Clinical Pharmacology, Genentech, South San Francisco, CA, USA.
QuantPharm LLC, North Potomac, MD, USA.
J Clin Pharmacol. 2018 Mar;58(3):386-398. doi: 10.1002/jcph.1031. Epub 2017 Nov 26.
Etrolizumab, a humanized monoclonal antibody, specifically binds to the β7 subunit of the heterodimeric integrins α4β7 and αEβ7. Pharmacokinetic (PK) and pharmacodynamic (PD) data were collected from an etrolizumab phase 1 trial in patients with moderate to severe ulcerative colitis (UC). We developed a mechanism-based model to simultaneously describe the kinetics of serum etrolizumab concentration and free β7 receptors on circulating intestinal-homing CD4 T lymphocytes. Included in the analysis were 38 phase 1 UC patients who received single or 3 monthly doses of etrolizumab intravenously or subcutaneously across a dose range of 0.3 to 10 mg/kg. A quasi-steady-state target-mediated drug disposition model was developed to describe the dynamic interaction between serum etrolizumab concentration and free β7 receptors on intestinal-homing CD4 T lymphocytes in UC patients. The time profiles of serum etrolizumab and absolute counts of β7 lymphocytes (expressed as percentage of baseline level) were well described by the quasi-steady-state target-mediated drug disposition model. The model was able to characterize the maximum drug occupancy of β7 receptors on intestinal-homing CD4 T lymphocytes and the concentration-dependent duration of occupancy. The 90% effective concentration for etrolizumab to saturate the β7 receptors on intestinal homing CD4 T cells was 1.3 μg/mL. PK and PD profiles predicted by the model were consistent with observations from a subsequent phase 2 study. In conclusion, an integrated PK/PD model developed in this analysis reasonably described serum etrolizumab PK profiles and the relationship between PK and PD (free β7 receptors on circulating intestinal-homing CD4 T lymphocytes) in UC patients.
依特立珠单抗是人源化单克隆抗体，特异性结合于异二聚体整合素 α4β7 和 αEβ7 的β7 亚单位。在中重度溃疡性结肠炎（UC）患者中进行的依特立珠单抗 1 期临床试验中收集了药代动力学（PK）和药效动力学（PD）数据。我们开发了一种基于机制的模型，以同时描述血清依特立珠单抗浓度和循环肠归巢 CD4 T 淋巴细胞上游离β7 受体的动力学。纳入分析的有 38 例 UC 患者，他们接受了单次或 3 个月静脉或皮下给予依特立珠单抗治疗，剂量范围为 0.3 至 10mg/kg。建立了准稳态靶向药物处置模型，以描述 UC 患者血清依特立珠单抗浓度与肠归巢 CD4 T 淋巴细胞上游离β7 受体之间的动态相互作用。血清依特立珠单抗和β7 淋巴细胞的绝对计数（表示为基线水平的百分比）时间曲线通过准稳态靶向药物处置模型得到了很好的描述。该模型能够描述β7 受体在肠归巢 CD4 T 淋巴细胞上的最大药物占有率和与浓度相关的占有率持续时间。依特立珠单抗使肠归巢 CD4 T 细胞上的β7 受体饱和的 90%有效浓度为 1.3μg/mL。模型预测的 PK 和 PD 特征与随后的 2 期研究的观察结果一致。总之，本分析中开发的整合 PK/PD 模型合理地描述了 UC 患者血清依特立珠单抗 PK 特征以及 PK 与 PD（循环肠归巢 CD4 T 淋巴细胞上的游离β7 受体）之间的关系。
