H3 Biomedicine Inc, 300 Technology Square, Cambridge, MA, 02139, USA.
Certara Strategic Consulting, Cambridge, MA, USA.
Cancer Chemother Pharmacol. 2019 Jan;83(1):151-160. doi: 10.1007/s00280-018-3716-3. Epub 2018 Nov 1.
H3B-6545, a novel selective estrogen receptor (ER)α covalent antagonist (SERCA) which inactivates both wild-type and mutant ERα, is in clinical development for the treatment of metastatic breast cancer. Preclinical studies were conducted to characterize the pharmacokinetics and metabolism of H3B-6545 in rat and monkeys.
The clearance and metabolic profiles of H3B-6545 were studied using rat, monkey and human hepatocytes, and reaction phenotyping was done using recombinant human cytochrome P450 enzymes. Blood stability, protein binding, and permeability were also determined in vitro. Pharmacokinetics of H3B-6545 was assessed after both intravenous and oral dosing. A nonclinical PBPK model was developed to assess in vitro-in vivo correlation of clearance.
H3B-6545 had a terminal elimination half-life of 2.4 h in rats and 4.0 h in monkeys and showed low to moderate bioavailability, in line with the in vitro permeability assessment. Plasma protein binding was similar across species, at 99.5-99.8%. Nine metabolites of H3B-6545 were identified in hepatocyte incubations, none of which were unique to humans. Formation of glutathione-related conjugate of H3B-6545 was minimal in vitro. H3B-6545, a CYP3A substrate, is expected to be mostly cleared via hepatic phase 1 metabolism. Hepatocyte clearance values were used to adequately model the time-concentration profiles in rat and monkey.
We report on the absorption and metabolic fate and disposition of H3B-6545 in rats and dogs and illustrate that in vitro-in vivo correlation of clearance is possible for targeted covalent inhibitors, provided reactivity is not a predominant mechanism of clearance.
H3B-6545 是一种新型的选择性雌激素受体（ER）α共价拮抗剂（SERCA），可使野生型和突变型 ERα失活，目前正在开发用于治疗转移性乳腺癌。进行了临床前研究，以研究 H3B-6545 在大鼠和猴子中的药代动力学和代谢特征。
使用大鼠、猴子和人肝细胞研究了 H3B-6545 的清除率和代谢特征，并使用重组人细胞色素 P450 酶进行了反应表型鉴定。还在体外测定了血液稳定性、蛋白结合和通透性。评估了静脉内和口服给药后 H3B-6545 的药代动力学。建立了非临床 PBPK 模型，以评估清除率的体外-体内相关性。
H3B-6545 在大鼠中的终末消除半衰期为 2.4 小时，在猴子中为 4.0 小时，并且表现出低至中等的生物利用度，与体外渗透性评估一致。血浆蛋白结合在各物种中相似，为 99.5-99.8%。在肝细胞孵育中鉴定出 H3B-6545 的 9 种代谢物，其中没有一种是人类特有的。H3B-6545 形成谷胱甘肽相关缀合物的体外作用最小。H3B-6545 是 CYP3A 的底物，预计主要通过肝相 1 代谢清除。肝细胞清除值用于充分模拟大鼠和猴子的时间浓度曲线。
我们报告了 H3B-6545 在大鼠和犬中的吸收、代谢命运和处置情况，并说明对于靶向共价抑制剂，清除率的体外-体内相关性是可能的，前提是反应不是清除的主要机制。
