LD-Aminopterin in the Canine Homologue of Human Atopic Dermatitis: A Randomized, Controlled Trial Reveals Dosing Factors Affecting Optimal Therapy

BackgroundOptions are limited for patients with atopic dermatitis (AD) who do not respond to topical treatments. Antifolate therapy with systemic methotrexate improves the disease, but is associated with adverse effects. The investigational antifolate LD-aminopterin may offer improved safety. It is not known how antifolate dose and dosing frequency affect efficacy in AD, but a primary mechanism is thought to involve the antifolate-mediated accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). However, recent in vitro studies indicate that AICAR increases then decreases as a function of antifolate concentration. To address this issue and understand how dosing affects antifolate efficacy in AD, we examined the efficacy and safety of different oral doses and schedules of LD-aminopterin in the canine model of AD.Methods and FindingsThis was a multi-center, double-blind trial involving 75 subjects with canine AD randomized to receive up to 12 weeks of placebo, once-weekly (0.007, 0.014, 0.021 mg/kg) or twice-weekly (0.007 mg/kg) LD-aminopterin. The primary efficacy outcome was the Global Score (GS), a composite of validated measures of disease severity and itch. GS improved in all once-weekly cohorts, with 0.014 mg/kg being optimal and significant (43%, PConclusionsOnce-weekly LD-aminopterin was safe and efficacious in canine AD. Twice-weekly dosing negated efficacy despite having the same daily and weekly dose as effective once-weekly regimens. Optimal dosing in this homologue of human AD correlated with the concentration-selective accumulation of AICAR in vitro, consistent with AICAR mediating LD-aminopterin efficacy in AD.背景：对于局部治疗无应答的特应性皮炎（atopic dermatitis, AD）患者，可用治疗选择十分有限。全身性甲氨蝶呤抗叶酸疗法可改善病情，但会伴随不良反应。在研抗叶酸制剂LD-氨基蝶呤（LD-aminopterin）或可提升治疗安全性。目前尚不明确抗叶酸的给药剂量与频率如何影响特应性皮炎的治疗效果，但已知其主要作用机制可能涉及抗叶酸介导的5-氨基咪唑-4-甲酰胺核糖核苷酸（5-aminoimidazole-4-carboxamide ribonucleotide, AICAR）蓄积。不过近期体外研究显示，AICAR水平会随抗叶酸浓度升高先上升后下降。为解决这一问题并阐明给药方案如何影响抗叶酸疗法在特应性皮炎中的疗效，我们在犬特应性皮炎模型中评估了不同口服剂量与给药方案的LD-氨基蝶呤的疗效与安全性。 方法与结果：本研究为多中心双盲试验，共纳入75名患特应性皮炎的犬只受试者，随机分配至多接受长达12周的安慰剂、每周一次（0.007、0.014、0.021 mg/kg）或每周两次（0.007 mg/kg）的LD-氨基蝶呤治疗。主要疗效终点为总体评分（Global Score, GS），这是一项经过验证的疾病严重程度与瘙痒症状综合评估指标。所有每周一次给药的队列中，GS均得到改善，其中0.014 mg/kg剂量组效果最优且具有统计学显著性（43%, P。 结论：每周一次给药的LD-氨基蝶呤在犬特应性皮炎模型中安全性良好且疗效确切。尽管每周两次给药方案与有效的每周一次给药方案的每日及每周总剂量一致，但其疗效却被抵消。在该人类特应性皮炎同源模型中，最优给药剂量与体外实验中AICAR的浓度选择性蓄积特征相符，这也支持AICAR介导了LD-氨基蝶呤在特应性皮炎中的治疗效果。