Kneller L.A. (1); Abad-Santos F. (2); Hempel G. (1)
(1) Institute of Pharmaceutical and Medicinal Chemistry, Clinical Pharmacy, Westfälische Wilhelms-Universität Münster, Corrensstr. 48, 48149 Münster, Germany. (2) Clinical Pharmacology Department, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IP), Diego de León 62. 28006 Madrid, Spain.
Objectives: The genetic polymorphism of Cytochrome P450 (CYP) 2D6 plays an influential role on the appearance of positive and adverse drug reactions to antipsychotics, such as risperidone (RIS) [1]. Consequently, pharmacokinetics of RIS and its active metabolite 9-Hydroxyrisperidone (9‑OH-RIS) can be substantially altered showing large inter-individual variability in its plasma concentrations between the different phenotypes [2,3].
The objective of the study is to develop a physiologically-based pharmacokinetic (PBPK) model considering the CYP2D6 genetic polymorphism for RIS and 9-OH-RIS taking CYP3A4 and P‑glycoprotein transporter into account [4].
Methods: Based on available literature knowledge about RIS, 9-OH-RIS, and relevant physiological changes according to different CYP2D6 phenotypes, several PBPK models were developed using the software PK‑Sim® as part of the Open Systems Pharmacology Suite [5,6].
The initial model was further evaluated based on RIS’s and 9-OH-RIS’s measured plasma concentrations from a single dose study including 71 genotyped healthy volunteers treated with 1 mg oral RIS. According to CYP2D6 genotype, all subjects were classified as [7]: extensive metabolizer (EM, n=33), intermediate metabolizer (IM, n=26), poor metabolizer (PM, n=6) and ultra-rapid metabolizer (UM, n=6).
In addition, all single dose simulations were transmitted to steady-state condition (3 mg RIS twice a day) due to linear pharmacokinetics of the active moiety (RIS plus 9-OH-RIS).
Results: PBPK models were able to accurately describe RIS exposure after 1 mg single dose administration especially in the concentration range ≥ 1 µg/L, illustrated by a minimal bias and a good precision. About 90.3% of all weighted residuals vs. observed plasma concentrations ≥ 1 µg/L were in the ± 30% range.
Regarding whole PBPK simulation over 96 h, mean prediction error (MPE) and mean absolute prediction error (MAPE) of RIS were 52.2 % and 54.2 % for EM’s, 37.4 % and 43.6 % for IM’s, 28.0 % and 49.4 % for PM’s and 45.4 % and 62.6 % for UM’s. MPE and MAPE of 9-OH-RIS amount -22.2 % and 22.7 % for EM’s, -10.6 % and 18.7 % for IM’s, -7.80 % and 15.4 % for PM’s and -28.3 % and 28.3 % for UM’s. In this connection a clear association between the number of active CYP2D6 alleles and the pharmacokinetic parameters for RIS and 9-OH-RIS was observed.
During steady-state, RIS/9-OH-RIS ratio increased progressively according to reduced CYP2D6 activity, resulting in a mean ratio of 4.96 for PM whereas EM show a mean ratio of 0.27.
Conclusions: PBPK modelling can provide a valuable tool to predict RIS’s and 9-OH-RIS’s pharmacokinetics in healthy volunteers, according to the different CYP2D6 phenotypes taking CYP3A4 and P‑glycoprotein transporter into account. All newly developed single dose PBPK models accurately describe RIS’s and 9-OH-RIS’s plasma concentrations of healthy volunteers.
Our simulation show that the calculation of RIS/9-OH-RIS ratio can be used to phenotype patients using clinical data from therapeutic drug monitoring. To ensure the best therapy for each subject, dose optimization according to different CYP2D6 phenotypes can be subsequently applied.
References:
[1] Zhou S-F. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet 2009;48(11):689–723.
[2] Balant-Gorgia AE, Gex-Fabry M, Genet C, Balant LP. Therapeutic drug monitoring of risperidone using a new, rapid HPLC method: reappraisal of interindividual variability factors. Ther Drug Monit 1999;21(1):105–15.
[3] Aravagiri M, Marder SR, Wirshing D, Wirshing WC. Plasma concentrations of risperidone and its 9-hydroxy metabolite and their relationship to dose in schizophrenic patients: simultaneous determination by a high performance liquid chromatography with electrochemical detection. Pharmacopsychiatry 1998;31(3):102–9.
[4] 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 [submitted for publication].
[5] www.open-systems-pharmacology.org.
[6] 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.
[7] Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther 2008;83(2):234–42.
Reference: PAGE 28 (2019) Abstr 8889 [www.page-meeting.org/?abstract=8889]
Poster: Drug/Disease Modelling - Absorption & PBPK