Risperdal

[Risperidone]

Clinical Pharmacology
CLINICAL PHARMACOLOGY

Pharmacodynamics

The mechanism of action of RISPERDAL ® ( risperidone) , as with other drugs used to treat schizophrenia, s unknown. However, it has been proposed that the drug s therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 ( D2) and serotonin Type 2 ( 5HT2) receptor antagonism. Antagonism at receptors other than D2 and 5HT2 may explain some of the other effects of RISPERDAL ® .

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RISPERDAL ® is a selective monoaminergic antagonist with high affinity ( Ki of 0.12 to 7. 3 nM) for the serotonin Type 2 ( 5HT2) , dopamine Type 2 ( D2) , 1 and 2 adrenergic, and H 1 histaminergic receptors. RISPERDAL ® acts as an antagonist at other receptors, but with lower potency.

RISPERDAL ® has low to moderate affinity ( Ki of 47 to 253 nM) for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity ( Ki of 620 to 800 nM) for the dopamine D1 and haloperidol-sensitive sigma site, and no affinity ( when tested at concentrations > 10 -5 M) for cholinergic muscarinic or ß1 and ß2 adrenergic receptors.

Pharmacokinetics

Absorption

Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% ( CV= 25% ) . The relative oral bioavailability of risperidone from a tablet is 94% ( CV= 10% ) when compared to a solution.

Pharmacokinetic studies showed that RISPERDAL ® M-TAB Orally Disintegrating Tablets and RISPERDAL ® Oral Solution are bioequivalent to RISPERDAL ® Tablets.

Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily ( 0.5 to 8 mg BID) . Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days ( measured in extensive metabolizers) .

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