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1.
Ann Allergy Asthma Immunol ; 132(3): 383-389.e3, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37949351

RESUMEN

BACKGROUND: Response to abrocitinib treatment for moderate-to-severe atopic dermatitis (AD) has not been evaluated across racial and ethnic subpopulations. OBJECTIVE: To assess the efficacy and safety of abrocitinib on the basis of patient race, ethnicity, and Fitzpatrick skin type (FST). METHODS: Data were pooled post hoc from patients treated with abrocitinib 200 mg, 100 mg, or placebo in 3 monotherapy trials (NCT02780167, NCT03349060, and NCT03575871). Race and ethnicity were self-reported; FST was determined by study investigators. Evaluations through Week 12 include the following: (1) Investigator's Global Assessment of clear or almost-clear skin; (2) greater than or equal to 75% improvement in Eczema Area and Severity Index or SCORing AD; (3) a greater-than-or-equal-to 4-point improvement in Peak Pruritus Numerical Rating Scale score; (4) least squares mean changes in Dermatology Life Quality Index and Patient-Oriented Eczema Measure scores; and (5) treatment-emergent adverse events. RESULTS: The sample comprised 628 White, 204 Asian, and 83 Black patients; 37 were Hispanic or Latino; 624 had FST I to III and 320 had FST IV to VI. Treatment with either abrocitinib dose was associated with greater proportions of patients achieving Investigator's Global Assessment of clear or almost-clear skin, ≥ 75% improvement in Eczema Area and Severity Index, ≥ 75% improvement in SCORing AD, and a ≥ 4-point improvement in Peak Pruritus Numerical Rating Scale, or greater score changes from baseline in Dermatology Life Quality Index and Patient-Oriented Eczema Measure vs placebo regardless of race, ethnicity, or FST. Dose-response was most prominent in White patients. In Black patients, the effects of the 2 doses were similar. Treatment-emergent adverse events were more common in White and Black than in Asian patients. CONCLUSION: Abrocitinib was more efficacious than placebo across the racial and ethnic groups and ranges of phototypes analyzed. Studies with increased representation of populations of color are warranted to elucidate potential variations in response across diverse populations. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02780167 (phase 2b), NCT03349060 (phase 3 MONO-1), and NCT03575871 (phase 3 MONO-2).


Asunto(s)
Dermatitis Atópica , Eccema , Pirimidinas , Sulfonamidas , Humanos , Dermatitis Atópica/tratamiento farmacológico , Eccema/tratamiento farmacológico , Etnicidad , Prurito/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Ensayos Clínicos como Asunto
2.
J Am Acad Dermatol ; 87(2): 351-358, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35439608

RESUMEN

BACKGROUND: Abrocitinib efficacy by prior dupilumab response status in patients with moderate-to-severe atopic dermatitis has not previously been assessed in phase 3 studies. OBJECTIVE: Examine efficacy and safety of abrocitinib among patients who received prior dupilumab. METHODS: Patients with moderate-to-severe atopic dermatitis received abrocitinib 200 mg or 100 mg once daily in JADE EXTEND (phase 3 extension) after dupilumab in double-blind, placebo-controlled phase 3 JADE COMPARE. RESULTS: Among prior dupilumab responders, ≥75% improvement in Eczema Area and Severity Index was achieved in 93.5% and 90.2% of patients who received 12 weeks of abrocitinib 200 mg and 100 mg, respectively; ≥4-point improvement in Peak Pruritus Numerical Rating Scale was achieved in 89.7% and 81.6%, respectively. Among prior dupilumab nonresponders, ≥75% improvement in Eczema Area and Severity Index was achieved with abrocitinib 200 mg and 100 mg in 80.0% and 67.7% and ≥4-point improvement in Peak Pruritus Numerical Rating Scale in 77.3% and 37.8%, respectively. Most common adverse events among abrocitinib-treated patients were nasopharyngitis, nausea, acne, and headache. Conjunctivitis occurred less frequently with abrocitinib in comparison to prior dupilumab. LIMITATIONS: Short-term, 12-week analysis; no placebo arm. CONCLUSION: Efficacy and safety profile of abrocitinib in JADE EXTEND supports the role of abrocitinib as a treatment for patients with moderate-to-severe atopic dermatitis, regardless of prior dupilumab response status.


Asunto(s)
Dermatitis Atópica , Eccema , Adulto , Anticuerpos Monoclonales Humanizados , Dermatitis Atópica/tratamiento farmacológico , Método Doble Ciego , Eccema/tratamiento farmacológico , Humanos , Inyecciones Subcutáneas , Prurito/inducido químicamente , Prurito/tratamiento farmacológico , Pirimidinas , Índice de Severidad de la Enfermedad , Sulfonamidas , Resultado del Tratamiento
3.
Drug Metab Dispos ; 42(4): 759-73, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24464803

RESUMEN

Tofacitinib is a novel, oral Janus kinase inhibitor. The objectives of this study were to summarize the pharmacokinetics and metabolism of tofacitinib in humans, including clearance mechanisms. Following administration of a single 50-mg (14)C-labeled tofacitinib dose to healthy male subjects, the mean (standard deviation) total percentage of administered radioactive dose recovered was 93.9% (±3.6), with 80.1% (±3.6) in the urine (28.8% parent), and 13.8% (±1.9) in feces (0.9% parent). Tofacitinib was rapidly absorbed, with plasma concentrations and total radioactivity peaking at around 1 hour after oral administration. The mean terminal phase half-life was approximately 3.2 hours for both parent drug and total radioactivity. Most (69.4%) circulating radioactivity in plasma was parent drug, with all metabolites representing less than 10% each of total circulating radioactivity. Hepatic clearance made up around 70% of total clearance, while renal clearance made up the remaining 30%. The predominant metabolic pathways of tofacitinib included oxidation of the pyrrolopyrimidine and piperidine rings, oxidation of the piperidine ring side-chain, N-demethylation and glucuronidation. Cytochrome P450 (P450) profiling indicated that tofacitinib was mainly metabolized by CYP3A4, with a smaller contribution from CYP2C19. This pharmacokinetic characterization of tofacitinib has been consistent with its clinical experience in drug-drug interaction studies.


Asunto(s)
Hidrocarburo de Aril Hidroxilasas/metabolismo , Citocromo P-450 CYP3A/metabolismo , Quinasas Janus/antagonistas & inhibidores , Hígado/metabolismo , Piperidinas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/farmacocinética , Pirroles/farmacocinética , Biotransformación , Cromatografía Líquida de Alta Presión , Citocromo P-450 CYP2C19 , Heces/química , Femenino , Humanos , Hígado/enzimología , Espectroscopía de Resonancia Magnética , Masculino , Tasa de Depuración Metabólica , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Piperidinas/sangre , Piperidinas/metabolismo , Piperidinas/orina , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/orina , Pirimidinas/sangre , Pirimidinas/metabolismo , Pirimidinas/orina , Pirroles/sangre , Pirroles/metabolismo , Pirroles/orina , Espectrometría de Masas en Tándem
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