A. Glatard (1,2), M. Guidi (2,3), C. Dubath (1), C. Grosu (1), N. Laaboub (1), A. Delacrétaz (1), A. von Gunten (4), P. Conus (5), C. Csajka (2,3)* and C.B. Eap (1,3)*
(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 Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland (5) Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland *joint corresponding authors
Objectives: Amisulpride is administered orally at a wide range of doses (100-800 mg daily) for treating schizophrenia. Therapeutic drug monitoring of amisulpride is strongly recommended with a therapeutic reference range of 100-320 ng/mL for plasma trough concentrations [1]. The advantage of amisulpride is its low propensity for body weight gain, the major adverse effect of second-generation antipsychotic. However, hyperprolactinemia is reported in more than 90% of patients [2]. While hyperprolactinemia is asymptomatic in some cases, it frequently results in gonadal dysfunctions. The objectives of this work were first to characterize the pharmacokinetic (PK) profile of amisulpride and to detect sources of variability in order to suggest optimal dosage regimens for reference range achievement. Secondly, we aimed to develop a PK/PD model describing the relationship between amisulpride concentrations and prolactin data in an adult and elderly psychiatric population.
Methods: PK and clinical data were obtained from patients from the Department of Psychiatry of the Lausanne University Hospital. With the use of a one-compartment model with first order absorption (Ka) and a bioavailability of 48%, the influence of demographic, clinical (body weight (BW), lean body weight (LBW) [3], body mass index (BMI), smoking status, creatinine clearance estimated by the Cockcroft-Gault formula (CLCRCG) if BMI< 25 kg/m2 and the Cockcroft-Gault formula integrating the LBW if BMI≥ 25 kg/m2 [4]) and genetic characteristics as well as comedications (inhibitor of P-gp or lithium) on amisulpride clearance (CL) and volume of distribution (V) was quantified. Trough concentrations at steady-state (CminSS) after administration of several dosage regimens were simulated with the final PK model in 500 virtual patients according to various influential covariates. The final PK model was combined with a direct Emax model to describe the prolactin data. As prolactin levels were markedly different in males and females, the gender effect on Emax (the typical maximum prolactin elevation) was directly included in the structural model development. Influence of age, menopause, BW, LBW, season and concomitant antipsychotics that might have increased prolactin levels were quantified on Emax. Finally, prolactin levels were predicted by using the final PK/PD model at time of trough amisulpride concentrations.
Results: A total of 513 amisulpride plasma concentrations from 242 patients (18-91 years, median BMI = 25 kg/m2) and 101 prolactin measurements from a subset of 68 patients were available for analyses. In the final PK/PD model, population parameters for CL, V, Ka, baseline prolactin levels, Emax in females and EC50 were 43.9 L/h, 926 L, 0.9 h-1 (fixed as previously published [5]), 16 ng/mL, 141 ng/mL and 42 ng/mL, respectively. Inter-individual variabilities on CL, V and Emax were 34%, 58% and 50%. Age (p ≤ 0.001) and LBW (p=0.007) had a significant effect on CL which was decreased by 0.5 in a 80-year compared to a 40-year individual (LBW = 50 kg) and increased by 1.5 in a 40-year individual with LBW = 100 kg vs. LBW = 50 kg. Emax parameter was decreased by 53% in males. CminSS were higher than the recommended range in 72% of the 60-year individuals receiving 400 mg b.i.d. and were lower than the recommended range in 79% of the 20-year individuals receiving 300 mg q.d. The maximum recommended dose in elderly patients, i.e. 200 mg b.i.d. [6] resulted in CminSS higher than the recommended range in 72% of those having a LBW of 40 kg. In our sample analysis when amisulpride trough concentrations are in the therapeutic reference range, model-predicted prolactin levels were over the normal values (model-predicted median = 71 ng/mL, range = 41-135 ng/mL and 138 ng/mL, 75-309 ng/mL, normal values: ≤ 20 ng/mL and ≤ 25 ng/mL in males and females respectively).
Conclusions: In the present study, LBW had a more significant effect on CL than BW supposedly because LBW better estimates body size in overweight or obese patients, representing half of our study population. This work suggests that amisulpride dose adaptation with age and LBW is essential in order to reach the recommended range in patients. When amisulpride CminSS are in the recommended range, model-predicted prolactin levels were above the normal values in all patients indicating that amisulpride dose reduction is not appropriate when aiming to reduce prolactin levels.
References:
[1] Hiemke C et al. Pharmacopsychiatry. 2017.
[2] Holt RI et al. Clin Endocrinol. 2011.
[3] Janmahasatian S et al. Clin Pharmacokinet. 2005.
[4] Pai MP. Adv Chronic Kidney Dis. 2010.
[5] Reeves S et al. Psychopharmacology. 2016.
[6] Taylor DM et al. The Maudsley Prescribing Guidelines in Psychiatry. 13th Edition. 2018.
Reference: PAGE 28 (2019) Abstr 8971 [www.page-meeting.org/?abstract=8971]
Poster: Drug/Disease Modelling - Endocrine