Collins T A, Hattersley M M, Yates Jwt, Clark E, Mondal M, Mettetal J T
Drug Safety and Metabolism, AstraZeneca, Cambridge, UK.
Oncology iMED, AstraZeneca, Waltham, Massachusetts, USA.
CPT Pharmacometrics Syst Pharmacol. 2017 Jun;6(6):357-364. doi: 10.1002/psp4.12194. Epub 2017 May 27.
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.
在本研究中，我们基于一项汉-威斯塔大鼠研究中血小板计数的降低情况，评估了BRD4抑制剂AZD5153在人体中导致血小板减少的潜在风险。对大鼠的效应进行建模，并用于对基线血细胞计数正常的人群进行临床预测。在剂量>10 mg时，预计对循环血小板有剂量依赖性效应，每日一次和每日两次给药方案的预测变化相似。这些结果表明，在预测的有效剂量下，AZD5153可能会使临床血小板计数有所降低，但在预测的有效剂量范围内仍处于正常范围。然后将该模型扩展，纳入先前存在的骨髓抑制情况，即急性髓系白血病抑制骨髓功能。在这些条件下，由于药物诱导的骨髓抑制，血小板计数恢复的持续时间有可能延长。
