Domperidone

Domperidone is a dopamine antagonist with anti-emetic properties, Domperidone does not readily cross the blood-brain barrier. In domperidone users, especially in adults, extrapyramidal side effects are very rare, but domperidone promotes the release of prolactin from the pituitary. Its anti-emetic effect may be due to a combination of peripheral (gastrokinetic) effects and antagonism of dopamine receptors in the chemoreceptor trigger zone, which lies outside the blood-brain barrier in the area postrema.

Animal studies, together with the low concentrations found in the brain, indicate a predominantly peripheral effect of domperidone on dopamine receptors. Studies in man have shown oral domperidone to increase lower oesophaegeal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion.

In accordance with ICH—E14 guidelines, a thorough QT study was performed. This study included a placebo, an active comparator and a positive control and was conducted in healthy subjects with up to 80 mg per day 10 or 20 mg administered 4 times a day of domperidone. This study found a maximal difference of QTc between domperidone and placebo in LS-means in the change from baseline of 3.4 msec for 20 mg domperidone administered 4 times a day on Day 4. The 2-sided 90% CI (1.0 to 5.9 msec) did not exceed 10 msec. No clinically relevant QTc effects were observed in this study when domperidone was administered at up to 80 mg/day (i.e., more than twice the maximum recommended dosing).

However, two previous drug-drug interaction studies showed some evidence of QTc prolongation when domperidone was administered as monotherapy (10 mg 4 times a day).The largest time-matched mean difference of QTcF between domperidone and placebo was 5.4 msec (95% CI: -1.7 to 12.4) and 7.5 msec (95% CI: 0.6 to 14.4), respectively.

Absorption

Domperidone is rapidly absorbed after oral administration, with peak plasma concentrations occurring at approximately 1hr after dosing. The C_max and AUC values of domperidone increased proportionally with dose in the 10 mg to 20 mg dose range. A 2- to 3-fold accumulation of domperidone AUC was observed with repeated four times daily (every 5 hr) dosing of domperidone for 4 days.

The low absolute bioavailability of oral domperidone (approximately 15%) is due to an extensive first-pass metabolism in the gut wall and liver. Although domperidone’s bioavailability is enhanced in normal subjects when taken after a meal, patients with gastro-intestinal complaints should take domperidone 15-30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when the oral drug is taken after a meal.

Distribution

Oral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 minutes of 21 ng/ml after two weeks oral administration of 30 mg per day was almost the same as that of 18 ng/ml after the first dose. Domperidone is 91-93% bound to plasma proteins. Distribution studies with radiolabelled drug in animals have shown wide tissue distribution, but low brain concentration. Small amounts of drug cross the placenta in rats.

Metabolism

Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is a major form of cytochrome P-450 involved in the N-dealkylation of domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation.

Excretion

Urinary and faecal excretions amount to 31 and 66% of the oral dose respectively. The proportion of the drug excreted unchanged is small (10% of faecal excretion and approximately 1% of urinary excretion). The plasma half-life after a single oral dose is 7-9 hours in healthy subjects but is prolonged in patients with severe renal insufficiency.

Hepatic impairment

In subjects with moderate hepatic impairment (Pugh score 7 to 9, Child-Pugh rating B), the AUC and C_max of domperidone is 2.9- and 1.5-fold higher, respectively, than in healthy subjects. The unbound fraction is increased by 25%, and the terminal elimination half-life is prolonged from 15 to 23 hours. Subjects with mild hepatic impairment have a somewhat lower systemic exposure than healthy subjects based on C_max and AUC, with no change in protein binding or terminal half-life. Subjects with severe hepatic impairment were not studied. Domperidone is contraindicated in patients with moderate or severe hepatic impairment.

Renal impairment

In subjects with severe renal insufficiency (creatinine clearance <30ml/min/1.73m²) the elimination half-life of domperidone is increased from 7.4 to 20.8 hours, but plasma drug levels are lower than in healthy volunteers. Since very little unchanged drug (approximately 1%) is excreted via the kidneys, it is unlikely that the dose of a single administration needs to be adjusted in patients with renal insufficiency.

However, on repeated administration, the dosing frequency should be reduced to once or twice daily depending on the severity of the impairment, and the dose may need to be reduced.

Paediatric population

No pharmacokinetic data are available in the paediatric population.

Electrophysiological in vitro and in vivo studies indicate an overall moderate risk of domperidone to prolong the QT interval in humans. In in vitro experiments on isolated cells transfected with hERG and on isolated guinea pig myocytes, exposure ratios ranged between 26- 47-fold, based on IC50 values inhibiting currents through IKr ion channels in comparison to the free plasma concentrations in humans after administration of the maximum daily dose of 10 mg administered 3 times a day. Safety margins for prolongation of action potential duration in in vitro experiments on isolated cardiac tissues exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by 45-fold. Safety margins in in vitro pro-arrhythmic models (isolated Langendorff perfused heart) exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by 9- up to 45-fold.

In in vivo models the no effect levels for QTc prolongation in dogs and induction of arrhythmias in a rabbit model sensitized for torsade de pointes exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by more than 22-fold and 435-fold, respectively. In the anesthetized guinea pig model following slow intravenous infusions, there were no effects on QTc at total plasma concentrations of 45.4 ng/mL, which are 3-fold higher than the total plasma levels in humans at maximum daily dose (10 mg administered 3 times a day). The relevance of the latter study for humans following exposure to orally administered domperidone is uncertain.

In the presence of inhibition of the metabolism via CYP3A4 free plasma concentrations of domperidone can rise up to 3-fold.

At a high, maternally toxic dose (more than 40 times the recommended human dose), teratogenic effects were seen in the rat. No teratogenicity was observed in mice and rabbits.