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

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-ldose (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 nonsmokers) 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'.