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

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.

SUBMITTER: Voronova V

PROVIDER: S-EPMC9292875 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Voronova Veronika V Cullberg Marie M Delff Philip P Parkinson Joanna J Dota Corina C Schiavon Gaia G Maroj Brijesh B Rekić Dinko D Cheung S Y Amy SYA

British journal of clinical pharmacology 20210928 2

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 usin ...[more]

PMID: 34309049

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Project description:BackgroundAbnormal cardiac repolarization, indicated by a prolongation of the QT interval, increases the risk for torsades de pointes, a potentially life-threatening arrhythmia. Many perioperatively administered drugs and conditions prolong the QT interval. Despite several reports of perioperative torsades de pointes, systematic evidence regarding perioperative QT interval prolongation is limited.MethodsSerial postoperative 12-lead electrocardiograms were obtained from 469 adult patients undergoing major noncardiac surgery under general anesthesia. Heart rate corrected QT-interval duration (Fridericia formula) was the primary outcome. All perioperatively administered drugs were recorded. Emphasis was placed on absolute QTc prolongation greater than 500 ms and relative increases of 30 and 60 ms.ResultsAt the end of surgery, 80% of the patients (345 of 429) experienced a significant QTc interval prolongation (ΔQTc 23 ± 26 ms (mean and SD), 95% CI 20-25 ms, P less than 0.001). Approximately 51% (219 of 429) had a QTc greater than 440 ms, and 4% (16 of 429) a QTc greater than 500 ms. In 39% (166 of 429), the ΔQTc was greater than 30 ms, in 8% (34 of 429) >60 ms, and in greater than 0.5% (2 of 429) >100 ms. No changes in ΔQTc occurred at subsequent time points. One patient developed torsades de pointes with a ΔQTc: 29 ms (0.4% incidence rate). Several drugs had a large effect on ΔQTc: isoflurane, methadone, ketorolac, cefoxitin, zosyn, unasyn, epinephrine, ephedrine, and calcium. Postoperative body temperature had a weak negative correlation with ΔQTc (r = -0.15, P = 0.02); serum magnesium, potassium, and calcium concentrations were not correlated.ConclusionPostoperative QT-interval prolongation is common. Several perioperatively administered drugs are associated with a substantial QT-interval prolongation. The exact cause and its clinical relevance are, however, unclear. Nevertheless, an association between postoperative QT prolongation and risk for torsades de pointes is likely.

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

Publications

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

Similar Datasets

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