Paliperidone - How It Works
Clinical pharmacology details from the US FDA-approved label: how Paliperidone works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone in schizophrenia is unclear. However, the drug's therapeutic effect in schizophrenia could be mediated through a combination of central dopamine Type 2 (D 2 ) and serotonin Type 2 (5HT 2A ) receptor antagonism.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Paliperidone is the major active metabolite of risperidone.
The mechanism of action of paliperidone in schizophrenia is unclear.
However, the drug's therapeutic effect in schizophrenia could be mediated through a combination of central dopamine Type 2 (D 2 ) and serotonin Type 2 (5HT 2A ) receptor antagonism.
12.2 Pharmacodynamics In vitro, paliperidone acts as an antagonist at the central dopamine Type 2 (D 2 ) and serotonin Type 2 (5HT 2A ) receptors, with binding affinities (Ki values) of 1.6–2.8 nM for D 2 and 0.8–1.2 nM for 5HT 2A receptors.
Paliperidone is also active as an antagonist at the α 1 and α 2 adrenergic receptors and H 1 histaminergic receptors, which may explain some of the other effects of the drug.
Paliperidone has no affinity for cholinergic muscarinic or β 1 - and β 2 -adrenergic receptors.
The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar in vitro.
12.3 Pharmacokinetics Following a single dose, the plasma concentrations of paliperidone gradually rise to reach peak plasma concentration (C max ) approximately 24 hours after dosing.
The pharmacokinetics of paliperidone following Paliperidone Extended-Release Tablets administration are doseproportional within the available dose range.
The terminal elimination half-life of paliperidone is approximately 23 hours.
Steady-state concentrations of paliperidone are attained within 4–5 days of dosing with Paliperidone Extended-Release Tablets in most subjects.
The mean steady-state peak:trough ratio for an Paliperidone Extended-Release Tablets dose of 9 mg was 1.7 with a range of 1.2–3.1.
Following administration of Paliperidone Extended-Release Tablets, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6 at steady state.
Absorption and Distribution The absolute oral bioavailability of paliperidone following Paliperidone Extended-Release Tablets administration is 28%.
Administration of a 12 mg paliperidone extended-release tablet to healthy ambulatory subjects with a standard high-fat/high-caloric meal gave mean C max and AUC values of paliperidone that were increased by 60% and 54%, respectively, compared with administration under fasting conditions.
Clinical trials establishing the safety and efficacy of Paliperidone Extended-Release Tablets were carried out in subjects without regard to the timing of meals.
While Paliperidone Extended-Release Tablets can be taken without regard to food, the presence of food at the time of Paliperidone Extended-Release Tablets administration may increase exposure to paliperidone [see Dosage and Administration ] .
Based on a population analysis, the apparent volume of distribution of paliperidone is 487 L.
The plasma protein binding of racemic paliperidone is 74%.
Metabolism and Elimination Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, in vivo results indicate that these isozymes play a limited role in the overall elimination of paliperidone [see Drug Interactions ] .
Pharmacokinetics
12.3 Pharmacokinetics Following a single dose, the plasma concentrations of paliperidone gradually rise to reach peak plasma concentration (C max ) approximately 24 hours after dosing. The pharmacokinetics of paliperidone following Paliperidone Extended-Release Tablets administration are doseproportional within the available dose range. The terminal elimination half-life of paliperidone is approximately 23 hours. Steady-state concentrations of paliperidone are attained within 4–5 days of dosing with Paliperidone Extended-Release Tablets in most subjects. The mean steady-state peak:trough ratio for an Paliperidone Extended-Release Tablets dose of 9 mg was 1.7 with a range of 1.2–3.1. Following administration of Paliperidone Extended-Release Tablets, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6 at steady state. Absorption and Distribution The absolute oral bioavailability of paliperidone following Paliperidone Extended-Release Tablets administration is 28%. Administration of a 12 mg paliperidone extended-release tablet to healthy ambulatory subjects with a standard high-fat/high-caloric meal gave mean C max and AUC values of paliperidone that were increased by 60% and 54%, respectively, compared with administration under fasting conditions. Clinical trials establishing the safety and efficacy of Paliperidone Extended-Release Tablets were carried out in subjects without regard to the timing of meals. While Palipe