title: Human hepatocyte assessment of imatinib drug-drug interactions - complexities in clinical translation.
abstract: OBJECTIVE
  Inducers and inhibitors of CYP3A, such as ritonavir and efavirenz, may be used as part of the highly active antiretroviral therapy (HAART) to treat HIV patients. HIV patients with chronic myeloid leukemia or gastrointestinal stromal tumour may need imatinib, a CYP3A4 substrate with known exposure response-relationships. Administration of imatinib to patients on ritonavir or efavirenz may result in altered imatinib exposure leading to increased toxicity or failure of therapy, respectively. We used primary human hepatocyte cultures to evaluate the magnitude of interaction between imatinib and ritonavir/efavirenz.
  
  
  METHODS
  Hepatocytes were pre-treated with vehicle, ritonavir, ketoconazole, efavirenz or rifampicin, and the metabolism of imatinib was characterized over time. Concentrations of imatinib and metabolite were quantitated in combined lysate and medium, using LC-MS.
  
  
  RESULTS
  The predicted changes in imatinib CLoral (95% CI) with ketoconazole, ritonavir, rifampicin and efavirenz were 4.0-fold (0, 9.2) lower, 2.8-fold (0.04, 5.5) lower, 2.9-fold (2.2, 3.5) higher and 2.0-fold (0.42, 3.5) higher, respectively. These predictions were in good agreement with clinical single dose drug-drug interaction studies, but not with reports of imatinib interactions at steady-state. Alterations in metabolism were similar after acute or chronic imatinib exposure.
  
  
  CONCLUSIONS
  In vitro human hepatocytes predicted increased clearance of imatinib with inducers and decreased clearance with inhibitors of CYP enzymes. The impact of HAART on imatinib may depend on whether it is being initiated or has already been dosed chronically in patients. Therapeutic drug monitoring may have a role in optimizing imatinib therapy in this patient population.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Pittsburgh, PA.|Cancer Therapeutics program, University of Pittsburgh Cancer Institute, Pittsburgh, PA.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Pittsburgh, PA.
authors.forename: Venkateswaran C
authors.initials: VC
authors.lastname: Pillai
authors.affiliation: Cancer Therapeutics program, University of Pittsburgh Cancer Institute, Pittsburgh, PA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Parise
authors.affiliation: Cancer Therapeutics program, University of Pittsburgh Cancer Institute, Pittsburgh, PA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Christner
authors.affiliation: Cancer Therapeutics program, University of Pittsburgh Cancer Institute, Pittsburgh, PA.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Kiesel
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Pittsburgh, PA.|Cancer Therapeutics program, University of Pittsburgh Cancer Institute, Pittsburgh, PA.|Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology*; D003521:Cyclopropanes; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000378:metabolism* / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D061251:Primary Cell Culture; D012293:Rifampin / Q000494:pharmacology*; D019438:Ritonavir / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D000068877:Imatinib Mesylate; C098320:efavirenz; D019438:Ritonavir; D007654:Ketoconazole; D012293:Rifampin
keywords: HIV drugs; drug-drug interactions; human hepatocytes; imatinib