title: A comprehensive safety analysis confirms rhabdomyolysis as an uncommon adverse reaction in patients treated with trabectedin.
abstract: OBJECTIVE
  This analysis determined the incidence of serious rhabdomyolysis events reported during trabectedin treatment since the first phase I clinical trial in April 1996 up to September 2010.
  
  
  METHODS
  Search was done in the Yondelis(®) Pharmacovigilance and Clinical Trials databases using a list of terms according to the Medical Dictionary for Regulatory Activities (MedDRA, v. 13.1), followed by a medical review of all cases retrieved. Total estimated sample was 10,841 patients: 2,789 from clinical trials; 3,926 from compassionate use programs; and 4,126 treated in the marketplace. Two groups were identified: (1) rhabdomyolysis and (2) clinically relevant creatine phosphokinase (CPK) increases without acute renal failure (ARF). Descriptive analysis included demographic, clinical/laboratory data, and contributing/confounding factors. Potential predictive factors were evaluated by multivariate stepwise logistic regression analysis. Possible changes of pharmacokinetics (PK) in patients with rhabdomyolysis were explored using a population PK model.
  
  
  RESULTS
  The global incidence of rhabdomyolysis was 0.7%, and most cases occurred in Cycle 2 of treatment. The incidence of fatal cases was 0.3%. None of the variables evaluated to detect potential risk factors of rhabdomyolysis were predictive. Additionally, CPK increases (without ARF) were detected in 0.4% of patients as an incidental finding with good prognosis.
  
  
  CONCLUSIONS
  Rhabdomyolysis is an uncommon event during trabectedin treatment. Multivariate analyses did not show any potential factor that could be predictive or represent a significantly higher risk of developing rhabdomyolysis. Nevertheless, close patient monitoring and adherence to drug administration guidelines may help to limit the incidence of this event.
authors.affiliation: SC Oncologia, SS Antonio and Biagio and C Arrigo General Hospital, Alessandria, Italy. fgrosso@ospedale.al.it
authors.forename: Federica
authors.initials: F
authors.lastname: Grosso
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Mirela
authors.initials: M
authors.lastname: Cartoafa
authors.forename: Antonio
authors.initials: A
authors.lastname: Nieto
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Teruel
authors.forename: Vicente
authors.initials: V
authors.lastname: Alfaro
authors.forename: Pilar
authors.initials: P
authors.lastname: Lardelli
authors.forename: Elena
authors.initials: E
authors.lastname: Roy
authors.forename: Javier
authors.initials: J
authors.lastname: Gómez
authors.forename: Carmen
authors.initials: C
authors.lastname: Kahatt
authors.forename: Arturo
authors.initials: A
authors.lastname: Soto-Matos
authors.forename: Ian
authors.initials: I
authors.lastname: Judson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D001853:Bone Marrow / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004149:Dioxoles / Q000009:adverse effects*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012206:Rhabdomyolysis / Q000139:chemically induced*; D044005:Tetrahydroisoquinolines / Q000009:adverse effects*; D000077606:Trabectedin
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D065692:Cytochrome P-450 CYP3A Inhibitors; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D003402:Creatine Kinase; D000077606:Trabectedin