PT  - JOURNAL ARTICLE
AU  - Xi Chen
AU  - Debra C DuBois
AU  - Richard R Almon
AU  - William J Jusko
TI  - Characterization and Interspecies Scaling of rhTNF-α Pharmacokinetics with Minimal Physiologically-Based Pharmacokinetic (mPBPK) Models
AID  - 10.1124/dmd.116.074799
DP  - 2017 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.116.074799
4099  - http://dmd.aspetjournals.org/content/early/2017/04/14/dmd.116.074799.short
4100  - http://dmd.aspetjournals.org/content/early/2017/04/14/dmd.116.074799.full
AB  - Tumor necrosis factor-α (TNF-α) is a soluble cytokine and target of specific monoclonal antibodies (mAbs) and other biological agents used for the treatment of inflammatory diseases. These biologics exert their pharmacological effects through binding and neutralizing TNF-α, and thus prevent TNF-α from interacting with its cell surface receptors. The magnitude of pharmacological effects is governed not only by the pharmacokinetics of mAbs, but also the kinetic fate of TNF-α. We have examined the pharmacokinetics of rhTNF-α in rats at low doses and quantitatively characterized its pharmacokinetic features with a minimal physiologically-based pharmacokinetic (mPBPK) model. Our experimental and literature-digitalized PK data of rhTNF-α in rats across a wide range of doses were applied for global model fitting. The rhTNF-α exhibits permeability rate-limited tissue distribution and its elimination is comprised of a saturable clearance pathway mediated by TNFR binding and disposition and renal filtration. The resulting model integrated with classic allometry was further utilized for interspecies PK scaling and resulted in model predictions that agreed well with experimental measurements in monkeys. In addition, a semi-mechanistic model was proposed and applied to explore the absorption kinetics of rhTNF-α following SC and other routes of administration. The model suggests substantial pre-systemic degradation of rhTNF-α for SC and IM routes and considerable lymph uptake contributing to the overall systemic absorption through the stomach (SW) and intestinal wall (GW) routes of dosing. This report provides comprehensive modeling and key insights into the complexities of absorption and disposition of a major cytokine.