药代动力学增强以实现类风湿关节炎和银屑病关节炎患者托法替布每日一次的低剂量给药（PRACTICAL研究）
Pharmacokinetic boosting to enable a once-daily reduced dose of tofacitinib in patients with rheumatoid arthritis and psoriatic arthritis (the PRACTICAL study).
作者信息
van der Togt Céleste J T, Verhoef Lise M, van den Bemt Bart J F, den Broeder Nathan, Ter Heine Rob, den Broeder Alfons A
机构信息
Department of Rheumatology, Sint Maartenskliniek, PO Box 9011, 6500 GM Nijmegen, The Netherlands.
Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
出版信息
Ther Adv Musculoskelet Dis. 2022 Dec 12;14:1759720X221142277. doi: 10.1177/1759720X221142277. eCollection 2022.
BACKGROUND
Tofacitinib is a Janus Kinase (JAK) inhibitor used for the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), dosed as 5 mg twice daily (BID). It is primarily metabolized by the cytochrome P-3A (CYP3A) enzyme, and therefore, the manufacturer recommends to halve the dose when using CYP3A-inhibiting co-medication. Combining half-dose tofacitinib with a registered CYP3A inhibitor (cobicistat) could reduce costs and improve patient experience.
OBJECTIVES
Primary: bioequivalence of tofacitinib 5 mg combined with cobicistat once daily (QD; intervention) to tofacitinib 5 mg BID (control). Secondary: safety, patient preference (7-point Likert scale at study end) and predicted differences in disease activity (DAS28-CRP and probability of ACR20 response) using a validated exposure-response model.
DESIGN
Open-label, cross-over pharmacokinetic study.
METHODS
We included patients with RA or PsA, treated with tofacitinib 5 mg BID for ⩾14 days without co-medication affected by CYP3A inhibition. Pharmacokinetic sampling was performed at baseline and after 2-6 weeks of intervention treatment. Bioequivalence was defined as 90% CI of the average tofacitinib concentration (C; intervention to control) falling between 80% and 125%, assessed by non-linear mixed-effects modelling.
RESULTS
Between 16 September 2019 and 15 January 2021, 30 patients were included, of whom 25 completed both PK measurements. The tofacitinib C was 85% (90% CI: 75-96%). No serious adverse events occurred. Patient preference was 56% for intervention 18% for control. No relevant differences in median predicted disease activity were found (DAS28-CRP: 0.03, 95% CI: -0.16 to 0.22; ACR20: -0.01, -0.07 to 0.05).
CONCLUSION
Due to slightly lower tofacitinib concentrations during intervention treatment, pharmacokinetic bioequivalence could not formally be established. However, pharmacokinetic boosting may be an attractive strategy for cost reduction of tofacitinib because of its safety, similar predicted pharmacodynamics and patient preference.
REGISTRATION
This study was registered on 29 May 2019 in the Netherlands Trial Register (register number: NL7766).
背景
托法替布是一种用于治疗类风湿性关节炎（RA）和银屑病关节炎（PsA）的 Janus 激酶（JAK）抑制剂，给药剂量为 5mg，每日两次（BID）。它主要通过细胞色素 P-3A（CYP3A）酶代谢，因此，制造商建议在使用 CYP3A 抑制性联合用药时将剂量减半。将半剂量托法替布与已注册的 CYP3A 抑制剂（考比司他）联合使用可降低成本并改善患者体验。
目的
主要目的：每日一次（QD；干预组）服用托法替布 5mg 联合考比司他与每日两次（BID；对照组）服用托法替布 5mg 的生物等效性。次要目的：使用经过验证的暴露-反应模型评估安全性、患者偏好（研究结束时的 7 点李克特量表）以及疾病活动度的预测差异（DAS28-CRP 和达到美国风湿病学会 20%改善标准（ACR20）反应的概率）。
设计
开放标签、交叉药代动力学研究。
方法
我们纳入了患有 RA 或 PsA 且接受托法替布 5mg BID 治疗至少 14 天且未使用受 CYP3A 抑制影响的联合用药的患者。在基线和干预治疗 2 - 6 周后进行药代动力学采样。生物等效性定义为托法替布平均浓度（C；干预组与对照组）的 90%置信区间（CI）落在 80%至 125%之间，通过非线性混合效应模型进行评估。
结果
在 2019 年 9 月 16 日至 2021 年 1 月 15 日期间，纳入了 30 名患者，其中 25 名完成了两次药代动力学测量。托法替布的 C 为 85%（90%CI：75 - 96%）。未发生严重不良事件。患者对干预组的偏好为 56%，对对照组的偏好为 18%。在预测的疾病活动度中位数方面未发现相关差异（DAS28-CRP：0.03，95%CI： - 0.16 至 0.22；ACR20： - 0.01， - 0.07 至 0.05）。
结论
由于干预治疗期间托法替布浓度略低，无法正式确立药代动力学生物等效性。然而，由于其安全性、相似的预测药效学和患者偏好，药代动力学增强可能是一种降低托法替布成本的有吸引力的策略。
注册情况
本研究于 2019 年 5 月 29 日在荷兰试验注册库注册（注册号：NL7766）。
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