Positioning Imatinib for Pulmonary Arterial Hypertension: A Dose Finding Phase 2 Study.

IF 19.3 1区医学 Q1 CRITICAL CARE MEDICINE American journal of respiratory and critical care medicine Pub Date : 2025-03-13 DOI:10.1164/rccm.202410-1929OC

Alexander M K Rothman, Sofia Villar, Jennifer Middleton, Andreas A Roussakis, Frances Varian, Hamza Zafar, Martin Law, Jane Apperley, Imke H Bartelink, Medhat M Said, Juan A Delgado-SanMartin, David G Kiely, Luke Howard, Mark Toshner, S John Wort, Martin R Wilkins

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Abstract

Rationale: Imatinib 400mg daily reduces pulmonary vascular resistance and improves exercise capacity in patients with pulmonary arterial hypertension. Concerns about safety and tolerability limit its use.

Objectives: To identify a safe and tolerated dose of oral imatinib between 100mg and 400mg daily and evaluate its efficacy.

Methods: Oral imatinib was added to the background therapy of 17 patients with pulmonary arterial hypertension, including 13 implanted with devices providing daily measurements of cardiopulmonary haemodynamics and physical activity. The first patient started on 100mg daily. The next 12 patients, recruited serially, started on 200mg, 300mg or 400mg daily, following a Continuous Reassessment Method sequence. An extension cohort (patients 14 to 17) received 100mg or 200mg daily.

Measurements and main results: The Continuous Assessment Method recommended starting dose was 200mg daily. The most common side effect was nausea. Imatinib reduced mean pulmonary artery pressure (-6.5 mmHg, 95%CI -2.4 to -10.6, P<0.01) and total pulmonary resistance (-2.8 Wood Units, 95%CI -1.5 to -4.2, P<0.001) with no significant change in cardiac output. The reduction in total pulmonary resistance was dose and exposure-dependent; the reduction from baseline with imatinib 200mg daily was -20.3% (95%CI -14.3 to -26.3%). Total pulmonary resistance and night heart rate declined steadily over the first 28 days of treatment and remained below baseline up to 40 days following imatinib withdrawal.

Conclusions: Oral imatinib 200mg daily is well tolerated as an add-on treatment in pulmonary arterial hypertension. A delay in the return of cardiopulmonary haemodynamics to baseline was observed after stopping imatinib. Clinical trial registration available at www.

Clinicaltrials: gov, ID: NCT04416750 This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

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来源期刊

American journal of respiratory and critical care medicine 医学-呼吸系统

CiteScore

27.30

自引率

4.50%

发文量

1313

审稿时长

3-6 weeks

期刊介绍： The American Journal of Respiratory and Critical Care Medicine focuses on human biology and disease, as well as animal studies that contribute to the understanding of pathophysiology and treatment of diseases that affect the respiratory system and critically ill patients. Papers that are solely or predominantly based in cell and molecular biology are published in the companion journal, the American Journal of Respiratory Cell and Molecular Biology. The Journal also seeks to publish clinical trials and outstanding review articles on areas of interest in several forms. The State-of-the-Art review is a treatise usually covering a broad field that brings bench research to the bedside. Shorter reviews are published as Critical Care Perspectives or Pulmonary Perspectives. These are generally focused on a more limited area and advance a concerted opinion about care for a specific process. Concise Clinical Reviews provide an evidence-based synthesis of the literature pertaining to topics of fundamental importance to the practice of pulmonary, critical care, and sleep medicine. Images providing advances or unusual contributions to the field are published as Images in Pulmonary, Critical Care, Sleep Medicine and the Sciences. A recent trend and future direction of the Journal has been to include debates of a topical nature on issues of importance in pulmonary and critical care medicine and to the membership of the American Thoracic Society. Other recent changes have included encompassing works from the field of critical care medicine and the extension of the editorial governing of journal policy to colleagues outside of the United States of America. The focus and direction of the Journal is to establish an international forum for state-of-the-art respiratory and critical care medicine.