title: Efficacy and Safety of Long-Term Sirolimus Therapy for Asian Patients with Lymphangioleiomyomatosis.
abstract: Sirolimus has been shown in a randomized, controlled clinical trial to stabilize lung function in patients with lymphangioleiomyomatosis (LAM) treated for a 12-month time period; however the pretreatment decline in lung function after the drug was discontinued indicated that continued exposure is required to suppress disease progression.
  
  
  
  To elucidate the durability and tolerability of long-term sirolimus treatment in Asian patients with LAM.
  
  
  
  We conducted a single-arm, open-label, investigator-initiated safety and efficacy study of sirolimus in 63 women with LAM at 9 sites in Japan. Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5-15 ng/ml.
  
  
  
  Fifty-two subjects (82.5%) completed the trial with mean drug compliance of more than 80% overall during the study. The number of adverse events was greatest during the initial 6 months of therapy, but they continued to occur with declining frequency throughout the 2-year study period. Of the 1,549 adverse events, 27 were classified as serious, including reversible sirolimus pneumonitis in 3 patients. New hypercholesterolemia occurred in 30 patients (48%); microcytosis in 10 patients; loss of body weight in 33 patients; and increase in blood pressure that required treatment in 5 patients. FEV1, FVC, and quality-of-life parameters were stable in the overall study cohort during the study period, but baseline to 2-year improvements in lung function occurred in the subset of patients with a prior history of chylothorax.
  
  
  
  Although long-term sirolimus treatment of Asian patients with LAM was associated with a large number of adverse events, including three episodes of pneumonitis, most patients completed the 2-year course of medication with good drug compliance and stable quality of life and lung function.
authors: 1 Uonuma Institute of Community Medicine.
authors: Toshinori
authors: T
authors: Takada
authors: 2 Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan.
authors: Ayako
authors: A
authors: Mikami
authors: 3 Protocol Data Center.
authors: Nobutaka
authors: N
authors: Kitamura
authors: 4 Division of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
authors: Kuniaki
authors: K
authors: Seyama
authors: 5 Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan.
authors: Yoshikazu
authors: Y
authors: Inoue
authors: 6 First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
authors: Katsura
authors: K
authors: Nagai
authors: 6 First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
authors: Masaru
authors: M
authors: Suzuki
authors: 7 Division of Respiratory Medicine.
authors: Hiroshi
authors: H
authors: Moriyama
authors: 1 Uonuma Institute of Community Medicine.|8 Bioscience Medical Research Center, and.
authors: Keiichi
authors: K
authors: Akasaka
authors: 8 Bioscience Medical Research Center, and.
authors: Ryushi
authors: R
authors: Tazawa
authors: 9 Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Toyohiro
authors: T
authors: Hirai
authors: 9 Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Michiaki
authors: M
authors: Mishima
authors: 10 First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors: Mie
authors: M
authors: Hayashida
authors: 5 Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan.
authors: Masaki
authors: M
authors: Hirose
authors: 5 Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan.
authors: Chikatoshi
authors: C
authors: Sugimoto
authors: 5 Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan.
authors: Toru
authors: T
authors: Arai
authors: 11 Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors: Noboru
authors: N
authors: Hattori
authors: 12 Department of Respiratory Medicine, Fukuoka University School of Medicine, Fukuoka, Japan.
authors: Kentaro
authors: K
authors: Watanabe
authors: 13 Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Tsutomu
authors: T
authors: Tamada
authors: 8 Bioscience Medical Research Center, and.
authors: Hirohisa
authors: H
authors: Yoshizawa
authors: 14 Department of Medical Informatics, Niigata University Medical and Dental Hospital, Niigata, Japan.
authors: Kohei
authors: K
authors: Akazawa
authors: 3 Protocol Data Center.
authors: Takahiro
authors: T
authors: Tanaka
authors: 15 Department of Clinical Pharmacology, Tokai University, Isehara, Japan.
authors: Keita
authors: K
authors: Yagi
authors: 16 Division of Pulmonary Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; and.
authors: Lisa R
authors: LR
authors: Young
authors: 17 Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio.
authors: Francis X
authors: FX
authors: McCormack
authors: 8 Bioscience Medical Research Center, and.
authors: Koh
authors: K
authors: Nakata
mesh_terms: D000328:Adult; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D006937:Hypercholesterolemia / Q000209:etiology; D007564:Japan; D008168:Lung / Q000503:physiopathology*; D018192:Lymphangioleiomyomatosis / Q000188:drug therapy*; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D015999:Multivariate Analysis; D011014:Pneumonia / Q000209:etiology; D011788:Quality of Life; D012044:Regression Analysis; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects*; D014797:Vital Capacity
chemical_list: D020123:Sirolimus
keywords: adverse events; lymphangioleiomyomatosis; sirolimus; tolerability