title: Translational Modeling of Drug-Induced Myelosuppression and Effect of Pretreatment Myelosuppression for AZD5153, a Selective BRD4 Inhibitor.
abstract: 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.
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Cambridge, UK.
authors.forename: T A
authors.initials: TA
authors.lastname: Collins
authors.affiliation: Oncology iMED, AstraZeneca, Waltham, Massachusetts, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Hattersley
authors.affiliation: Oncology iMED, AstraZeneca, Cambridge, UK.
authors.forename: Jwt
authors.initials: J
authors.lastname: Yates
authors.affiliation: Oncology iMED, AstraZeneca, Waltham, Massachusetts, USA.
authors.forename: E
authors.initials: E
authors.lastname: Clark
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Waltham, Massachusetts, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mondal
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Waltham, Massachusetts, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Mettetal
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects; D018797:Cell Cycle Proteins; D003198:Computer Simulation; D004285:Dogs; D005260:Female; D006574:Heterocyclic Compounds, 2-Ring / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy; D008954:Models, Biological; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D010976:Platelet Count; D011720:Pyrazoles; D011724:Pyridazines; D051381:Rats; D011919:Rats, Inbred Strains; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D006574:Heterocyclic Compounds, 2-Ring; D009687:Nuclear Proteins; D010879:Piperazines; D011720:Pyrazoles; D011724:Pyridazines; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C000621120:AZD5153