title: Relationship between Pulmonary Adverse Events and Everolimus Exposure in Japanese and Non-Japanese Patients: A Meta-Analysis of Oncology Trials.
abstract: OBJECTIVE
  This meta-analysis explores the relationship between the everolimus minimum (Cmin) and maximum (Cmax) exposure and the risk for pulmonary adverse events (AEs) in Japanese versus non-Japanese patients.
  
  
  METHODS
  Patient-level data from patients treated with daily everolimus in advanced solid tumor trials were evaluated using a Cox regression model, stratified by cancer type or treatment arm, with log-transformed time-averaged Cmin or Cmax as a time-varying covariate. Kaplan-Meier analysis was used to evaluate the relationship between pulmonary AEs and pharmacokinetic parameters.
  
  
  RESULTS
  Thirty studies were identified. In the Cmin population (n = 1,962), all-grade pulmonary AE incidence was significantly higher in Japanese versus non-Japanese patients (19.9 vs. 9.4%). Pharmacokinetic parameters were similar between Japanese and non-Japanese patients. A 2-fold increase in everolimus Cmin significantly increased the risk for the first any-grade pulmonary AE in Japanese (risk ratio: 1.824; 95% CI: 1.141-2.918) and non-Japanese patients (risk ratio: 1.406; 95% CI: 1.156-1.710).
  
  
  CONCLUSIONS
  The risk for pulmonary AEs is related to everolimus exposure. Local monitoring and reporting differences might account for the significantly higher reported incidence of low-grade everolimus-associated pulmonary AEs in Japanese versus non-Japanese patients. Patients should be carefully monitored for early signs of pulmonary AEs, and appropriate medical management should be implemented.
authors.affiliation: Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Shinzaburo
authors.initials: S
authors.lastname: Noguchi
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shinohara
authors.forename: Tetsuhide
authors.initials: T
authors.lastname: Ito
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.forename: Alain
authors.initials: A
authors.lastname: Ravaud
authors.forename: Guy
authors.initials: G
authors.lastname: Jerusalem
authors.forename: Nobutsugu
authors.initials: N
authors.lastname: Ohno
authors.forename: Jorge
authors.initials: J
authors.lastname: Gallo
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bouillaud
authors.forename: Jenna
authors.initials: J
authors.lastname: Fan
authors.forename: Norio
authors.initials: N
authors.lastname: Nonomura
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D044466:Asian People; D002986:Clinical Trials as Topic; D000068338:Everolimus / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D008171:Lung Diseases / Q000139:chemically induced*; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus
keywords: Lung pathology; Neoplasm; Pharmacokinetics; Solid tumor