title: Physiologically based pharmacokinetic models for everolimus and sorafenib in mice.
abstract: OBJECTIVE
  Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved as an immunosuppressant and for second-line therapy of hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Sorafenib is a multikinase inhibitor used as first-line therapy in HCC and RCC. This study assessed the pharmacokinetics (PK) of everolimus and sorafenib alone and in combination in plasma and tissues, developed physiologically based pharmacokinetic (PBPK) models in mice, and assessed the possibility of PK drug interactions.
  
  
  METHODS
  Single and multiple oral doses of everolimus and sorafenib were administered alone and in combination in immunocompetent male mice and to severe combined immune-deficient (SCID) mice bearing low-passage, patient-derived pancreatic adenocarcinoma in seven different studies. Plasma and tissue samples including tumor were collected over a 24-h period and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Distribution of everolimus and sorafenib to the brain, muscle, adipose, lungs, kidneys, pancreas, spleen, liver, GI, and tumor was modeled as perfusion rate-limited, and all data from the diverse studies were fitted simultaneously using a population approach.
  
  
  RESULTS
  PBPK models were developed for everolimus and sorafenib. PBPK analysis showed that the two drugs in combination had the same PK as each drug given alone. A twofold increase in sorafenib dose increased tumor exposure tenfold, thus suggesting involvement of transporters in tumor deposition of sorafenib.
  
  
  CONCLUSIONS
  The developed PBPK models suggested the absence of PK interaction between the two drugs in mice. These studies provide the basis for pharmacodynamic evaluation of these drugs in patient-derived primary pancreatic adenocarcinomas explants.
authors: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14260, USA.
authors: Dipti K
authors: DK
authors: Pawaskar
authors: Robert M
authors: RM
authors: Straubinger
authors: Gerald J
authors: GJ
authors: Fetterly
authors: Bonnie H
authors: BH
authors: Hylander
authors: Elizabeth A
authors: EA
authors: Repasky
authors: Wen W
authors: WW
authors: Ma
authors: William J
authors: WJ
authors: Jusko
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics; D002853:Chromatography, Liquid / Q000379:methods; D004347:Drug Interactions; D000068338:Everolimus; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008954:Models, Biological; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000077157:Sorafenib; D053719:Tandem Mass Spectrometry / Q000379:methods; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; D020123:Sirolimus