Pharmacokinetics of Risperidone: Clinical Summary

Risperidone is a second-generation antipsychotic metabolized by the enzyme cytochrome P450 2D6 (CYP2D6). It is available as long-acting injection (depot injection) as well as oral formulations. This clinical summary highlights pharmacokinetic features relevant to mental health prescribers.

Formulations

• Oral formulations:
  • Tablets
  • Orally disintegrating tablets
  • Liquid formulation
• Long-acting injection: risperidone microspheres (Risperdal Consta)

General pharmacokinetics

Distribution

• Volume of distribution: 1-2 L/kg.
• Risperidone binds to albumin and alpha1-acid glycoprotein.
• Plasma protein binding:
  • For risperidone: 90%
  • For 9-hydroxyrisperidone: 77%

Metabolism

Risperidone metabolism by CYP2D6

• CYP 2D6 is the enzyme that catalyzes hydroxylation of risperidone to 9-hydroxyrisperidone.
• The metabolite 9-hydroxyrisperidone has similar pharmacological activity as risperidone.
• CYP 2D6 is subject to genetic polymorphism:
  • Extensive metabolizers convert risperidone rapidly into 9-hydroxyrisperidone
  • Poor CYP 2D6 metabolizers convert risperidone much more slowly.
  • Pharmacokinetics of risperidone and 9-hydroxyrisperidone combined after single and multiple doses are similar in extensive and poor metabolizers.

Pharmacokinetics of Oral Formulations

Absorption

• Orally disintegrating tablets and oral solution are bioequivalent to tablets.
• Rapidly absorbed after oral administration.
• Peak plasma levels achieved within 1 hour.
• Linear pharmacokinetics.
• Time to reach steady state ( between 4 and 5 half-lives for all drugs):
  • For risperidone:
    • 1 day in extensive metabolizers.
    • 5 days in poor metabolizers.
  • For 9-hydroxyrisperidone:
    • 5-6 days, measured in extensive metabolizers.
• Food effect: risperidone can be administered with or without meals.

Excretion

• Apparent half-life of risperidone:
  • 3 hours in extensive metabolizers
  • 20 hours in poor metabolizers
• Apparent half-life of 9-hydroxyrisperidone:
  • 21 hours in extensive metabolizers
  • 30 hours in poor metabolizers

Pharmacokinetics of Long-Acting Injection (Risperidone Microspheres)

• Risperidone microspheres release considerable amounts of drug 3 weeks after injection.
• Long-acting risperidone should be supplemented with oral risperidone for 3 weeks.

• Apparent half-life or risperidone plus 9-hydroxyrisperidone is 3 to 6 days (related to the erosion of the microspheres and subsequent absorption of risperidone).

Related Information on Risperidone

• Mechanism of Action of Risperidone
• Risperidone Indications: FDA-Approved and Off-Label Uses

References

1. Janicak, P G., Marder S R., and. Pavuluri M N. Principles and Practice of Psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.
2. Stahl, S M. The Prescriber’s Guide. 4th ed. New York: Cambrigde University Press; 2011
3. Janssen Pharmaceuticals, Inc. Risperdal prescribing information. Retrieved from http://www.janssenpharmaceuticalsinc.com/assets/risperdal.pdf. [retrieval date: April 12, 2013]
4. Janssen Pharmaceuticals, Inc. Risperdal Consta prescribing information. Retrieved from http://www.janssencns.com/risperdal-prescribing-information