title: Phase 1 pharmacokinetic and drug-interaction study of dasatinib in patients with advanced solid tumors.
abstract: BACKGROUND
  The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once-daily dasatinib regimen.
  
  
  METHODS
  The authors conducted a phase 1 trial of dasatinib in 29 patients with advanced solid tumors. Segment 1 of the trial was short term and sequential and was designed to determine whether the coadministration of the potent CYP3A4 inhibitor ketoconazole had an effect on the pharmacokinetics of dasatinib. Segment 2 was designed to evaluate the safety of dasatinib as dosing was increased. QT intervals were monitored closely in both segments. Efficacy was assessed in Segment 2 using both positron emission tomography and computed tomography.
  
  
  RESULTS
  Hematologic toxicities were markedly less than those observed in patients with leukemia, whereas nonhematologic toxicities were similar. The authors determined that the maximum recommended dose was 180 mg once daily based on the incidence of pleural effusion. Coadministration of ketoconazole led to a marked increase in dasatinib exposure, which was correlated with an increase in corrected QT (QTc) values of approximately 6 msec. No adverse cardiac events were observed.
  
  
  CONCLUSIONS
  The dose-limiting toxic effect for dasatinib was pleural effusion. The pharmacokinetic and cardiac studies indicated that coadministration of dasatinib with potent CYP3A4 inhibitors or agents that prolong the QTc interval should be avoided if possible. Close monitoring for toxicity and dose reduction should be considered if the coadministration of such agents cannot be avoided.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, Unit 432, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA. fmjohns@mdanderson.org
authors.forename: Faye M
authors.initials: FM
authors.lastname: Johnson
authors.forename: Shruti
authors.initials: S
authors.lastname: Agrawal
authors.forename: Howard
authors.initials: H
authors.lastname: Burris
authors.forename: Lee
authors.initials: L
authors.lastname: Rosen
authors.forename: Navneet
authors.initials: N
authors.lastname: Dhillon
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.forename: Anne
authors.initials: A
authors.lastname: Blackwood-Chirchir
authors.forename: Feng R
authors.initials: FR
authors.lastname: Luo
authors.forename: Oumar
authors.initials: O
authors.lastname: Sy
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kaul
authors.forename: Alberto A
authors.initials: AA
authors.lastname: Chiappori
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D000069439:Dasatinib; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013844:Thiazoles / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; D000069439:Dasatinib