PMID- 23455451
OWN - NLM
STAT- MEDLINE
DCOM- 20130620
LR  - 20211021
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 71
IP  - 5
DP  - 2013 May
TI  - Physiologically based pharmacokinetic models for everolimus and sorafenib in 
      mice.
PG  - 1219-29
LID - 10.1007/s00280-013-2116-y [doi]
AB  - PURPOSE: 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.
FAU - Pawaskar, Dipti K
AU  - Pawaskar DK
AD  - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical 
      Sciences, State University of New York at Buffalo, Buffalo, NY 14260, USA.
FAU - Straubinger, Robert M
AU  - Straubinger RM
FAU - Fetterly, Gerald J
AU  - Fetterly GJ
FAU - Hylander, Bonnie H
AU  - Hylander BH
FAU - Repasky, Elizabeth A
AU  - Repasky EA
FAU - Ma, Wen W
AU  - Ma WW
FAU - Jusko, William J
AU  - Jusko WJ
LA  - eng
GR  - P30 CA016056/CA/NCI NIH HHS/United States
GR  - R01 GM057980/GM/NIGMS NIH HHS/United States
GR  - GM57980/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130303
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Phenylurea Compounds)
RN  - 25X51I8RD4 (Niacinamide)
RN  - 9HW64Q8G6G (Everolimus)
RN  - 9ZOQ3TZI87 (Sorafenib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adenocarcinoma/drug therapy/pathology
MH  - Administration, Oral
MH  - Animals
MH  - Antineoplastic Agents/administration & dosage/*pharmacokinetics
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics
MH  - Chromatography, Liquid/methods
MH  - Drug Interactions
MH  - Everolimus
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, SCID
MH  - *Models, Biological
MH  - Niacinamide/administration & dosage/*analogs & derivatives/pharmacokinetics
MH  - Pancreatic Neoplasms/drug therapy/pathology
MH  - Phenylurea Compounds/administration & dosage/*pharmacokinetics
MH  - Sirolimus/administration & dosage/*analogs & derivatives/pharmacokinetics
MH  - Sorafenib
MH  - Tandem Mass Spectrometry/methods
MH  - Tissue Distribution
PMC - PMC3755750
MID - NIHMS493089
COIS- Conflict of interest: None.
EDAT- 2013/03/05 06:00
MHDA- 2013/06/21 06:00
PMCR- 2014/05/01
CRDT- 2013/03/05 06:00
PHST- 2012/08/17 00:00 [received]
PHST- 2013/02/05 00:00 [accepted]
PHST- 2013/03/05 06:00 [entrez]
PHST- 2013/03/05 06:00 [pubmed]
PHST- 2013/06/21 06:00 [medline]
PHST- 2014/05/01 00:00 [pmc-release]
AID - 10.1007/s00280-013-2116-y [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2013 May;71(5):1219-29. doi: 
      10.1007/s00280-013-2116-y. Epub 2013 Mar 3.