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. 2024 Nov 24;8(1):1516-1528.
doi: 10.1177/25424823241289373. eCollection 2024.

Therapeutic drug monitoring for dose optimization in Alzheimer's disease and in dementia with Lewy bodies: A randomized single-blinded clinical trial

Michael Hén Forbord Fischer  1 , Ivan Chrilles Zibrandtsen  2 , Peter Johannsen  3 , Volkert Siersma  4 , Jan Borg Rasmussen  5 , Jens Borggaard Larsen  6 , Peter Høgh  1   2
Affiliations

Therapeutic drug monitoring for dose optimization in Alzheimer's disease and in dementia with Lewy bodies: A randomized single-blinded clinical trial

Michael Hén Forbord Fischer et al. J Alzheimers Dis Rep. .

Abstract

Background: Previous evidence suggests serum concentrations of donepezil varies in clinical populations and that a dose higher than standard may have additional positive effect on cognition. Therapeutic drug monitoring (TDM) is a tool for dose optimization (DO) whereby treatment is adjusted based on previous quantification of the prescribed drug.

Objective: Investigate whether TDM-based DO of donepezil or memantine improves clinical outcomes and/or reduce the frequency of adverse reactions (ARs) in neurodegenerative conditions commonly treated with these two study drugs.

Methods: Single-blinded 1:1 randomized controlled study in an outpatient memory clinic. Eligible participants either newly diagnosed with Alzheimer's disease dementia (AD), dementia with Lewy bodies (DLB), or Parkinson's disease dementia (PDD) scheduled for treatment with donepezil or memantine. The intervention group received TDM based DO. The control group received DO solely based on clinical assessment. Clinical outcomes were change in Mini-Mental State Examination, Addenbrooke's Cognitive Examination, Neuropsychiatric Inventory, and Disability Assessment in Dementia from baseline to 12 months. Additionally, data on incidence and severity of ARs and proportion of participants with a serum concentration within the therapeutic reference range were collected.

Results: 132 participants recruited (125 AD, 7 DLB, none with PDD) of whom 107 completed the study (101 AD and 6 DLB), fewer in the control group than planned. Statistical analysis did not reveal significant differences between groups neither for clinical outcomes nor for frequency of ARs.

Conclusions: TDM based DO did not significantly improve clinical outcomes nor reduce the frequency of ARs albeit important caveats to the results apply.

Clincialtrialsgov identifier: NCT04117178 (first posted October 7, 2019).

Keywords: Alzheimer's disease; dementia with Lewy bodies; precision medicine; randomized controlled trial; therapeutic drug monitoring.

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Conflict of interest statement

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Outline of the method and study visits. AD: Alzheimer's disease dementia; DLB: dementia with Lewy bodies: PDD, Parkinson's disease dementia: MMSE, Mini-Mental State Examination; ACE: Addenbrooke's Cognitive Examination; GDS: Geriatric Depression Scale; NPI: Neuropsychiatric Inventory; DAD: Disability Assessment in Dementia; S-donepezil: serum donepezil; S-memantine: serum memantine; cyp2D6: cytochrome P450 2D6 genotype; APOE: Apolipoprotein E; BchE-K: Butyrylcholinesterase K-variant; formula image: blood sample collection; formula image: cognitive assessment.
Figure 2.
Figure 2.
Treatment optimization in the intervention group.
Figure 3.
Figure 3.
Outline of screening and enrollment of participants.
Figure 4.
Figure 4.
Details on participant withdrawal during the study.
Figure 5.
Figure 5.
Visual display of clinical outcomes.
Figure 6.
Figure 6.
Boxplots showing the distribution of serum concentrations for donepezil and memantine at the 12-month follow-up visit. x-axis: group allocation of participants, either intervention group (left) or control group (right); y-axis: measured serum concentration of study drug in nanogram per milliliter; Blue color dots: serum donepezil for participants adherent to therapy; Blue color circles: serum donepezil for participants poorly adherent to therapy; Red dots: serum memantine for participants adherent to therapy; Opaque blue colored bar: therapeutic reference range for donepezil; Opaque red colored bar: therapeutic reference range for memantine.
See this image and copyright information in PMC

References

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