearance of the medicinal product following an i.v. dose is relatively high at between 0.54 ± 0.14 L/h/kg and 1.14 ± 0.31 L/h/kg. As this exceeds the glomerular filtration rate and it appears that more than 50% of the dose is excreted unchanged in the urine, it is probable that the renal elimination of glycopyrronium involves both glomerular filtration and proximal tubular secretion by the base secretory mechanism.
A mean increase in total systemic exposure (AUClast) of up to 1.4 fold was seen in adult subjects with mild and moderate renal impairment (GFR ≥30mL/min/1.73m2) and up to 2.2 fold in subjects with severe renal impairment or end stage renal disease (estimated GFR <30 mL/min/1.73m2). A 30% dose reduction (see Table 2) is required for patients with mild to moderate renal impairment. Glycopyrronium is contraindicated in patients with severe renal impairment.
Baseline characteristics (age, weight, gender and race) do not affect the pharmacokinetics of glycopyrronium.


Rybrila penetrates the blood-brain barrier poorly. Rybrila crosses the placenta to a limited extent; and is not known whether it is distributed into milk.

Biotransformation

In adult patients who underwent surgery for cholelithiasis and were given a single IV dose of tritiated glycopyrronium bromide, 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 i.v.
Rybrila is excreted as one or more metabolites.

Elimination

A study using intravenous 3H-glycopyrronium bromide in humans showed the disappearance of more than 90% from the serum in 5 minutes and almost 100% in 30 minutes. Urinary radioactivity was highest in the first 3 hours and 85% was excreted in the urine within 48 hours. Paper chromatography showed 80% of the radioactivity in bile and urine corresponding to unchanged glycopyrronium bromide. Following oral administration to mice, 7.6% was excreted in the urine and about 79% in the faeces.

Impaired hepatic function is not expected to affect the pharmacokinetics of glycopyrronium since the majority of the medicinal product is eliminated through the kidneys.