An exposure-safety analysis to support the dosage of the novel AKT inhibitor capivasertib.

Purpose: This study aimed to evaluate capivasertib exposure-response relationships for clinical safety events to support dosage selection.

Methods: Data from 277 patients with solid tumors participating in three phase 1 studies were analyzed. Capivasertib 80-800 mg was administered as monotherapy orally twice daily (BID) on continuous or intermittent (4 days on, 3 days off [4/3] or 2 days on, 5 days off [2/5]) schedules. Relationships between exposure related metrics (dose, weekly dose, AUC, AUC_PWD, C_max, and C_min) and probability of safety endpoints (adverse event [AE] leading to dose discontinuation, AE leading to dose modification, serious AE [SAE], AE grade ≥ 3, AE grade ≥ 1, diarrhea AE grade ≥ 2, rash AE grade ≥ 2, hyperglycemia AE grade ≥ 3 and increased blood glucose > 13.9 mmol/L) were evaluated by logistic regression.

Results: Significant exposure-response relationships were identified for all safety endpoints evaluated, except for AE grade ≥ 1. The analysis suggested that most of the safety endpoints are driven by the total weekly exposure, whereas glucose elevations are driven by the exposure achieved within a dosing interval. The probability of experiencing an AE leading to dose discontinuation, AE leading to dose modification, SAE, AE grade ≥ 3, diarrhea or rash were lower with the 480 mg BID [4/3] schedule than with the 320 mg BID continuous schedule.

Conclusion: Significant exposure-response relationships were identified for safety endpoints when capivasertib was administered to patients with solid tumors suggesting that the intermittent [4/3] schedule is better tolerated than the continuous schedule due to lower total weekly exposure.