Personalizing dosing of risperidone, paliperidone and clozapine using therapeutic drug monitoring and pharmacogenetics

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33 Scopus citations

Abstract

By combining knowledge of pharmacogenetics, therapeutic drug monitoring (TDM) and drug-drug interactions (DDIs) the author developed a model for personalizing antipsychotic dosing, which is applied to risperidone, 9-hydroxyrisperidone or paliperidone, and clozapine. Drugs are approved using an average dose for an ideal average patient, but pharmacologists have described outliers: genetic poor metabolizers (PMs) and ultrarapid metabolizers (UMs). Environmental and personal variables can also make patients behave as PMs or UMs. Drug clearance is represented by the concentration-to-dose (C/D) ratio under steady-state and trough conditions. A very low C/D ratio indicates a UM, while a very high C/D ratio indicates a PM. Total risperidone C/D ratio for the oral formulation is around 7 ng/ml per mg/day and can be influenced by CYP2D6 polymorphism, DDIs with inducers and inhibitors, and renal function. Oral paliperidone has low availability; its C/D ratio is around 4.1 ng/ml per mg/d and can be influenced by inducers and renal impairment. Once-a-month long-acting paliperidone provides a C/D ratio around 7.7 ng/ml per mg/day at steady state, which is expected to be in the 8th month (before the 9th injection). TDM is particularly important for long-acting paliperidone formulations that may accumulate once steady state is reached (after years for the 3- and 6-month formulations). In the US, clozapine C/D ratios typically range from 0.6 (male smokers) to 1.2 (female non-smokers) ng/ml per mg/day. East Asians’ clozapine C/D ratios appear to be twice as high. Inhibitors (including fluvoxamine and oral contraceptives) and inflammation can also increase clozapine C/D ratios. This article is part of the issue entitled ‘Special Issue on Antipsychotics’.

Original languageEnglish
Article number107656
JournalNeuropharmacology
Volume168
DOIs
StatePublished - May 15 2020

Bibliographical note

Funding Information:
The author acknowledges Lorraine Maw, M.A. from the University of Kentucky Mental Health Research Center at Eastern State Hospital, who helped in editing the article and the reviewers who provided important suggestions for improving the article.

Publisher Copyright:
© 2019 Elsevier Ltd

Keywords

  • Antipsychotic agents/administration & dosage
  • Clozapine
  • Delayed-action preparations
  • Drug monitoring
  • Paliperidone palmitate
  • Risperidone

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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