Intermittent mTOR Inhibitor Regimens for Efficacy and Tolerability
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Solution Overview
Problem
Current treatments for disorders involving the mTOR pathway, such as cancer and inflammatory diseases, often face challenges with tolerability and side effects, leading to inadequate patient compliance and reduced therapeutic efficacy due to severe adverse events and insufficient plasma concentrations of mTORC1/mTORC2 inhibitors.
Innovation Solution
An intermittent regimen for administering mTORC1/mTORC2 inhibitors achieves plasma concentrations above 100 nM for extended periods and higher peak concentrations compared to daily dosing, maintaining similar or better pathway inhibition and tolerability while reducing adverse events.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mTORC1/mTORC2 inhibitors are administered at high doses to achieve sufficient plasma concentrations for therapeutic efficacy, then pathway inhibition is improved, but tolerability and side effects worsen
Solution Approach 1:
The patent employs intermittent dosing regimens where mTORC1/mTORC2 inhibitors are administered periodically rather than continuously. This allows plasma concentrations to oscillate between therapeutic levels (above 100 nM during dosing periods) and lower levels during inter-dose intervals, maintaining pathway inhibition efficacy while reducing cumulative toxicity and side effects associated with sustained high-dose exposure
2Reliability
If mTORC1/mTORC2 inhibitors are administered daily to maintain continuous pathway inhibition, then therapeutic efficacy is improved, but tolerability worsens due to severe adverse events
Solution Approach 1:
The intermittent dosing schedule creates periodic cycles of therapeutic action followed by recovery periods. This periodic pattern maintains sufficient pathway inhibition during treatment phases while providing tolerance recovery during interruption phases, thereby improving patient compliance by reducing the burden of continuous high-dose administration and associated adverse events
3Ease of operation
If mTORC1/mTORC2 inhibitors are administered at low doses to improve tolerability, then side effects are reduced, but plasma concentrations become insufficient for effective pathway inhibition
Solution Approach 1:
The intermittent dosing strategy delivers higher peak doses periodically to achieve sufficient plasma concentrations (above 100 nM) for effective pathway inhibition, then allows concentrations to decline to lower, better-tolerated levels during inter-dose intervals. This temporal separation of high and low concentration phases resolves the contradiction between achieving therapeutic efficacy and maintaining tolerability
4Reliability
If continuous high-dose mTORC1/mTORC2 inhibition is maintained to ensure therapeutic efficacy, then pathway inhibition is improved, but adverse events increase
Solution Approach 1:
The patent implements periodic interruption of continuous high-dose inhibition, creating cycles where therapeutic efficacy is achieved during treatment phases followed by reduction of adverse events during interruption phases. This periodic modulation allows the therapeutic outcome to be maintained over the treatment course while significantly reducing the cumulative burden of adverse events compared to continuous high-dose administration
Data Source
AI summary
The present invention provides for methods and pharmaceutical compositions comprising inhibitors of mTorC1 and/or mTorC2. In some aspects, the invention provides for treatment regimens resulting in enhanced treatment efficacy and better tolerability.