Pharmacology: Risperidone is a benzisoxazole derivative antipsychotic agent. Its mechanism of action is unclear but 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.
Risperidone, as a potent D2 antagonist, improves the positive symptoms of schizophrenia but causes less depression of motor activity and induction of catalepsy than typical antipsychotic drugs. Balanced central serotonin and dopamine antagonism may reduce extrapyramidal side effect liability and extend the therapeutic activity to the negative and affective symptoms of schizophrenia. The antipsychotic activity of risperidone is considered to be attributable to both risperidone and its active metabolite 9-hydroxyrisperidone.
Risperidone is a selective monoaminergic antagonist with high affinity for 5HT2, D2, α1 and α2 adrenergic, and H1 histaminergic receptors. Risperidone acts as an antagonist at other receptors, but with lower potency. Risperidone has low to moderate affinity for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity for the D1 and haloperidol-sensitive sigma site, and no affinity for cholinergic muscarinic or β1 and β2 adrenergic receptors.
Pharmacokinetics: Risperidone is completely absorbed after oral administration, reaching peak plasma concentrations within 1 to 2 hours. The absolute oral bioavailability is 70%. The relative oral bioavailability of risperidone from a tablet is 94% compared with a solution; food does not affect either the rate or extent of absorption of risperidone.
Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dose range of 1 to 16 mg per day (0.5 to 8 mg twice a day). After oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about one hour. Peak concentrations of 9-hydroxyrisperidone occurred at about three hours in extensive metabolizers and 17 hours in poor metabolizers. Steady state concentrations of risperidone are reached in one day in extensive metabolizers and would be expected to reach steady state in about five days in poor metabolizers. Steady state concentrations of 9-hydroxyrisperidone are reached in 5 to 6 days (measured in extensive metabolizers).
Risperidone is rapidly distributed. The volume of distribution is 1 to 2 L/kg. In plasma, risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone and 9-hydroxyrisperidone is 90% and 77%, respectively. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL) and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Risperidone is extensively metabolized in the liver by CYP2D6 (also called debrisoquin hydroxylase) to 9-hydroxyrisperidone, which has a similar pharmacological activity as risperidone. CYP2D6 is subject to genetic polymorphism (about 6 to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers.
Another metabolic pathway of risperidone is N-dealkylation. In vitro studies in human liver microsomes showed that risperidone at clinically relevant concentration does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5.
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. A mass balance study of a single 1 mg oral dose of 14C-risperidone administered as a solution to three healthy male volunteers showed that total recovery of radioactivity at one week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone was three hours in extensive metabolizers and 20 hours in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours in extensive metabolizers and 30 hours in poor metabolizers. The overall mean elimination half-life of risperidone and its active metabolite is about 20 hours.
Special Population: Renal Impairment: In patients with moderate to severe renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60% compared to young healthy subjects. Risperidone doses should be reduced in these patients.
Hepatic Impairment: Although the pharmacokinetics of risperidone in patients with liver disease were comparable to those in young healthy subjects, the mean fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein. Risperidone doses should be reduced in these patients.
Elderly: In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased by 30%, and elimination half-lives were prolonged compared to young healthy subjects.
Risperidone doses should be adjusted in these patients.
Children: The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those in adults after correcting for the difference in body weight.