title: Sunitinib for metastatic renal cell cancer patients: observational study highlighting the risk of important drug-drug interactions.
abstract: OBJECTIVE
  Sunitinib, a CYP3A4 substrate, is standard of care treatment in metastatic renal cell carcinoma (mRCC) and is administered orally as a single dose of 50 mg, in a 4 weeks on/2 weeks off regimen. Frequently, dose reduction is necessary because of toxicity, as is the association of comedication to treat side effects. In addition, existing comorbidities in these patients necessitate the intake of various classes of chronic medication. Only limited data are available on the risk of drug-drug interactions (DDI). The objective of our paper was to evaluate prescribed dose, comedication, risk of drug-drug interactions and outcome among patients with mRCC treated with sunitinib.
  
  
  METHODS
  A single-centre, retrospective analysis was performed for patients with mRCC treated with sunitinib. The drug interaction databases 'Clinical Pharmacology' and 'Lexicomp' were used to screen for possible interactions.
  
  
  CONCLUSIONS
  The hospital files of 36 patients with mRCC were evaluated. Twenty-two patients received sunitinib as first-line treatment. Progression-free survival (PFS) in this first-line group was longer for patients that started with full-dose sunitinib (21·1 months; n = 12) than for patients started on reduced dose (3·5 months; n = 10). In the whole group of 36 patients, an average of 6·8 comedications was taken. Possible pharmacodynamic drug-drug interactions were most frequently found (47%) and reported as major interactions (QT prolongation). Risk of pharmacokinetic interactions due to co-administration of CYP inhibitors, CYP inducers, CYP substrates and PgP substrates was reported for 8%, 11%, 53% and 19%, respectively. These interactions were reported as major or moderate.
  
  
  CONCLUSIONS
  Patients with mRCC under treatment with sunitinib at a reduced starting dose had a decreased PFS compared with patients started with full-dose sunitinib. Due to adverse drug reactions and comorbidity, patients under sunitinib, a CYP3A4 substrate, took an average of 6·8 comedications provoking an important risk of major-to-moderate drug-drug interactions. With the help of a multidisciplinary team, avoidance of drug-drug interactions could be obtained. Moreover, serial ECG monitoring is recommended for patients at high risk of QT prolongation.
authors.affiliation: Department of Medical Oncology, Ghent University Hospital, Gent, Belgium; Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
authors.forename: V
authors.initials: V
authors.lastname: Kruse
authors.forename: A
authors.initials: A
authors.lastname: Somers
authors.forename: L
authors.initials: L
authors.lastname: Van Bortel
authors.forename: A
authors.initials: A
authors.lastname: De Both
authors.forename: S
authors.initials: S
authors.lastname: Van Belle
authors.forename: S
authors.initials: S
authors.lastname: Rottey
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012189:Retrospective Studies; D012307:Risk Factors; D000077210:Sunitinib
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib
keywords: adverse drug reactions; comedications; drug-drug interactions; metastatic renal cell cancer; sunitinib