ATR-101 Urea Derivative Mitigates Mitotane Side Effects
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Solution Overview
Problem
Current treatments for adrenocortical carcinoma (ACC) such as mitotane have severe side effects, a narrow therapeutic window, and poor pharmacokinetic properties, limiting their effectiveness and safety, necessitating a more effective and safer alternative for managing this deadly disease.
Innovation Solution
Administration of N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)cyclopentyl)-methyl)urea hydrochloride (ATR-101) alone or in combination with other therapeutic agents like mitotane, mifepristone, metformin, everolimus, or IGFR antagonists to treat ACC, benign adenomas, and related hormone production disorders, reducing tumor size and hormone production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mitotane is used to treat adrenocortical carcinoma, then therapeutic benefit is achieved in one-quarter to one-third of patients, but severe side effects occur including gastrointestinal dysfunctions, CNS symptoms, elevated cholesterol and triglycerides, lowered thyroid hormone function, elevated liver enzymes, and leukopenia
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of mitotane to create ATR-101, which changes the pharmacological parameters including selective inhibition of adrenal steroidogenesis while improving the therapeutic index. This structural modification allows achieving therapeutic benefit with reduced severe side effects compared to parenterally administered mitotane.
Solution Approach 2:
The patent uses an intermediary approach by developing ATR-101 as a prodrug that requires metabolic activation to its active form. This intermediary state allows the drug to be administered orally and selectively target adrenal cortex cells, mediating between the need for systemic delivery and selective adrenal toxicity while reducing non-specific side effects.
2Duration of action of moving object
If mitotane is used to treat adrenocortical carcinoma, then disease progression is delayed by an average of five months, but the therapeutic window is narrow requiring precise dose control
Solution Approach 1:
The patent changes the pharmacokinetic parameters of the treatment by switching from parenteral mitotane to oral ATR-101, which has improved absorption and a broader therapeutic window. This parameter change makes dose control easier while maintaining or extending progression-free survival benefits.
3Reliability
If mitotane is used to treat adrenocortical carcinoma, then therapeutic effect is achieved, but pharmacokinetic properties are poor with frequent dose adjustments needed and accumulation in fat tissue with elimination half-life of months
Solution Approach 1:
The patent improves pharmacokinetic efficiency by changing from mitotane to ATR-101, which has better oral bioavailability, more predictable pharmacokinetics, and reduced accumulation in fat tissue. These parameter changes eliminate the need for frequent dose adjustments while maintaining reliable therapeutic effect.
4Adaptability or versatility
If mitotane interferes with metabolism of other drugs, then comprehensive cancer treatment can be provided, but medical management becomes challenging
Solution Approach 1:
The patent changes the metabolic profile parameter by using ATR-101 instead of mitotane, which has fewer drug-drug interactions. This allows comprehensive cancer treatment to be provided with simpler medical management, as ATR-101 does not significantly interfere with the metabolism of other concomitant medications.
Data Source
AI summary
Methods and compositions are provided for treatment of disorders associated with aberrant adrenal cortex cell behavior, including (but not limited to) treatment of adrenocortical carcinoma (ACC), Cushing's syndrome and/or pituitary ACTH excess (Cushing's Disease). Such methods involve administration of an effective amount N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethyl amino)phenyl)cyclopentyl)-methyl)urea hydrochloride to the patient.