What is the half-life of Risperdal (risperidone)?

Half-Life of Risperdal (Risperidone)

The half-life of risperidone is approximately 3 hours in extensive metabolizers and 20 hours in poor metabolizers, but the clinically relevant "active moiety" (risperidone plus its equipotent metabolite 9-hydroxyrisperidone) has a combined elimination half-life of approximately 20 hours in both metabolizer types. 1

Pharmacokinetic Details

Parent Drug vs. Active Moiety

• Risperidone itself has a short half-life of about 3 hours in extensive CYP2D6 metabolizers (representing 92-94% of Caucasians) 1, 2
• In poor CYP2D6 metabolizers (6-8% of Caucasians, very low percentage of Asians), risperidone's half-life extends to approximately 19-22 hours 1, 3
• The major metabolite 9-hydroxyrisperidone has a half-life of approximately 21 hours in extensive metabolizers and 30 hours in poor metabolizers 1

Clinical Significance of the Active Moiety

• The combined "active fraction" (risperidone plus 9-hydroxyrisperidone) is the clinically relevant measure because 9-hydroxyrisperidone has pharmacological activity equivalent to the parent compound 1, 3
• This active moiety has an overall mean elimination half-life of approximately 20 hours regardless of metabolizer status 1, 2
• Steady-state is reached within 1 day for risperidone and within 5 days for the active fraction 3

Metabolic Considerations

CYP2D6 Polymorphism Impact

• CYP2D6 enzyme is responsible for converting risperidone to 9-hydroxyrisperidone, and this enzyme exhibits genetic polymorphism 1
• Extensive metabolizers rapidly convert risperidone to 9-hydroxyrisperidone, resulting in lower risperidone concentrations and higher metabolite concentrations 1
• Poor metabolizers convert risperidone much more slowly, but the overall pharmacokinetics of the combined active moiety remain similar between the two groups 1, 2
• Despite these metabolic differences, observations in poor metabolizers do not suggest important clinical differences in therapeutic benefits or adverse effects compared to extensive metabolizers 1

Drug Interactions Affecting Half-Life

• CYP2D6 inhibitors (such as quinidine) interfere with conversion to 9-hydroxyrisperidone, essentially giving all recipients a pharmacokinetic profile typical of poor metabolizers 1
• Enzyme inducers (carbamazepine, phenytoin, rifampin, phenobarbital) may decrease combined plasma concentrations of risperidone and 9-hydroxyrisperidone 1

Special Population Considerations

Elderly Patients

• In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone is decreased, and elimination half-lives are prolonged compared to young healthy subjects 1
• Dosing modifications are recommended in elderly patients based on these pharmacokinetic changes 1

Pediatric Patients

• The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children are similar to those in adults after correcting for body weight differences 1

Renal and Hepatic Impairment

• Patients with renal or hepatic impairment may have altered pharmacokinetics requiring dosing adjustments 1

Tissue Distribution

• In brain tissue, the elimination half-life from frontal cortex and striatum is 3-4 hours for risperidone, with mean residence times of 4-6 hours for risperidone and approximately 12 hours for 9-hydroxyrisperidone 4
• These brain tissue half-lives are 3-5 times longer than in plasma, indicating preferential retention in receptor-rich brain regions 4