Kneller L.A. (1); Hempel G. (1)
(1) Institute of Pharmaceutical and Medicinal Chemistry, Clinical Pharmacy, Westfälische Wilhelms-Universität Münster, Corrensstr. 48, 48149 Münster, Germany.
Introduction Globally, the population is aging [1]. Thereby, the age-related comorbidities such as psychotic disorders will rise and the craving for individual treatment in geriatric patients are gaining in importance. Since psychotropic agents often exhibit great interindividual variability in their pharmacokinetics (PK) and pharmacodynamics, little is known about the impact of aging on risperidone and its active metabolite 9-hydroxyrisperidone. Hence, a better understanding of age-related effects of Cytochrome P450 (CYP) 2D6 phenotype-related physiological alterations could help to optimize dosing regimens, especially in the elderly.
Objectives
- Extrapolation and verification of a developed whole-body physiologically based pharmacokinetic (PBPK) model of risperidone including its active metabolite 9-hydroxyrisperidone in the elderly (> 65 years)
- Application of the metabolic ratio (risperidone/9-hydroxyrisperidone) to classify geriatric patients over the age of 65 years in different CYP2D6 metabolizers, using PBPK approach
Methods PBPK modelling for risperidone and its active metabolite was performed using PK-Sim®/MoBi® (Version 7.3.0) as part of the Open System Pharmacology Suite [2]. Previously developed models were extrapolated to predict age-related changes in the PK from young adults (18-35 years) compared to the elderly aged 65+ years [3]. For a more accurate prediction, all elderly patients were subdivided into young-olds (65-74 years), medium-olds (75-84 years), and oldest-olds (85-100 years). In the following, PBPK models were verified with clinical data from 17 geriatric inpatients aged 65 years of age or older and treated under naturalistic conditions, admitted to the inpatient programs of the Western Psychiatric Institute and Clinic between November 1996 and March 1998 [4]. Patient characteristics as well as plasma profiles of the drug (range 0.32 µg/L to 22.3 µg/L) and its active metabolite (range 1.87 µg/L to 24.8 µg/L) after oral administration were obtained and metabolic ratio calculated as a marker for CYP2D6 phenotype.
Results Based on risperidone/9-hydroxyrisperidone ratio for each CYP2D6 phenotype, the metabolic ratio combined with the developed PBPK models were able to classify all 17 geriatric inpatients in different CYP2D6 metabolizers during steady-state. Overall, ten inpatients show a non-reduced metabolic capacity for CYP2D6 (extensive and ultra-rapid metabolizer) and six inpatients a reduced function (intermediate metabolizer) whereas one of the inpatients was identified as poor metabolizer. Predicted plasma concentrations of the parent drug and its metabolite were in close agreement to the observed clinical data of each individual. 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, indicating a possible influence of individual concomitant medication on the metabolizing enzymes CYP2D6 and CYP3A4 for the remaining four plasma samples. In general, predicted Cmax and AUC of risperidone and 9-hydroxyrisperidone increased with age in all types of CYP2D6 metabolizer, while tmax did not change with age. Comparing a population of 18-35 years with one of 85-100 years, Cmax of risperidone increased by 24-44% and 35-37% for the active metabolite, respectively. The predicted AUC of the 85-100 years population showed the highest predicted increase with up to a 1.52-fold difference (range: 1.47 to 1.52) for risperidone and up to 1.39-fold difference (range: 1.34 to 1.39) for 9-hydroxyrisperidone compared to a 18-35 years population.
Conclusions The successfully developed whole-body PBPK models of risperidone and 9-hydroxyrisperidone including CYP2D6 and CYP3A4 metabolism predict a progressive increase in the PK parameter Cmax and AUC while aging. Calculated metabolic ratio combined with the PBPK models can provide a powerful tool to identify potential CYP2D6 poor metabolizer during therapeutic drug monitoring in the elderly. Based on genetically, anatomical and physiological changes during aging, PBPK models ultimately support decision-making regarding dose-optimization strategies for patients over the age of 65 years.
References:
[1] https://www.un.org/en/development/desa/population/publications/pdf/ageing/WorldPopulationAgeing2019-Highlights.pdf.
[2] Eissing T, Kuepfer L, Becker C, et al. A computational systems biology software platform for multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks. Front Physiol 2011;2:4.
[3] Kneller LA, Abad-Santos F, Hempel G. Physiologically Based Pharmacokinetic Modelling to Describe the Pharmacokinetics of Risperidone and 9-Hydroxyrisperidone According to Cytochrome P450 2D6 Phenotypes. Clin Pharmacokinet. 2020 Jan;59(1):51-65.
[4] Maxwell RA, Sweet RA, Mulsant BH et al. Risperidone and 9-hydroxyrisperidone concentrations are not dependent on age or creatinine clearance among elderly subjects. J Geriatr Psychiatry Neurol. 2002;15:77–81.
Reference: PAGE () Abstr 9321 [www.page-meeting.org/?abstract=9321]
Poster: Drug/Disease Modelling - Absorption & PBPK