PMID- 28411279
OWN - NLM
STAT- MEDLINE
DCOM- 20180320
LR  - 20230120
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Print)
IS  - 0090-9556 (Linking)
VI  - 45
IP  - 7
DP  - 2017 Jul
TI  - Characterization and Interspecies Scaling of rhTNF-alpha Pharmacokinetics with 
      Minimal Physiologically Based Pharmacokinetic Models.
PG  - 798-806
LID - 10.1124/dmd.116.074799 [doi]
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a soluble cytokine and target of specific 
      monoclonal antibodies (mAbs) and other biologic agents used in the treatment of 
      inflammatory diseases. These biologics exert their pharmacological effects 
      through binding and neutralizing TNF-alpha, and thus they prevent TNF-alpha from 
      interacting with its cell surface receptors. The magnitude of the pharmacological 
      effects is governed not only by the pharmacokinetics (PK) of mAbs, but also by 
      the kinetic fate of TNF-alpha We have examined the pharmacokinetics of recombinant 
      human TNF-alpha (rhTNF-alpha) in rats at low doses and quantitatively characterized its 
      pharmacokinetic features with a minimal physiologically based pharmacokinetic 
      model. Our experimental and literature-digitalized PK data of rhTNF-alpha in rats 
      across a wide range of doses were applied to global model fitting. rhTNF-alpha 
      exhibits permeability rate-limited tissue distribution and its elimination is 
      comprised of a saturable clearance pathway mediated by tumor necrosis factor 
      receptor binding and disposition and renal filtration. The resulting model 
      integrated with classic allometry was further used for interspecies PK scaling 
      and resulted in model predictions that agreed well with experimental measurements 
      in monkeys. In addition, a semimechanistic model was proposed and applied to 
      explore the absorption kinetics of rhTNF-alpha following s.c. and other routes of 
      administration. The model suggests substantial presystemic degradation of rhTNF-alpha 
      for s.c. and i.m. routes and considerable lymph uptake contributing to the 
      overall systemic absorption through the stomach wall and gastrointestinal wall 
      routes of dosing. This report provides comprehensive modeling and key insights 
      into the complexities of absorption and disposition of a major cytokine.
CI  - Copyright (c) 2017 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Chen, Xi
AU  - Chen X
AD  - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical 
      Sciences (X.C., D.C.D, R.R.A, W.J.J.), and Department of Biological Sciences 
      (D.C.D, R.R.A), State University of New York at Buffalo, Buffalo, New York.
FAU - DuBois, Debra C
AU  - DuBois DC
AD  - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical 
      Sciences (X.C., D.C.D, R.R.A, W.J.J.), and Department of Biological Sciences 
      (D.C.D, R.R.A), State University of New York at Buffalo, Buffalo, New York.
FAU - Almon, Richard R
AU  - Almon RR
AD  - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical 
      Sciences (X.C., D.C.D, R.R.A, W.J.J.), and Department of Biological Sciences 
      (D.C.D, R.R.A), State University of New York at Buffalo, Buffalo, New York.
FAU - Jusko, William J
AU  - Jusko WJ
AD  - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical 
      Sciences (X.C., D.C.D, R.R.A, W.J.J.), and Department of Biological Sciences 
      (D.C.D, R.R.A), State University of New York at Buffalo, Buffalo, New York 
      wjjusko@buffalo.edu.
LA  - eng
GR  - R01 GM024211/GM/NIGMS NIH HHS/United States
GR  - R37 GM024211/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 - 20170414
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Recombinant Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Absorption, Physiological
MH  - Animals
MH  - Dose-Response Relationship, Drug
MH  - Haplorhini
MH  - Infusions, Subcutaneous
MH  - Injections, Intravenous
MH  - Injections, Subcutaneous
MH  - Male
MH  - *Models, Biological
MH  - Organ Specificity
MH  - Rats, Inbred Lew
MH  - Recombinant Proteins/*administration & dosage/blood/*pharmacokinetics
MH  - Species Specificity
MH  - Tissue Distribution
MH  - Tumor Necrosis Factor-alpha/*administration & dosage/blood/*pharmacokinetics
PMC - PMC5469399
EDAT- 2017/04/16 06:00
MHDA- 2018/03/21 06:00
PMCR- 2018/07/01
CRDT- 2017/04/16 06:00
PHST- 2016/12/23 00:00 [received]
PHST- 2017/04/12 00:00 [accepted]
PHST- 2017/04/16 06:00 [pubmed]
PHST- 2018/03/21 06:00 [medline]
PHST- 2017/04/16 06:00 [entrez]
PHST- 2018/07/01 00:00 [pmc-release]
AID - dmd.116.074799 [pii]
AID - DMD_074799 [pii]
AID - 10.1124/dmd.116.074799 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2017 Jul;45(7):798-806. doi: 10.1124/dmd.116.074799. Epub 2017 
      Apr 14.