Diaminophenothiazine Split Dosing for Consistent Therapeutic Levels
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Solution Overview
Problem
Current treatments for neurodegenerative disorders such as Alzheimer's disease and Frontotemporal dementia are inadequate as they do not address the underlying disease pathology and are hindered by inter-individual variability in drug absorption, leading to inconsistent efficacy and potential side effects.
Innovation Solution
A novel pharmacokinetic model is developed to optimize the dosing regimen of methylthioninium compounds, specifically in the reduced form (LMTM), to achieve a consistent therapeutic concentration range of 20-60 mg/day, split into multiple doses, which can be used as monotherapy or in combination with symptomatic treatments to enhance efficacy and minimize side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current approved treatments (AChEls and memantine) are used, then symptomatic relief is achieved, but the underlying disease pathology is not addressed and efficacy is limited
Solution Approach 1:
The patent extracts and addresses the root cause of the disease (aberrant protein aggregation and tau pathology) rather than merely treating symptoms. By targeting the underlying pathological mechanism with TAI compounds, the treatment removes the harmful aggregation process itself, thereby improving reliability of efficacy while potentially reducing side effects associated with symptomatic treatments.
Solution Approach 2:
The patent employs preliminary action by targeting tau aggregation early in the disease process, before significant neurodegeneration occurs. The optimized dosing regimen is designed to prevent or slow the progression of tau pathology from an early stage, thereby improving long-term efficacy and avoiding the need for more aggressive interventions later that might have greater side effects.
2Reliability
If higher doses of diaminophenothiazines are administered, then therapeutic benefit is increased, but inter-individual variability leads to inconsistent efficacy and potential side effects
Solution Approach 1:
The patent applies parameter changes by optimizing the dosing regimen to a specific range (20-60 mg/day) based on pharmacokinetic modeling. This parameter optimization ensures that therapeutic concentrations are achieved consistently across different individuals while minimizing variability in efficacy and reducing the risk of side effects associated with excessive dosing.
Solution Approach 2:
The patent employs dynamics by using a flexible dosing approach that can be adjusted based on individual patient response and pharmacokinetic characteristics. The optimized regimen allows for personalized dosing within the 20-60 mg/day range, enabling the treatment to adapt to inter-individual variability in absorption and metabolism, thereby improving dosing consistency and therapeutic reliability.
3Reliability
If dosing is optimized to 20-60 mg/day, then therapeutic concentration is achieved consistently, but this requires a novel pharmacokinetic model and split dosing regimen
Solution Approach 1:
The patent applies segmentation by dividing the daily dose into multiple smaller administrations throughout the day. This split dosing regimen maintains consistent therapeutic concentrations of diaminophenothiazines in the body by avoiding large peaks and troughs that would occur with single daily dosing, thereby improving concentration consistency while managing the complexity through a straightforward scheduling approach.
Data Source
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AI summary
The invention provides novel dosing regimens for Leuco-Methylthioninium (LMT) compounds which maximise the proportion of subjects in which the MT concentration will exceed concentrations in which therapeutic efficacy in relation to treatment of neurodegenerative disorders such as Alzheimer's disease and rontotemporal dementias can be achieved, while maintaining a desirable clinical profile. Also provided are LMT-containing dosage units and other compositions.