PRMT5 Inhibitor Dosing Regimen for Cancer Treatment
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Solution Overview
Problem
There is a strong need for novel PRMT5 inhibitors to treat or prevent cancer, as few selective PRMT5 inhibitors have been developed, and existing treatments lack efficacy and safety profiles suitable for clinical use.
Innovation Solution
JNJ-64619178, a potent and selective small molecule inhibitor that binds to the PRMT5/(MEP50)4 complex with a long residence time, is administered in a specific dosing schedule involving initial and subsequent dosing periods with optional 'off' periods to maintain pharmacodynamic modulation and reduce toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PRMT5 inhibitors are administered continuously to maintain therapeutic effect, then cancer treatment efficacy is improved, but toxicity increases
Solution Approach 1:
The patent implements periodic dosing regimens with treatment cycles separated by interruption periods. Specifically, it describes administering PRMT5 inhibitor compounds in cycles where treatment is given for a defined period followed by an interruption period before the next cycle. This periodic approach maintains therapeutic efficacy while allowing recovery from toxic effects, directly resolving the contradiction between continuous treatment benefit and toxicity accumulation.
2Reliability
If PRMT5 inhibitors are administered at high doses to achieve tumor regression, then treatment efficacy is improved, but safety and tolerability worsen
Solution Approach 1:
The patent employs dynamic dosing strategies where the dose and frequency are adjusted based on treatment response and tolerance. It describes adapting the dosing regimen by modifying the duration of treatment cycles, the length of interruption periods, and the dosage amount based on patient response and tolerability. This dynamic approach allows achieving tumor regression at effective doses while managing safety and tolerability through flexible adjustment.
3Productivity
If PRMT5 inhibitors are administered frequently to maintain pharmacodynamic modulation, then treatment effectiveness is improved, but toxicity profiles worsen
Solution Approach 1:
The patent implements periodic dosing regimens with treatment cycles separated by interruption periods. Specifically, it describes administering PRMT5 inhibitor compounds in cycles where treatment is given for a defined period followed by an interruption period before the next cycle. This periodic approach maintains therapeutic efficacy while allowing recovery from toxic effects, directly resolving the contradiction between continuous treatment benefit and toxicity accumulation.
Data Source
AI summary
The present disclosure provides methods for treating a human patient diagnosed with a cancer, comprising administering a therapeutically effective amount of a PRMT5 (protein arginine methyltransferase 5) inhibitor, certain methods comprising (i) administering to the patient initial doses of at least about 0.1 mg per day of the PRMT5 inhibitor that is (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol or a pharmaceutically acceptable addition salt or solvate thereof for an initial dosing period of about 5 to about 21 days; and (ii) administering to the patient subsequent doses of at least about 0.1 mg per day of the PRMT5 inhibitor for one or more subsequent dosing periods of about 5 to about 21 days each. In these methods, a first subsequent dosing period is separated in time from the initial dosing period by at least about 5 days and the subsequent dosing periods are separated in time from each other by at least about 5 days.