Translational Modeling of Drug-Induced Myelosuppression and Effect of Pretreatment Myelosuppression for AZD5153, a Selective BRD4 Inhibitor.
| Autor: | Collins TA; Drug Safety and Metabolism, AstraZeneca, Cambridge, UK., Hattersley MM; Oncology iMED, AstraZeneca, Waltham, Massachusetts, USA., Yates J; Oncology iMED, AstraZeneca, Cambridge, UK., Clark E; Oncology iMED, AstraZeneca, Waltham, Massachusetts, USA., Mondal M; Drug Safety and Metabolism, AstraZeneca, Waltham, Massachusetts, USA., Mettetal JT; Drug Safety and Metabolism, AstraZeneca, Waltham, Massachusetts, USA. |
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| Jazyk: | angličtina |
| Zdroj: | CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2017 Jun; Vol. 6 (6), pp. 357-364. Date of Electronic Publication: 2017 May 27. |
| DOI: | 10.1002/psp4.12194 |
| Abstrakt: | In this work, we evaluate the potential risk of thrombocytopenia in man for a BRD4 inhibitor, AZD5153, based on the platelet count decreases from a Han Wistar rat study. The effects in rat were modeled and used to make clinical predictions for human populations with healthy baseline blood counts. At doses >10 mg, a dose-dependent effect on circulating platelets is expected, with similar predicted changes for both q.d. and b.i.d. dose schedules. These results suggest that at predicted efficacious doses, AZD5153 is likely to have some reductions in the clinical platelet counts, but within the normal range at projected efficacious doses. The model was then extended to incorporate preexisting myelosuppression where bone marrow function is inhibited by acute myeloid leukemia. Under these conditions, duration of platelet count recovery has the potential to be prolonged due to drug-induced myelosuppression. (© 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.) |
| Databáze: | MEDLINE |
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