Abstract
PurposeDose-optimization strategies for risperidone are gaining in importance, especially in the elderly. Based on the genetic polymorphism of cytochrome P 450 (CYP) 2D6 genetically and age-related changes cause differences in the pharmacokinetics of risperidone and 9-hydroxyrisperidone. The goal of the study was to develop physiologically based pharmacokinetic (PBPK) models for the elderly aged 65+ years. Additionally, CYP2D6 phenotyping using metabolic ratio were applied and different pharmacokinetic parameter for different age classes predicted.MethodsPlasma concentrations of risperidone and 9-hydroxyrisperidone were used to phenotype 17 geriatric inpatients treated under naturalistic conditions. For this purpose, PBPK models were developed to examine age-related changes in the pharmacokinetics between CYP2D6 extensive metabolizer, intermediate metabolizer, poor metabolizer, (PM) and ultra-rapid metabolizer.ResultsPBPK-based metabolic ratio was able to predict different CYP2D6 phenotypes during steady-state. One inpatient was identified as a potential PM, showing a metabolic ratio of 3.39. About 88.2% of all predicted plasma concentrations of the inpatients were within the 2-fold error range. Overall, age-related changes of the pharmacokinetics in the elderly were mainly observed in Cmax and AUC. Comparing a population of young adults with the oldest-old, Cmax of risperidone increased with 24–44% and for 9-hydroxyrisperidone with 35–37%.ConclusionsMetabolic ratio combined with PBPK modelling can provide a powerful tool to identify potential CYP2D6 PM during therapeutic drug monitoring. Based on genetic, anatomical and physiological changes during aging, PBPK models ultimately support decision-making regarding dose-optimization strategies to ensure the best therapy for each patient over the age of 65 years.
Highlights
Based on a previously developed risperidone/9hydroxyrisperidone ratio for each CYP2D6 phenotype, the ratio was applied to clinically observed data of 17 geriatric inpatients treated under naturalistic conditions to identify the individual type of CYP2D6 metabolizer (Table 1)
Ten geriatric inpatients show a non-reduced metabolic capacity for CYP2D6 (EM and ultra-rapid metabolizer (UM)) and six inpatients a reduced function (IM) whereas one of the 17 geriatric inpatients (5.88%) was identified as PM, showing a plasma concentration of 6.33 μg/L for the parent drug compared to a value of 1.87 μg/L for the active metabolite
Predicted plasma concentrations of risperidone and 9-hydroxyrisperidone were in close agreement to the observed clinical data of each individual, as can be seen by the individual plasma concentration-time curve profile of each geriatric inpatient (Fig. 1). 52.9% of all predicted plasma concentrations were within the 1.25-fold error range and 88.2% were within the 2-fold error range in the plot of predicted versus observed data (Fig. 2)
Summary
In Germany, the number of people aged 65 years and above was reported at 17.8 million (21%) in 2018, exhibiting an upward trend [1,2]. Thereby, the age-related comorbidities such as psychotic disorders will rise and the craving for individual treatment in geriatric patients is gaining in importance. One potential treatment option in geriatric patients is risperidone, an atypical antipsychotic. In Norway, 30% of the overall number of risperidone-treated patients are 65 years or older [3]. Despite the growing population of elderly individuals, they are often omitted from clinical trials [4]. Since psychotropic agents often exhibit great inter-individual variability, only little is known about the impact of aging on the pharmacokinetics (PK) of risperidone and its active metabolite 9-hydroxyrisperidone
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