PMID- 17431753
OWN - NLM
STAT- MEDLINE
DCOM- 20070921
LR  - 20220716
IS  - 1567-567X (Print)
IS  - 1567-567X (Linking)
VI  - 34
IP  - 3
DP  - 2007 Jun
TI  - Physiologically based pharmacokinetic (PBPK) modeling of everolimus (RAD001) in 
      rats involving non-linear tissue uptake.
PG  - 373-400
AB  - Everolimus is a novel macrolide immunosuppressant developed for the prophylaxis 
      of allogeneic renal or cardiac transplant rejection. Treatments with 
      immunosuppressants are often associated with organ toxicity that is linked to 
      high organ exposure. Therefore, gaining insight into the pharmacokinetics of 
      everolimus in various organs is highly desirable especially those organs of 
      therapeutic interest or those that pose safety concerns. The aim of this work was 
      to characterize the disposition kinetics of everolimus in rats by physiologically 
      based pharmacokinetic (PBPK) modeling. Blood and tissue samples were collected 
      from male Wistar rats over 24 hr following intravenous (iv) bolus and iv infusion 
      of 1 mg/kg and 10 mg/kg/2 hr of everolimus. Further blood samples were collected 
      between 1 and 170 hr from a third group of rats, which received iv infusion of 1 
      mg/kg/2 hr of everolimus. Drug concentrations in blood and tissues were 
      determined by a liquid chromatography reverse dilution method. Distribution of 
      everolimus between blood fractions was determined in vitro at 37 degrees C. The 
      results of the study demonstrated that everolimus exhibited moderate non-linear 
      binding to red blood cells. Also, the tissue-to-blood concentration ratio 
      decreased in all tissues as blood concentration increased. A PBPK model involving 
      non-linear tissue binding was able to successfully describe the observed data in 
      blood and all the organs investigated. The highest binding potential was observed 
      in thymus, lungs, and spleen with the greatest tissue affinity observed in 
      thymus, skin, and muscle as compared to other tissues. Everolimus exhibited a 
      high clearance rate that was limited to the hepatic blood flow (47.2 ml/min/kg). 
      The PBPK model was also able to predict the venous blood concentration reasonably 
      well following oral administration. The oral bioavailability value, as estimated 
      with the PBPK, was 12% and was similar to the value obtained by non-compartmental 
      analysis. In conclusion, A PBPK model has been developed that successfully 
      predicts the time course of everolimus in blood and a variety of organs. This 
      model takes into account the non- linear binding of everolimus to red blood cells 
      and tissues. This model may be used to predict everolimus concentration-time 
      course in organs from other species including humans.
FAU - Laplanche, Robert
AU  - Laplanche R
AD  - Biomarker Development, Novartis Pharma AG, Basel, Switzerland.
FAU - Meno-Tetang, Guy M L
AU  - Meno-Tetang GM
FAU - Kawai, Ryosei
AU  - Kawai R
LA  - eng
PT  - Journal Article
DEP - 20070313
PL  - United States
TA  - J Pharmacokinet Pharmacodyn
JT  - Journal of pharmacokinetics and pharmacodynamics
JID - 101096520
RN  - 0 (Immunosuppressive Agents)
RN  - 9HW64Q8G6G (Everolimus)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Biological Availability
MH  - Erythrocytes/metabolism
MH  - Everolimus
MH  - Immunosuppressive Agents/administration & dosage/blood/*pharmacokinetics
MH  - Infusions, Intravenous
MH  - Injections, Intravenous
MH  - Liver Circulation
MH  - Male
MH  - *Models, Biological
MH  - *Nonlinear Dynamics
MH  - Rats
MH  - Rats, Wistar
MH  - Reproducibility of Results
MH  - Sirolimus/administration & dosage/*analogs & derivatives/blood/pharmacokinetics
MH  - Tissue Distribution
EDAT- 2007/04/14 09:00
MHDA- 2007/09/22 09:00
CRDT- 2007/04/14 09:00
PHST- 2006/07/30 00:00 [received]
PHST- 2007/01/30 00:00 [accepted]
PHST- 2007/04/14 09:00 [pubmed]
PHST- 2007/09/22 09:00 [medline]
PHST- 2007/04/14 09:00 [entrez]
AID - 10.1007/s10928-007-9051-7 [doi]
PST - ppublish
SO  - J Pharmacokinet Pharmacodyn. 2007 Jun;34(3):373-400. doi: 
      10.1007/s10928-007-9051-7. Epub 2007 Mar 13.