Medicine, Alfred Hospital, Melbourne, VIC, Australia.
Clinical Trials, Sinclair Dermatology, East Melbourne, VIC, Australia.
Int J Dermatol. 2021 Sep;60(9):1135-1139. doi: 10.1111/ijd.15657. Epub 2021 May 18.
Tofacitinib is a JAK1/3 inhibitor used off-label to treat alopecia areata (AA). Oral tofacitinib undergoes extensive hepatic metabolism and has numerous drug interactions and a half-life of 3 hours necessitating twice daily dosing. Sublingual delivery bypasses hepatic first-pass metabolism, which may provide pharmacokinetic benefits and reduce gastrointestinal side effects. We investigate sublingual tofacitinib as a novel form of administration in a cohort of treatment-resistant patients. The objective of this work is to assess the efficacy and pharmacokinetics of sublingual tofacitinib in moderate-to-severe AA patients. An open-label, roll-over pilot clinical trial was conducted. Participants were recruited from a preceding trial. All responders (≥50% reduction in Severity of Alopecia Tool [SALT] score, SALT50) in the preceding trial continued on the same treatment (cyclosporine/placebo), whereas nonresponders rolled over to receive open-label sublingual tofacitinib 5 mg twice daily for 12 weeks. Treatment response as reduction in SALT score after 12 weeks (low: 15-29%, medium: 30-49%, good: 50-75%, and high grade: 75-100%) was measured. Pharmacokinetics was analyzed using liquid chromatography tandem mass spectrometry. Eighteen participants completed the trial. Total treatment response to tofacitinib was 37.5%. SALT50 was achieved in 12.5%. The mean improvement in SALT score was 15.57%. Mean maximum plasma concentration was 43.18 ng/ml occurring after 1 hour. Elimination half-life is estimated to be up to 11 hours. An estimated half-life of up to 11 hours may be achieved with sublingual tofacitinib, which is significantly longer than the oral form and may facilitate daily dosing. Larger clinical trials are required to further characterize its pharmacokinetics and efficacy.
托法替尼是一种 JAK1/3 抑制剂，被批准用于治疗斑秃（AA）。口服托法替尼在肝脏中经历广泛的代谢，并且有许多药物相互作用和半衰期为 3 小时，需要每日两次给药。舌下给药可绕过肝脏首过代谢，这可能提供药代动力学优势并减少胃肠道副作用。我们研究了舌下托法替尼作为一种新的给药方式，在一组难治性患者中进行了研究。这项工作的目的是评估舌下托法替尼在中重度 AA 患者中的疗效和药代动力学。进行了一项开放标签、滚动试验的临床试验。参与者是从之前的试验中招募的。前一个试验中所有（SALT 评分降低≥50%，SALT50）的应答者（≥50%）继续接受相同的治疗（环孢素/安慰剂），而无应答者则转为接受开放标签的舌下托法替尼 5mg，每日两次，持续 12 周。12 周后 SALT 评分降低（低：15-29%，中：30-49%，好：50-75%，高：75-100%）作为治疗反应来衡量。使用液相色谱串联质谱法分析药代动力学。18 名参与者完成了试验。托法替尼的总治疗反应率为 37.5%。达到 SALT50 的比例为 12.5%。SALT 评分的平均改善为 15.57%。平均最大血浆浓度为 43.18ng/ml，发生在 1 小时后。消除半衰期估计长达 11 小时。舌下托法替尼的半衰期估计长达 11 小时，明显长于口服形式，可能便于每日给药。需要更大规模的临床试验来进一步描述其药代动力学和疗效。
