A Population approach to guide amisulpride dose adjustments in older patients with Alzheimer's disease

Suzanne Reeves, Julie Bertrand, Emma McLachlan, Fabrizia D'Antonio, Stuart Brownings, Akshay Nair, Suki Greaves, Alan Smith, Joel T. Dunn, Paul Marsden, Robert Kessler, Hiroyuki Uchida, David Taylor, Robert Howard

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Objective: We have previously reported high dopamine D2/3 receptor occupancies at low amisulpride concentrations in older people with Alzheimer's disease (AD), during off-label treatment of AD-related psychosis. This post hoc analysis explored pharmacokinetic (concentration) and pharmacodynamic (prolactin, D2/3 occupancy) contributions to symptom reduction and extrapyramidal side effects (EPS) to inform AD-specific dose adjustments. Methods: Population pharmacokinetic-pharmacodynamic models were developed by combining pharmacokinetic data from a phase 1 study in 20 healthy older people with pharmacokinetic prolactin, [18F]fallypride D2/3 receptor imaging, and clinical outcome data from 28 older patients prescribed open amisulpride (25-75 mg/d) to treat AD-related psychosis. Model predictions were used to simulate dose-response and dose-EPS. Results: Symptom reduction (delusions) was associated with amisulpride concentration (P = 1.3e-05) and D2/3 occupancy (P <.01, caudate, putamen, thalamus). Model predictions suggested that across concentrations of 40-100 ng/mL, and occupancies of 40% to 70% in the caudate and thalamus and 30% to 60% in the putamen, there was a 50% to 90% probability of response and < 30% probability of EPS. Simulations, based on concentration-delusions and concentration-EPS model outputs, showed that 50 mg/d of amisulpride was the appropriate dose to achieve this target range in those aged > 75 years; increasing the dose to 75 mg/d increased the risk of EPS, particularly in those aged > 85 years of low body weight. Conclusions: These findings argue strongly for the consideration of age- and weight-based dose adjustments in older patients with AD-related psychosis and indicate that 50 mg/d of amisulpride may be both the minimal clinically effective dose and, in those aged > 75 years, the maximally tolerated dose.

Original languageEnglish
Pages (from-to)e844-e851
JournalJournal of Clinical Psychiatry
Volume78
Issue number7
DOIs
Publication statusPublished - 2017 Jul 1

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Social Adjustment
Alzheimer Disease
Pharmacokinetics
Psychotic Disorders
Population
Prolactin
Delusions
Maximum Tolerated Dose
Dopamine D2 Receptors
Body Weight
sultopride
Weights and Measures

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Reeves, S., Bertrand, J., McLachlan, E., D'Antonio, F., Brownings, S., Nair, A., ... Howard, R. (2017). A Population approach to guide amisulpride dose adjustments in older patients with Alzheimer's disease. Journal of Clinical Psychiatry, 78(7), e844-e851. https://doi.org/10.4088/JCP.16m11216

A Population approach to guide amisulpride dose adjustments in older patients with Alzheimer's disease. / Reeves, Suzanne; Bertrand, Julie; McLachlan, Emma; D'Antonio, Fabrizia; Brownings, Stuart; Nair, Akshay; Greaves, Suki; Smith, Alan; Dunn, Joel T.; Marsden, Paul; Kessler, Robert; Uchida, Hiroyuki; Taylor, David; Howard, Robert.

In: Journal of Clinical Psychiatry, Vol. 78, No. 7, 01.07.2017, p. e844-e851.

Research output: Contribution to journalArticle

Reeves, S, Bertrand, J, McLachlan, E, D'Antonio, F, Brownings, S, Nair, A, Greaves, S, Smith, A, Dunn, JT, Marsden, P, Kessler, R, Uchida, H, Taylor, D & Howard, R 2017, 'A Population approach to guide amisulpride dose adjustments in older patients with Alzheimer's disease', Journal of Clinical Psychiatry, vol. 78, no. 7, pp. e844-e851. https://doi.org/10.4088/JCP.16m11216
Reeves, Suzanne ; Bertrand, Julie ; McLachlan, Emma ; D'Antonio, Fabrizia ; Brownings, Stuart ; Nair, Akshay ; Greaves, Suki ; Smith, Alan ; Dunn, Joel T. ; Marsden, Paul ; Kessler, Robert ; Uchida, Hiroyuki ; Taylor, David ; Howard, Robert. / A Population approach to guide amisulpride dose adjustments in older patients with Alzheimer's disease. In: Journal of Clinical Psychiatry. 2017 ; Vol. 78, No. 7. pp. e844-e851.
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AU - Brownings, Stuart

AU - Nair, Akshay

AU - Greaves, Suki

AU - Smith, Alan

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N2 - Objective: We have previously reported high dopamine D2/3 receptor occupancies at low amisulpride concentrations in older people with Alzheimer's disease (AD), during off-label treatment of AD-related psychosis. This post hoc analysis explored pharmacokinetic (concentration) and pharmacodynamic (prolactin, D2/3 occupancy) contributions to symptom reduction and extrapyramidal side effects (EPS) to inform AD-specific dose adjustments. Methods: Population pharmacokinetic-pharmacodynamic models were developed by combining pharmacokinetic data from a phase 1 study in 20 healthy older people with pharmacokinetic prolactin, [18F]fallypride D2/3 receptor imaging, and clinical outcome data from 28 older patients prescribed open amisulpride (25-75 mg/d) to treat AD-related psychosis. Model predictions were used to simulate dose-response and dose-EPS. Results: Symptom reduction (delusions) was associated with amisulpride concentration (P = 1.3e-05) and D2/3 occupancy (P <.01, caudate, putamen, thalamus). Model predictions suggested that across concentrations of 40-100 ng/mL, and occupancies of 40% to 70% in the caudate and thalamus and 30% to 60% in the putamen, there was a 50% to 90% probability of response and < 30% probability of EPS. Simulations, based on concentration-delusions and concentration-EPS model outputs, showed that 50 mg/d of amisulpride was the appropriate dose to achieve this target range in those aged > 75 years; increasing the dose to 75 mg/d increased the risk of EPS, particularly in those aged > 85 years of low body weight. Conclusions: These findings argue strongly for the consideration of age- and weight-based dose adjustments in older patients with AD-related psychosis and indicate that 50 mg/d of amisulpride may be both the minimal clinically effective dose and, in those aged > 75 years, the maximally tolerated dose.

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