AZD8233 antisense oligonucleotide targeting PCSK9 does not prolong QT interval.
Br J Clin Pharmacol
; 88(11): 4839-4844, 2022 11.
Article
em En
| MEDLINE
| ID: mdl-35653229
ABSTRACT
AIMS:
AZD8233 is a proprotein convertase subtilisin/kexin type 9 (PCSK9) antisense oligonucleotide under development for treatment of hypercholesterolaemia. A prespecified concentration-QT analysis was performed based on data from a single ascending dose study that was prospectively designed to act as a TQT study substitute.METHODS:
Subcutaneous single doses ranging from 4 to 120 mg were evaluated in 73 adult healthy male subjects. Time-matched 12-lead digital ECG and plasma concentrations (n = 15) were measured at baseline and up to 48 hours after dose in each subject. The analysis was performed using a linear mixed effect model, where change from baseline QTc (ΔQTc) was a dependent variable and time-matched AZD8233 concentration was an independent variable.RESULTS:
The high clinical exposure scenario was defined as 1.7-fold the expected Cmax following an assumed therapeutic dose of 60 mg, which corresponds to AZD8233 plasma concentration of 1.39 µg/mL. Estimated placebo-corrected and baseline-adjusted QTcF interval (ΔΔQTcF) at this concentration was -2.2 ms (90% CI -4.11, -0.28). Furthermore, the upper 90% ΔΔQTcF confidence interval was estimated to be below 10 ms at all observed concentrations.CONCLUSION:
As the effect on ΔΔQTcF is below the threshold for regulatory concern (10 ms), it can be concluded that AZD8233 does not induce QTcF prolongation at the high clinical exposure scenario.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oligonucleotídeos
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Síndrome do QT Longo
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Adult
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Humans
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Male
Idioma:
En
Revista:
Br J Clin Pharmacol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Suécia