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Amisulpride: Real-World Evidence of Dose Adaptation and Effect on Prolactin Concentrations and Body Weight Gain by Pharmacokinetic/Pharmacodynamic Analyses

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Abstract

Background

Amisulpride is an antipsychotic used in a wide range of doses. One of the major adverse events of amisulpride is hyperprolactinemia, and the drug might also induce body weight gain.

Objective

The aims of this work were to characterize the pharmacokinetics of amisulpride in order to suggest optimal dosage regimens to achieve the reference range of trough concentrations at steady-state (Cmin,ss) and to describe the relationship between drug pharmacokinetics and prolactin and body weight data.

Methods

The influence of clinical and genetic characteristics on amisulpride pharmacokinetics was quantified using a population approach. The final model was used to simulate Cmin,ss under several dosage regimens, and was combined with a direct Emax model to describe the prolactin data. The effect of model-based average amisulpride concentrations over 24 h (Cav) on weight was estimated using a linear model.

Results

A one-compartment model with first-order absorption and elimination best fitted the 513 concentrations provided by 242 patients. Amisulpride clearance significantly decreased with age and increased with lean body weight (LBW). Cmin,ss was higher than the reference range in 65% of the patients aged 60 years receiving 400 mg twice daily, and in 82% of the patients aged > 75 years with a LBW of 30 kg receiving 200 mg twice daily. The pharmacokinetic/pharmacodynamic model included 101 prolactin measurements from 68 patients. The Emax parameter was 53% lower in males compared with females. Model-predicted prolactin levels were above the normal values for Cmin,ss within the reference range. Weight gain did not depend on Cav.

Conclusions

Amisulpride treatment might be optimized when considering age and body weight. Hyperprolactinemia and weight gain do not depend on amisulpride concentrations. Modification of the amisulpride dosage regimen is not appropriate to reduce prolactin concentrations and alternative treatment should be considered.

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Acknowledgements

The authors thank A. C. Aubert, M. Brawand, M. Brocard, C. Brogli, N. Cochard, C. Darbellay, M. Delessert, S. Jaquet, G. Viret and A. Vullioud for sample analyses and data collection; E. Retamales for help with the bibliography; M. Gholamrezaee for his helpful advice on statistical analysis; and G. Sibailly for her instructive and helpful comments on the clinical aspect of this work. The authors are also grateful to the patients who agreed to participate in the study, and to the nursing and medical staff who were involved in the metabolic monitoring program.

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Author notes

  1. Chantal Csajka and Chin B. Eap were joint corresponding authors.

Authors and Affiliations

  1. Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Hospital of Cery, Prilly, Switzerland

    Anaïs Glatard, Aurélie Delacrétaz, Céline Dubath, Claire Grosu, Nermine Laaboub & Chin B. Eap

  2. Service of Clinical Pharmacology, Service of Biomedicine, Department of Laboratory, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland

    Anaïs Glatard, Monia Guidi & Chantal Csajka

  3. Institute of Pharmaceutical Sciences of Western Switzerland, Geneva, Switzerland

    Monia Guidi, Chantal Csajka & Chin B. Eap

  4. Service of Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Prilly, Switzerland

    Armin von Gunten

  5. Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Prilly, Switzerland

    Philippe Conus

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  1. Anaïs Glatard
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Contributions

AG wrote the manuscript and analyzed the data. MG reviewed the manuscript and supervised the data analysis. AD reviewed the manuscript and collected the data. CD reviewed the manuscript and collected the data. CG reviewed the manuscript and collected the data. NL reviewed the manuscript and collected the data. AG reviewed the manuscript and collected the data. PC reviewed the manuscript, collected the data, and obtained funding. CC reviewed the manuscript and supervised the data analysis. CBE reviewed the manuscript, designed the research, and obtained funding.

Corresponding authors

Correspondence to Chantal Csajka or Chin B. Eap.

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Funding

This work has been funded in part by the Swiss National Research Foundation (CE and PC: 320030-120686, 324730-144064, and 320030-173211). The funding sources had no role in the writing of the manuscript or in the decision to submit the manuscript for publication. CE received honoraria for conferences or teaching continuing medical education courses from Astra Zeneca, Forum für Medizinische Fortbildung, Janssen-Cilag, Lundbeck, Mepha, Otsuka, Sandoz, Servier, Vifor-Pharma and Zeller over the past 3 years, and for writing a review article for the journal ‘Dialogues in Clinical Neurosciences’ (Servier).

Conflict of interest

Anaïs Glatard, Monia Guidi, Aurélie Delacrétaz, Céline Dubath, Claire Grosu, Nermine Laaboub, Armin von Gunten, Philippe Conus, Chantal Csajka and Chin B. Eap declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript.

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Glatard, A., Guidi, M., Delacrétaz, A. et al. Amisulpride: Real-World Evidence of Dose Adaptation and Effect on Prolactin Concentrations and Body Weight Gain by Pharmacokinetic/Pharmacodynamic Analyses. Clin Pharmacokinet 59, 371–382 (2020). https://doi.org/10.1007/s40262-019-00821-w

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