# An exposure–safety analysis to support the dosage of the novel AKT inhibitor capivasertib

## TL;DR

This study analyzed how capivasertib dosage affects safety in cancer patients, finding that an intermittent schedule reduces side effects compared to continuous dosing.

## Contribution

The study identifies exposure–response relationships for capivasertib safety endpoints and recommends an intermittent dosing schedule for better tolerability.

## Key findings

- Intermittent [4/3] dosing reduces the probability of safety events compared to continuous dosing.
- Total weekly exposure drives most safety endpoints, while glucose elevations depend on exposure within a dosing interval.
- Exposure–response relationships were found for all safety endpoints except AE grade ≥ 1.

## Abstract

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

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, AUCPWD, Cmax, and Cmin) 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.

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.

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.

The online version contains supplementary material available at 10.1007/s00280-025-04775-8.