Anaïs Glatard (1,2), Monia Guidi (2,3), Aurélie Delacrétaz (1), Céline Dubath (1), Axel Levier (1), Philippe Conus (4), Armin von Gunten (5), Chin Bin Eap (1,3)*, Chantal Csajka (2,3)*
(1) Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Hospital of Cery, Prilly, Switzerland (2) Service of Clinical Pharmacology, Service of Biomedicine, Department of Laboratory, Lausanne University Hospital, Lausanne, Switzerland (3) School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland (4) Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland (5) Service of Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland *joint corresponding authors
Objectives: The atypical antipsychotic drug amisulpride is used orally at a wide range of doses (50-800 mg daily) for the treatment of negative and positive psychotic symptoms [1]. Amisulpride is mainly eliminated unchanged via the kidney and the elimination half-life is around 12h. This low membrane permeability drug is a substrate of Permeability Glycoprotein (P-gp) and of Organic Cation Transporters (OCT1, OCT2) responsible for the tubular secretion of the drug [2]. A low fraction of the dose (12%) is metabolized by the cytochrome P450 3A4 (CYP3A4) in two inactive metabolites. Because amisulpride may provoke important dose-dependent adverse effects (e.g. hyperprolactinemia, extrapyramidal symptoms) and because a dose-therapeutic response relationship has been demonstrated, therapeutic drug monitoring of this antipsychotic is strongly recommended [3]. The aim of this study was to describe the pharmacokinetic profile of amisulpride in psychiatric patients and to detect genetic and non-genetic sources of variability in order to better individualize doses.
Methods: The population pharmacokinetic analysis was performed by use of NONMEM® based on plasma samples from a cohort of hospitalized patients or followed in ambulatory care at the Department of Psychiatry of the Lausanne University Hospital. Seventeen single nucleotide polymorphisms (SNP) of the OCT transporters, P-gp and nuclear receptors that regulate OCT transporters were selected for analysis and genotyped using the Cardio-MetaboChip (Illumina) containing customized SNPs for pharmacokinetic genes when an informed consent was obtained from patients. With the use of a one-compartment model with first order absorption and integrating a known bioavailability of 48%, the influence of demographic (age, sex), clinical (body weight, body mass index, smoking status, creatinine clearance estimated by the Cockcroft-Gault (CLCG) or the Salazar-Corcoran formula (CLSZ)) and genetic characteristics as well as comedications (inhibitor or substrate of OCT transporters, inhibitor or substrate of P-gp, inhibitor of CYP3A4) on amisulpride clearance and volume of distribution was quantified.
Results: A total of 517 amisulpride plasma concentrations from 245 patients (18-91 years) were collected for the analysis. Systemic clearance (CL) was 45.7 L/h (Relative Standard Error RSE 4%) with an inter-individual variability of 23% (RSE 20%) and the volume of distribution (V) was 846 L (RSE 10%) with 44% of inter-individual variability (RSE 29%). The absorption rate constant was 0.4 h-1 (RSE 25%). Univariate analysis revealed a significant linear relationship between amisulpride CL and CLSZ, body weight, age and smoking (p<0.001) as well as between V and age (p=0.02). No significant influence of the 17 single nucleotide polymorphisms of transporters and nuclear receptors was found on amisulpride elimination. Multivariate analysis with forward selection (p=0.05) and backward deletion (Bonferroni-adjusted p<0.003) revealed an amisulpride CL increase of 25% in a 120-kg patient compared to a 75-kg patient and a CL decrease of 55% for a 80-year patient compared to a 40-year patient. Body weight and age explained 8% and 58% of the inter-individual variability of amisulpride CL, respectively. Body weight and age were correlated with CLSZ (Pearson correlation coefficient r2=0.41 and r2=-0.68, respectively) and had less missing data than CLSZ (38%) explaining that CLSZ was not retained. In addition, the influence of age on V was not retained.
Conclusions: The present study showed an important influence of body weight and age on amisulpride concentration and highlight the importance of a personalized dosage adjustment especially in elderly individuals with a low body weight. This model may be implemented in a Bayesian tool for dosage adjustment to predict amisulpride concentrations in psychiatric patients. Finally, the present model will be used to characterize the relationship between amisulpride concentrations and weight gain during the treatment.
References:
[1] Schoemaker, H., et al. (1997). “Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity.” The Journal of pharmacology and experimental therapeutics. 280: 83-97.
[2] Dos Santos Pereira, J. N., et al. (2014). “The poorly membrane permeable antipsychotic drugs amisulpride and sulpiride are substrates of the organic cation transporters from the SLC22 family.” The AAPS journal. 16: 1247-1258.
[3] Hiemke, C., et al. (2017). “Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.” Pharmacopsychiatry.
Reference: PAGE 27 (2018) Abstr 8655 [www.page-meeting.org/?abstract=8655]
Poster: Drug/Disease Modelling - CNS