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Adavosertib (AZD1775) does not prolong the QTc interval in patients with advanced solid tumors: a phase I open-label study.
| Content Provider | Europe PMC |
|---|---|
| Author | Någård, Mats Ah-See, Mei-Lin Strauss, James Wise-Draper, Trisha Safran, Howard P. Nadeau, Laura Edenfield, William J. Lewis, Lionel D. Rekić, Dinko Dota, Corina Ottesen, Lone H. Li, Yan Mugundu, Ganesh M. |
| Abstract | PurposeAdavosertib is a small-molecule, ATP-competitive inhibitor of Wee1 kinase. Molecularly targeted oncology agents have the potential to increase the risk of cardiovascular events, including prolongation of QT interval and associated cardiac arrhythmias. This study investigated the effect of adavosertib on the QTc interval in patients with advanced solid tumors.MethodsEligible patients were ≥ 18 years of age with advanced solid tumors for which no standard therapy existed. Patients received adavosertib 225 mg twice daily on days 1–2 at 12-h intervals and once on day 3. Patients underwent digital 12-lead electrocardiogram and pharmacokinetic assessments pre-administration and time-matched assessments during the drug administration period. The relationship between maximum plasma drug concentration (Cmax) and baseline-adjusted corrected QT interval by Fridericia (QTcF) was estimated using a prespecified linear mixed-effects model.ResultsTwenty-one patients received adavosertib. Concentration–QT modeling of ΔQTcF and the upper limit of the 90% confidence interval corresponding to the geometric mean of Cmax observed on days 1 and 3 were below the threshold for regulatory concern (not > 10 ms). No significant relationship between ΔQTcF (vs baseline) and adavosertib concentration was identified (P = 0.27). Pharmacokinetics and the adverse event (AE) profile were consistent with previous studies at this dose. Eleven (52.4%) patients experienced 17 treatment-related AEs in total, including diarrhea and nausea (both reported in six [28.6%] patients), vomiting (reported in two [9.5%] patients), anemia, decreased appetite, and constipation (all reported in one [4.8%] patient).ConclusionAdavosertib does not have a clinically important effect on QTc prolongation.ClinicalTrials.govNCT03333824.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00280-023-04555-2. |
| Related Links | https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC10326086&blobtype=pdf |
| ISSN | 03445704 |
| Journal | Cancer Chemotherapy and Pharmacology [Cancer Chemother Pharmacol] |
| Volume Number | 92 |
| DOI | 10.1007/s00280-023-04555-2 |
| PubMed Central reference number | PMC10326086 |
| Issue Number | 2 |
| PubMed reference number | 37368100 |
| e-ISSN | 14320843 |
| Language | English |
| Publisher | Springer Berlin Heidelberg |
| Publisher Date | 2023-06-27 |
| Publisher Place | Berlin/Heidelberg |
| Access Restriction | Open |
| Rights License | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2023 |
| Subject Keyword | Adavosertib AZD1775 QT interval Wee1 inhibitor Pharmacokinetics Pharmacodynamics |
| Content Type | Text |
| Resource Type | Article |
| Subject | Toxicology Cancer Research Pharmacology Pharmacology (medical) Oncology |
