Anaïs Glatard1,2, Monia Guidi2,3, Aurélie Delacrétaz1, Céline Dubath1, Claire Grosu1, Nermine Laaboub1, Armin von Gunten4, Philippe Conus5, Chantal Csajka6,7, Chin B Eap8,9. 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. 2. Service of Clinical Pharmacology, Service of Biomedicine, Department of Laboratory, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. 3. Institute of Pharmaceutical Sciences of Western Switzerland, Geneva, Switzerland. 4. Service of Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Prilly, Switzerland. 5. Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Prilly, Switzerland. 6. Service of Clinical Pharmacology, Service of Biomedicine, Department of Laboratory, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. Chantal.csajka@chuv.ch. 7. Institute of Pharmaceutical Sciences of Western Switzerland, Geneva, Switzerland. Chantal.csajka@chuv.ch. 8. 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. Chin.eap@chuv.ch. 9. Institute of Pharmaceutical Sciences of Western Switzerland, Geneva, Switzerland. Chin.eap@chuv.ch.
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.
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.
Authors: C Hiemke; N Bergemann; H W Clement; A Conca; J Deckert; K Domschke; G Eckermann; K Egberts; M Gerlach; C Greiner; G Gründer; E Haen; U Havemann-Reinecke; G Hefner; R Helmer; G Janssen; E Jaquenoud; G Laux; T Messer; R Mössner; M J Müller; M Paulzen; B Pfuhlmann; P Riederer; A Saria; B Schoppek; G Schoretsanitis; M Schwarz; M Silva Gracia; B Stegmann; W Steimer; J C Stingl; M Uhr; S Ulrich; S Unterecker; R Waschgler; G Zernig; G Zurek; P Baumann Journal: Pharmacopsychiatry Date: 2017-09-14 Impact factor: 5.788
Authors: Takashi Tsuboi; Robert R Bies; Takefumi Suzuki; David C Mamo; Bruce G Pollock; Ariel Graff-Guerrero; Masaru Mimura; Hiroyuki Uchida Journal: Prog Neuropsychopharmacol Biol Psychiatry Date: 2013-05-29 Impact factor: 5.067