JAK1 inhibitors for the treatment of atopic dermatitis: a focus on pharmacokinetic considerations

ABSTRACTIntroduction Atopic dermatitis (AD) is associated with reduced quality of life, depression, and anxiety, making efficacious and safe treatments a priority. We will focus on the safety, efficacy, and pharmacokinetics of JAK1 inhibitors used in the treatment of AD.Areas Covered In this review, the pharmacodynamics, pharmacokinetics, safety, and efficacy of JAK1 inhibitors for the treatment of atopic dermatitis are discussed. The data was obtained by searching ClinicalTrials.gov, PubMed, and Google Scholar. Articles between January 2012 and March 2023 were considered for inclusion.Expert Opinion Given the rare, but serious black box warnings with JAK inhibitors, patients and providers may be weary of initiating treatment. In these instances, clinicians may weigh the risks and benefits of treatment with this class. Risk is relative, and while there are risks to treating AD with JAK inhibitors, there are also risks to untreated or undertreated AD, including infection and impairments in mental, physical, and psychosocial function. While JAK1 inhibitors appear to be safe, they were only recently approved for AD in January 2022, and more long-term safety data is needed. We expect to see additional FDA approval of these drugs, new formulations, and more safety and efficacy data in the future.KEYWORDS: AtopicdermatitisJAKpharmacodynamicspharmacokineticssafetyefficacy Article highlights JAK inhibitors are small molecules that bind to JAK receptors and block the downstream signaling from cytokines implicated in atopic dermatitis (AD), specifically IL-4 and IL-13.There are two classes of JAK inhibitors. The first generation – baricitinib, delgocitinib, tofacitinib, and ruxolitinib – inhibit multiple JAK isoforms. The second generation – abrocitinib and uadacitinib – are more selective, targeting primarily only one JAK isoform and inhibiting a smaller range of cytokines.JAK inhibitors were efficacious for AD in phase II and III clinical trials. In particular, upadacitinib was more efficacious than dupilumab in a head-to-head trial.As a class, the JAK inhibitors have similar safety profiles with the most frequent adverse events including nasopharyngitis and upper respiratory infections.Given the rare, but serious black box warnings for an increased risk of serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis with JAK inhibitors, conversations surrounding using JAK inhibitors should involve risk stratification and shared decision-making between patients and their doctors.Declaration of interestS Feldman has received research, speaking and/or consulting support from Eli Lilly and Company, GaxoSmithKline/Stiefel, AbbVie, Janssen, Alovtech, vTv Therapeutics, Bristol-Myers Squibb, Samsung, Pfizer, Boehringer Ingelheim, Amgen, Dermavant, Arcutis, Novartis, Novan, UCB, Helsinn, Sun Pharma, Almirall, Galderma, Leo Pharma, Mylan, Celgene, Ortho Dermatology, Menlo, Merck & Co, Qurient, Forte, Arena, Biocon, Accordant, Argenx, Sanofi, Regeneron, the National Biological Corporation, Caremark, Teladoc, Ono, Micreos, Eurofins, Informa, UpToDate and the National Psoriasis Foundation. He is founder and part owner of Causa Research and holds stock in Sensal Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresOne reviewer has served on the advisory board of or as a consultant for; Regeneron, Sanofi Genzyme, AbbVie, Pfizer, Janssen-Cilag, LEO Pharma, Novartis, Eli-Lilly, Teva, L'Oreal, Pierre Fabre, Cantabria Labs, Organon, Viatris, Evelo Biosciences and Amgen. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.Additional informationFundingThis paper was not funded.