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Pharmacology: Aspidon: 1 mg: Risperidone with the precise mechanism of action as other antipsychotic drugs, is known but the antipsychotic activity is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism.
Risperidone 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) a1 and a2 adrenergic, and H1 histaminic receptors. Risperidone has no affinity for cholinergic muscarinic or b1 and b2 adrenergic receptors.
The relative oral bioavailability of Risperidone after administration of a single 1 mg tablet was 94%. After oral administration of solution or tablet, mean peak plasma concentrations occurred at about 1 hour. The apparent half-life of Risperidone was three hours. Steady state concentrations of Risperidone are reached in 1 day in extensive metabolizers.
Total plasma protein binding of Risperidone was about 90% over the in vitro concentration range of 0.5 to 200mg/mL and increased with increasing concentrations of a1 acid glycoprotein. After oral administration, the elimination half-life of the active antipsychotic fraction is 24 hours.
Total recovery of Risperidone at one week was nearly up to 85%, including 70% in the urine and 15% in the feces. Risperidone is extensively metabolized in the liver to a major active metabolite, 9-hydroxyrisperidone that is equi-effective with Risperidone with respect to receptor binding activity and some effects in animals. Plasma concentrations of Risperidone, 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 b.i.d). Food does not affect either the rate of extent of absorption. Thus, Risperidone can be given with or without meals. The absolute oral bioavailability was 70%.
Pharmacodynamics: Aspidon: 2 mg: The mechanism of action of risperidone, as with other antipsychotic drugs, is unknown. However, it has been proposed that this drug's antipsychotic activity is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism. Antagonism at receptors other than D2 and 5HT2 may explain some of the other effects of risperidone.
Risperidone is a selective monoaminergic antagonist with high affinity for the serotonin type 2 (5HT2), dopamine type 2 (D2), a1 and a2 adrenergic, and H1 histaminergic receptors. Risperidone antagonizes other receptors, but with lower potency. Risperidone has low to moderate affinity for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity for the dopamine D1 and haloperidol-sensitive, sigma site, and no affinity for cholinergic muscarinic or B1 and B2 adrenergic receptors.
Aspidon OS: Risperidone is a selective monoaminergic antagonist with unique properties. It has a high affinity for serotoninergic 5-HT2 and dopaminergic D2 receptors. Risperidone binds also to alpha1-adrenergic receptors, and, with lower affinity, to H1-histaminergic and alpha1-adrenergic receptors. Risperidone has no affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, which is considered to improve the positive symptoms of schizophrenia, it causes less depression of motor activity and induction of catalepsy than classical antipsychotics. 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.
Pharmacokinetics: Aspidon: 1 mg: Risperidone is readily absorbed after oral doses, peak plasma concentrations being reached within 1 to 2 hours. It is extremely metabolized in the liver to hydroxylation to its main active metabolite, 9-hydroxylation; oxidative N-dealkylation is a minor metabolic pathway. Hydroxylation is mediated by the cytochrome P450 isozyme CYP2D6 and is the subject of genetic polymorphism. Excretion is mainly in the urine and to a lesser extent, in the feces. Risperidone and 9-hydroxyrisperidone are about 88% and 77% bound to plasma proteins, respectively.
2 mg: 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.
Plasma concentration 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 twice daily). Following oral administration of a solution or tablet, mean peak plasma concentrations of risperidone occurred 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).
Food Effect: Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone can be given with or without meals.
Distribution: Risperidone is rapidly distributed. The volume of distribution is 1-2 L/Kg. In plasma, risperidone is bound to albumin and 1-acid glycoprotein. The plasma protein binding of risperidone is 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. 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 slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Metabolism: Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%-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 CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor 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-hydoxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers.
Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone. This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in patients receiving quinidine have not been evaluated, but observations in a modest number (n=70) poor metabolizers given risperidone do not suggest important differences between poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g., carbamazepine, phenytoin, rifampin, and phenobarbital) with risperidone may cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone. It would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely.
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, risperidone is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
In vitro studies demonstrated that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
Excretion: Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone administered as solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and 20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours.
Special Populations: Renal Impairment: In patients with moderate to severe (Clcr 59 to 15 mL/min) 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 patients with renal disease.
Hepatic Impairment: While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free 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 patients with liver disease.
Elderly: In healthy elderly subjects renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in the elderly patients.
Pediatric: The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those in adults after correcting for the difference in body weight.
Race and Gender Effects: No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether corrected for body weight or not) or race.
Aspidon OS: Risperidone oral solution is bio-equivalent to risperidone film-coated tablets.
Risperidone is metabolized to 9-hydroxy-risperidone, which has a similar pharmacological activity to risperidone.
Risperidone is completely absorbed after oral administration, reaching peak plasma concentrations within 1 to 2 hours. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) compared with a solution. The absorption is not affected by food and thus risperidone can be given with or without meals. Steady-state of risperidone is reached within 1 day in most patients. Steady-state of 9-hydroxy-risperidone is reached within 4-5 days of dosing.
Risperidone is rapidly distributed. The volume of distribution is 1-2l/kg. In plasma, risperidone is bound to albumin and alpha1-acid glycoprotein. The plasma protein binding of risperidone is 90%, that of 9-hydroxyrisperidone is 77%.
Risperidone is metabolized by CYP2D6 to 9-hydroxy-risperidone, which has a similar pharmacological activity as risperidone. Risperidone plus 9-hydroxy-risperidone form the active antipsychotic fraction. CYP2D6 is subject to genetic polymorphism. Extensive CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxy-risperidone, whereas poor CYP2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxy-risperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxy-risperidone combined (i.e., the active antipsychotic fraction), after single and multiple doses, are similar in extensive and poor metabolizers of CYP2D6.
