MCL1 Inhibitor Formulation and Dosing for IV Cancer Therapy
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Solution Overview
Problem
There is a need for suitable formulations, doses, and dosing schedules that include compounds inhibiting MCL1 protein for treating cancers such as acute myelogenous leukemia, multiple myeloma, and non-Hodgkin's lymphoma.
Innovation Solution
A pharmaceutical formulation comprising a compound of Formula I or its salt, cyclodextrin, buffer, and water, with specific concentration and pH ranges, and an aqueous solution containing the compound, sodium chloride, and buffer, suitable for intravenous infusion, administered in defined amounts and schedules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments are used for hematological malignancies, then treatment options are limited, but they are inadequate in addressing MCL1 over-expression
Solution Approach 1:
The patent introduces a novel small molecule compound with specific chemical structure (Formula I) that targets MCL1 protein, changing the therapeutic parameter from conventional chemotherapy to MCL1-specific inhibition. This enables effective treatment of hematological malignancies with MCL1 over-expression that were previously resistant to standard therapies
Solution Approach 2:
The compound of Formula I acts as an intermediary that disrupts the protein-protein interaction between MCL1 and BH3-only proteins. By binding to MCL1, it prevents MCL1 from blocking pro-apoptotic signals, thereby inducing apoptosis in cancer cells that over-express MCL1
2Reliability
If MCL1 protein is inhibited to induce apoptosis, then tumor growth is inhibited, but formulation and dosing requirements become complex
Solution Approach 1:
The patent specifies precise formulation parameters including pH range (6.0-8.0), concentration ranges (10-50 mg/mL), and cyclodextrin content (5-20% w/v) to ensure compound stability and solubility. These parameter specifications create a standardized formulation that simplifies manufacturing and clinical administration while maintaining therapeutic efficacy
Solution Approach 2:
The patent provides detailed dosing regimens based on body surface area (mg/m²) with specific dose ranges (25-960 mg/m²) and administration schedules (once weekly, twice weekly, or daily). This standardized dosing protocol copies successful clinical approaches and simplifies the complex relationship between compound potency and therapeutic outcome
Data Source
AI summary
The present disclosure is drawn to pharmaceutical formulations, aqueous solutions, and methods of treating cancer using the disclosed pharmaceutical formulations and aqueous solutions. The formulations and solutions comprise compounds of Formula I and may further comprise a cyclodextrin compound, such as hydroxypropyl-β-cyclodextrin and a buffer, such as glycine. The methods of treating cancer include the treatment of hematological malignances such as acute myelogenous leukemia, multiple myeloma, and non-Hodgkin's lymphoma.