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.

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. - ISSN 0160-6689. - (2017). [10.4088/JCP.16m11216]

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

Fabrizia D'antonio;
2017

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.
2017
Psychotic Disorder
01 Pubblicazione su rivista::01a Articolo in rivista
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. - ISSN 0160-6689. - (2017). [10.4088/JCP.16m11216]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1019486
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