Clinical Pharmacology and Pharmacometrics, Abbvie, North Chicago, Illinois, USA.
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Twin Cities, Minnesota, USA.
J Clin Pharmacol. 2021 Mar;61(3):307-318. doi: 10.1002/jcph.1744. Epub 2020 Sep 22.
Elevated cytokine levels in inflammatory diseases are associated with downregulation of certain cytochrome P450 (CYP) enzymes. Upon treatment with some cytokine-targeting therapeutic proteins, the CYP enzymes levels may be restored resulting in therapeutic protein-mediated drug interactions (TP-DI). These analyses characterized the worst-case scenario for CYP1A2, 2C9, and 3A-based TP-DI potential in patients with psoriasis by comparing the pharmacokinetics of probe substrates between healthy volunteers and subjects with moderate to severe psoriasis. Data for the CYP probe substrates midazolam (CYP3A), caffeine (CYP1A2), and S-warfarin (CYP2C9) from 7 drug interaction studies (1 in patients with psoriasis and 6 in healthy subjects) were pooled to develop a population pharmacokinetics model for each substrate. A 2-compartment model with absorption lag time for midazolam, a 1-compartment model with 5 transit absorption compartments for caffeine, and a 3-compartment model with absorption lag time for S-warfarin best described the observed data. Apparent oral clearance and relative bioavailability for caffeine and S-warfarin were not significantly different between the subject populations. Psoriasis patients were estimated to have 17% lower midazolam oral bioavailability than healthy volunteers. Compounded with other covariate effects, the ratio of median post hoc area under the plasma concentration-time estimates in subjects with psoriasis relative to healthy subjects was 0.96, 1.13, and 0.65 for midazolam, caffeine, and S-warfarin, respectively. Therefore, inflammation in psoriasis had no relevant effect on reducing CYP1A2, 2C9, and 3A activities in vivo and no significant TP-DIs mediated through these enzymes are expected in patients with psoriasis. This approach can potentially be used in lieu of dedicated TP-DI studies to identify TP-DI risks within a disease area.
在炎症性疾病中，细胞因子水平升高与某些细胞色素 P450（CYP）酶的下调有关。在使用某些细胞因子靶向治疗蛋白进行治疗后，CYP 酶水平可能会恢复，从而导致治疗性蛋白介导的药物相互作用（TP-DI）。这些分析通过比较健康志愿者和中重度银屑病患者之间探针底物的药代动力学，来确定银屑病患者中 CYP1A2、2C9 和 3A 为基础的 TP-DI 潜在风险的最坏情况。对来自 7 项药物相互作用研究（1 项在银屑病患者中进行，6 项在健康受试者中进行）的 CYP 探针底物咪达唑仑（CYP3A）、咖啡因（CYP1A2）和 S-华法林（CYP2C9）的数据进行了汇总，为每个底物开发了群体药代动力学模型。咪达唑仑具有吸收滞后时间的 2 隔室模型、咖啡因具有 5 个转运吸收隔室的 1 隔室模型以及 S-华法林具有吸收滞后时间的 3 隔室模型，这些模型最佳地描述了观察到的数据。咖啡因和 S-华法林的表观口服清除率和相对生物利用度在两个受试者群体之间没有显著差异。与健康志愿者相比，银屑病患者的咪达唑仑口服生物利用度估计降低了 17%。与其他协变量效应相结合，银屑病患者相对于健康受试者的中位数事后血浆浓度-时间估计的比值分别为 0.96、1.13 和 0.65，用于咪达唑仑、咖啡因和 S-华法林。因此，银屑病中的炎症不会对体内 CYP1A2、2C9 和 3A 活性产生相关影响，预计在银屑病患者中不会发生通过这些酶介导的显著 TP-DI。这种方法可用于替代专门的 TP-DI 研究，以识别疾病领域内的 TP-DI 风险。
