Relacorilant Co-Administration Without CYP2C9 Dose Reduction
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Solution Overview
Problem
Concomitant administration of drugs that are substrates and inhibitors of the CYP2C9 enzyme can lead to increased plasma levels of the substrate drug, potentially causing toxic effects due to reduced metabolism, as observed with relacorilant, a potent CYP2C9 inhibitor.
Innovation Solution
Relacorilant can be safely administered with unmodified doses of CYP2C9 substrates like tolbutamide, glimepiride, and glipizide, without the need for dose reduction, even in patients receiving paclitaxel treatment for cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If relacorilant is co-administered with CYP2C9 substrate drugs, then the treatment of hypercortisolism and cancer can be achieved, but the plasma exposure of CYP2C9 substrates is expected to increase significantly due to CYP2C9 inhibition
Solution Approach 1:
The patent converts the potentially harmful CYP2C9 inhibition effect into a beneficial or neutral outcome by demonstrating through clinical studies that relacorilant does not actually inhibit CYP2C9 in vivo despite in vitro evidence suggesting otherwise. This allows concomitant administration of relacorilant with CYP2C9 substrates without dose adjustments, transforming a predicted harmful interaction into a safe combination therapy approach
Solution Approach 2:
The patent changes the understanding of relacorilant's metabolic interaction profile by contrasting in vitro IC50 values with in vivo clinical data. The parameter of CYP2C9 inhibition is shown to be context-dependent, varying between in vitro and in vivo conditions, allowing the drug to be classified as having minimal clinical interaction potential despite biochemical evidence of inhibition
2Object-affected harmful factors
If the dose of CYP2C9 substrate drugs is reduced to prevent toxicity, then the risk of toxic effects is decreased, but the therapeutic efficacy of the substrate drugs is compromised
Solution Approach 1:
The patent eliminates the need for dose reduction by demonstrating that relacorilant does not inhibit CYP2C9 in clinical settings. This converts the potential harm of toxicity into a safe co-administration scenario, allowing full therapeutic doses of CYP2C9 substrates to be maintained without compromising efficacy or safety
3Object-affected harmful factors
If in vitro CYP2C9 inhibition data is used to guide clinical dosing, then drug safety can be ensured, but unnecessary dose adjustments are required leading to reduced therapeutic efficacy
Solution Approach 1:
The patent changes the interpretation of CYP2C9 inhibition parameters by demonstrating the discrepancy between in vitro IC50 values and in vivo clinical outcomes. This leads to a revised parameter assessment where relacorilant is classified as having minimal clinical interaction potential, eliminating unnecessary dose adjustments while maintaining safety
Solution Approach 2:
The patent introduces clinical pharmacokinetic studies as an intermediary between in vitro inhibition data and clinical dosing decisions. These studies serve as a mediator that reconciles the conflicting in vitro and theoretical in vivo predictions, providing empirical evidence that relacorilant does not require dose adjustments when co-administered with CYP2C9 substrates
Data Source
AI summary
Relacorilant is useful in the treatment of hypercortisolism and cancer. Many drugs useful in treating hypercortisolism or cancer are metabolized by CYP2C9 enzymes. The effects of concomitant administration of relacorilant and a CYP2C9 substrate are disclosed herein.Relacorilant potently inhibited CYP2C9 in an in vitro test, indicating that co-administration of relacorilant and a CYP2C9 substrate would be expected to increase the CYP2C9 substrate plasma exposure more than five-fold in vivo. Significant reductions in CYP2C9 substrate doses would be expected to be required when administered with relacorilant.Surprisingly, no such increase in plasma exposure was seen in human studies. Applicant discloses that relacorilant may be safely co-administered with unmodified doses of a CYP2C9 substrate such as, e.g., tolbutamide, glimepiride, and glipizide. Relacorilant and unmodified doses of CYP2C9 substrate such as tolbutamide, glimepiride, and glipizide may be co-administered to treat hypercortisolism, or may be co-administered to a cancer patient.