14 Physiologically based pharmacokinetic modelling of risperidone and 9-hydroxyrisperidone to determine cytochrome P450 2D6 phenotypes in schizophrenia patients

Introduction Therapeutic drug monitoring (TDM) of risperidone and its active metabolite 9-hydroxyrisperidone is recommended by many experts [1], as a large interindividual variability in plasma concentrations can be observed. One reason for this is the genetic polymorphism of cytochrome P450 (CYP) 2D6. Therefore, different physiologically based pharmacokinetic (PBPK) models were developed on the one hand to determine the phenotypes and on the other hand to use them for dose optimization in future.

Methods Based on available plasma concentrations of risperidone and 9-hydroxyrisperidone, modelling software PK-Sim^® was used to develop PBPK models for all types of CYP2D6 metabolizer. In the next step all models were extrapolated to the elderly and clinical data of geriatric inpatients from the literature were integrated. Subsequently, CYP2D6 phenotype was determined using metabolic ratio (risperidone / 9-hydroxyrisperidone) and modelling.

Results PBPK models were able to predict the plasma concentrations for all types of CYP2D6 metabolizers. Mean prediction error of risperidone and 9-hydroxyrisperidone amounts to 52.2 % and −22.2 % (extensive metabolizer), 37.4 % and −10.6 % (intermediate metabolizer), 28.0 % and −7.8 % (poor metabolizer) as well as 45.4 % and −28.3 % (ultra-rapid metabolizer). After model extrapolation, plasma concentrations and phenotypes of all inpatients were predicted. Here, 88.2 % of the plasma concentrations were within the 2-fold error range. Finally, one patient was identified as a poor metabolizer.

Conclusions PBPK modelling in combination with calculated metabolic ratio is a cost-effective and fast new approach to draw conclusions about CYP2D6 phenotyping that can easily be done during TDM to finally adjust the dosage during therapy.

Publication History

Article published online:
30 April 2020

• References

• 1 Hiemke C, Bergemann N, Clement HW. et al. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry 2018; 51 (1–02): 9-62.