title: Two drug interaction studies of sirolimus in combination with sorafenib or sunitinib in patients with advanced malignancies.
abstract: OBJECTIVE
  Sirolimus is the prototypical mTOR inhibitor. Sorafenib and sunitinib are small molecule inhibitors of multiple kinases including VEGF receptor (VEGFR) kinases. These agents have different mechanisms of action, providing a strong rationale for combination.
  
  
  METHODS
  Patients with advanced cancer were assigned to receive either sirolimus or the VEGFR inhibitor alone for a 2-week lead-in period, followed by combination therapy. The primary end point of each trial was to determine whether a drug interaction exists between sirolimus and either sorafenib or sunitinib, as defined by a difference in C(max) for each drug alone compared with its C(max) during combination therapy.
  
  
  RESULTS
  The sorafenib and sunitinib trials enrolled 34 and 23 patients, respectively. There were no clinically significant differences in C(max) for any of the drugs alone compared with the C(max) during combination therapy. Toxicity profiles were similar to those expected for each drug alone. One patient with adrenal cortical cancer had a partial response to sirolimus and sunitnib.
  
  
  CONCLUSIONS
  Sirolimus can be safely combined with sorafenib or sunitinib. Our trial design is feasible and informative in screening for potential drug-drug interactions, using a relatively small number of patients and limited pharmacokinetic sampling.
authors: Division of Hematology and Oncology, University of Chicago, Chicago, Illinois 60637, USA.
authors: Tara C
authors: TC
authors: Gangadhar
authors: Ezra E W
authors: EE
authors: Cohen
authors: Kehua
authors: K
authors: Wu
authors: Linda
authors: L
authors: Janisch
authors: David
authors: D
authors: Geary
authors: Masha
authors: M
authors: Kocherginsky
authors: Larry K
authors: LK
authors: House
authors: Jackie
authors: J
authors: Ramirez
authors: Samir D
authors: SD
authors: Undevia
authors: Michael L
authors: ML
authors: Maitland
authors: Gini F
authors: GF
authors: Fleming
authors: Mark J
authors: MJ
authors: Ratain
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001557:Benzenesulfonates / Q000008:administration & dosage; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage; D000077157:Sorafenib; D000077210:Sunitinib; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001557:Benzenesulfonates; D007211:Indoles; D010671:Phenylurea Compounds; D011725:Pyridines; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D000077210:Sunitinib; D020123:Sirolimus