Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
Data and Statistical Sciences, AbbVie Inc., North Chicago, IL, USA.
Clin Pharmacokinet. 2019 Jun;58(6):805-814. doi: 10.1007/s40262-018-0730-x.
The objective of this study was to characterize the effects of risankizumab on the in vivo activity of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A in psoriasis patients using a cocktail approach.
Patients with moderate to severe chronic plaque psoriasis (n = 21) received single oral doses of sensitive probe substrates for CYP1A2 (caffeine 100 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), CYP2D6 (metoprolol 50 mg), and CYP3A (midazolam 2 mg) on day 1, followed by 12 weeks of subcutaneous risankizumab treatment of 150 mg once every 4 weeks from day 8 to day 92, and again the same cocktail of substrates on day 98. Serial blood samples were collected for determination of the CYP probe drugs and metabolites with and without risankizumab. Trough samples were collected for risankizumab.
The 90% confidence intervals (CIs) for the area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC) ratios for the CYP probe substrates administered with risankizumab versus without risankizumab were within the default 0.8-1.25 equivalence bounds. Similar results were observed for maximum plasma concentration (C), except for omeprazole, for which the lower bound of the 90% CI for C (0.73) extended slightly below the default equivalence limit. No differences were observed in metabolite-to-parent drug C or AUC ratios with risankizumab versus without risankizumab. Risankizumab trough plasma concentrations significantly exceeded those of the phase III regimen of risankizumab in psoriasis (150 mg subcutaneously at weeks 0 and 4 and every 12 weeks thereafter).
Risankizumab did not affect the in vivo activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A enzymes in patients with moderate or severe plaque psoriasis and therefore has no potential for drug interactions through these enzymes.
ClinicalTrials.gov Identifier: NCT02772601.
本研究旨在采用鸡尾酒法研究 risankizumab 对中重度慢性斑块型银屑病患者细胞色素 P450（CYP）1A2、CYP2C9、CYP2C19、CYP2D6 和 CYP3A 体内活性的影响。
21 例中重度慢性斑块型银屑病患者于第 1 天单次口服 CYP1A2（咖啡因 100mg）、CYP2C9（华法林 10mg）、CYP2C19（奥美拉唑 20mg）、CYP2D6（美托洛尔 50mg）和 CYP3A（咪达唑仑 2mg）敏感探针底物，第 8 天至第 92 天每 4 周皮下注射 risankizumab 150mg 一次，第 98 天再次给予相同的探针药物鸡尾酒。采集血样，测定有和无 risankizumab 时 CYP 探针药物及其代谢物的浓度。采集 risankizumab 的谷浓度样本。
与无 risankizumab 相比，risankizumab 给药时 CYP 探针底物的 AUC 比值（AUC）的 90%置信区间（CI）在默认的 0.8-1.25 等效区间内。最大血浆浓度（C）也观察到了类似的结果，除了奥美拉唑，其 C 的 90%CI 的下限（0.73）略低于默认的等效限值。与无 risankizumab 相比，有和无 risankizumab 时代谢物与母体药物 C 或 AUC 比值无差异。risankizumab 的谷浓度显著高于银屑病的 III 期治疗方案（0、4 周时皮下注射 150mg，此后每 12 周一次）。
在中重度斑块型银屑病患者中，risankizumab 不影响 CYP1A2、CYP2C9、CYP2C19、CYP2D6 或 CYP3A 酶的体内活性，因此通过这些酶发生药物相互作用的潜力较小。
ClinicalTrials.gov 标识符：NCT02772601。
