Concentration‐QT modelling shows no evidence of clinically significant QT interval prolongation with capivasertib at expected therapeutic concentrations

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 ris...

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Published inBritish journal of clinical pharmacology Vol. 88; no. 2; pp. 858 - 864
Main Authors Voronova, Veronika, Cullberg, Marie, Delff, Philip, Parkinson, Joanna, Dota, Corina, Schiavon, Gaia, Maroj, Brijesh, Rekić, Dinko, Cheung, S. Y. Amy
Format Journal Article
LanguageEnglish
Published England John Wiley and Sons Inc 01.02.2022
Subjects
AKT
arrhythmia
breast cancer
capivasertib
concentration‐QT modelling
Dose-Response Relationship, Drug
Electrocardiography
Heart Rate
Humans
Long QT Syndrome - chemically induced
Neoplasms - drug therapy
prostate cancer
Pyrimidines
Pyrroles
Short Communication
Short Communications
concentration-QT modelling
breast cancer
capivasertib
prostate cancer
AKT
arrhythmia
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Summary: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.
Bibliography:Funding information
AstraZeneca, Grant/Award Number: NCT01226316; Institute of Cancer Research, Grant/Award Number: AZD5363
This manuscript describes a secondary investigation that addresses a specific scientific question with a modelling approach using previously collected clinical trial data. No new clinical data, requiring medical supervision, were collected for this manuscript. The Principal Investigator of the original study was an author on the primary publication but does not meet ICMJE criteria for authorship of this manuscript.
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Funding information AstraZeneca, Grant/Award Number: NCT01226316; Institute of Cancer Research, Grant/Award Number: AZD5363
ISSN:0306-5251
1365-2125
DOI:10.1111/bcp.15006