Concentration-QT modelling shows no evidence of clinically significant QT interval prolongation with capivasertib at expected therapeutic concentrations.
Br J Clin Pharmacol
; 88(2): 858-864, 2022 02.
Article
en En
| MEDLINE
| ID: mdl-34309049
ABSTRACT
Pharmacokinetics-matched digital electrocardiogram data (n = 503 measurements from 180 patients) collected in a first-in-human, multi-part, dose-escalation (from 80 to 800 mg) and dose expansion (at 480 mg) phase 1 study in patients with advanced solid malignancies, were used to assess potential risk of QT prolongation associated with the AKT inhibitor capivasertib. The relationship between plasma drug concentrations and baseline-adjusted Fridericia-corrected QT (ΔQTcF) values was estimated using a prespecified linear mixed-effects model. The model provided an unbiased reproduction of the experimental data set, estimating a small but positive correlation between capivasertib concentration and ΔQTcF. At the expected therapeutic dose (400 mg twice daily) the predicted mean ΔQTcF at the steady state maximum concentration was 3.97 ms with an upper limit of the 90% CI of 5.07 ms; below the 10 ms limit proposed by ICH E14 guidance. This analysis suggests that capivasertib is not expected to present a clinically significant risk for QT prolongation that is associated with pro-arrhythmic effects.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Síndrome de QT Prolongado
/
Neoplasias
Tipo de estudio:
Guideline
/
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2022
Tipo del documento:
Article