Mitigating ipatasertib-induced glucose increase through dose and meal timing modifications.

Area of Science:

• Oncology
• Pharmacology
• Endocrinology

Background:

• Ipatasertib is an AKT inhibitor investigated for metastatic castration-resistant prostate cancer (mCRPC).
• Hyperglycemia is a known on-target effect of ipatasertib treatment.
• Combination therapy with prednisone and abiraterone is being evaluated for mCRPC.

Purpose of the Study:

• To evaluate glucose level changes during different treatment regimens of ipatasertib in mCRPC patients.
• To compare glucose dynamics under ipatasertib monotherapy versus combination therapies.
• To assess the impact of morning versus evening dosing of ipatasertib-prednisone-abiraterone on glucose control.

Main Methods:

• An open-label, single-arm study involving 25 mCRPC patients.
• Continuous glucose monitoring (CGM) was employed to track glucose fluctuations.
• Key parameters analyzed included average glucose, peak glucose, and time in glycemic range (70-180 mg/dL and >180 mg/dL).

Main Results:

• The ipatasertib-prednisone-abiraterone combination, particularly when given in the morning, significantly increased average and peak glucose levels compared to ipatasertib alone.
• Co-administration of ipatasertib with abiraterone increased ipatasertib and its M1 metabolite exposure.
• Evening dosing of the combination therapy resulted in lower peak glucose and improved time in range compared to morning dosing.

Conclusions:

• Increased ipatasertib exposure in combination with abiraterone is linked to elevated glucose levels.
• Administering ipatasertib-prednisone-abiraterone in the evening may be a strategy to mitigate hyperglycemia.
• Evening dosing following a meal and overnight fasting shows potential for managing drug-induced glucose changes in mCRPC patients.