Dataset Information

FG-3019, a Human Monoclonal Antibody Recognizing Connective Tissue Growth Factor, is Subject to Target-Mediated Drug Disposition.

ABSTRACT: To evaluate and model the pharmacokinetic and pharmacodynamic behavior in rats of FG-3019, a human monoclonal antibody targeting connective tissue growth factor (CTGF).FG-3019, human CTGF (rhCTGF), or the N-terminal domain of rhCTGF were administered intravenously to rats and concentrations of these proteins as well as endogenous CTGF were determined by immunoassays. FG-3019, or (125)I-labeled FG-3019, and human CTGF (rhCTGF) were co-administered to assess the impact of CTGF on the elimination rate and tissue localization of FG-3019, which was further characterized by immunohistochemical analysis. A PK/PD model for target-mediated elimination of FG-3019 was developed to fit the kinetic data.FG-3019 exhibited non-linear pharmacokinetics in rats. Circulating concentrations of the N-terminal half of CTGF increased after dosing with FG-3019, reached maximal levels after 1-5 days, and returned toward baseline levels as FG-3019 cleared from the circulation, whereas the concentration of intact CTGF was unaffected by administration of FG-3019. Co-administration of rhCTGF dramatically enhanced the rate of FG-3019 elimination, redistributing the majority of (125)I-labeled FG-3019 from the blood to the liver, kidney, spleen and adrenal gland. FG-3019 co-administered with CTGF was found along the sinusoids of the liver and adrenal glands, the capillaries of the kidney glomeruli and in the spleen. A pharmacokinetic model for target-mediated elimination of FG-3019 was used to fit the time courses of FG-3019 and endogenous CTGF plasma concentrations, as well as time courses of rhCTGF and rhCTGF N-fragment after intravenous administration of these species.FG-3019 is subject to target mediated elimination in rats.

SUBMITTER: Brenner MC

PROVIDER: S-EPMC4942499 | biostudies-other | 2016 Aug

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

FG-3019, a Human Monoclonal Antibody Recognizing Connective Tissue Growth Factor, is Subject to Target-Mediated Drug Disposition.

Brenner Mitchell C MC Krzyzanski Wojciech W Chou James Z JZ Signore Pierre E PE Fung Cyra K CK Guzman David D Li Dongxia D Zhang Weihua W Olsen David R DR Nguyen Viet-Tam L VT Koo Carolyn W CW Sternlicht Mark D MD Lipson Kenneth E KE

Pharmaceutical research 20160408 8

<h4>Purpose</h4>To evaluate and model the pharmacokinetic and pharmacodynamic behavior in rats of FG-3019, a human monoclonal antibody targeting connective tissue growth factor (CTGF).<h4>Methods</h4>FG-3019, human CTGF (rhCTGF), or the N-terminal domain of rhCTGF were administered intravenously to rats and concentrations of these proteins as well as endogenous CTGF were determined by immunoassays. FG-3019, or (125)I-labeled FG-3019, and human CTGF (rhCTGF) were co-administered to assess the imp ...[more]

PMID: 27059922

Similar Datasets

Project description:Target-mediated drug disposition (TMDD) usually accounts for nonlinear pharmacokinetics (PK) of drugs whose distribution and/or clearance are affected by their targets owing to high affinity and limited capacity. TMDD is frequently reported for monoclonal antibodies (mAb) for such reason. Minimal physiologically-based pharmacokinetic models (mPBPK), which accommodate the unique PK behaviors of mAb, provide a general approach for analyzing mAbs PK and predicting mAb interstitial concentrations in two groups of tissues. This study assessed the feasibility of incorporating TMDD into mPBPK models to consider target-binding in either plasma (cTMDD) or interstitial fluid (ISF) (pTMDD). The dose-related signature profiles of the pTMDD model reveal a parallel early decay phase, in contrast with the cTMDD model that exhibits a faster initial decline for low doses. The parallel early phase in the pTMDD model is associated with the slow perivascular extravasation of mAb, which restricts the initial decline regardless of interstitial target-mediated elimination. The cTMDD and pTMDD models both preserve the long terminal phase that is typically perceived in conventional two-compartment (2CM) and TMDD models. Having TMDD in ISF impacts the typical relationships between plasma concentrations and receptor occupancy, and between saturation of apparent nonlinear clearance and saturation of receptors. The vascular reflection coefficient (? v ) was found to affect receptor occupancy in ISF. In the cTMDD model, saturation of nonlinear clearance is equivalent to saturation of receptors. However, in the pTMDD model, they are no longer equal and all parameters pertaining to receptors or receptor binding (R total , K D , K ss , k int ) shifts such relationships. Different TMDD models were utilized in analyzing PK for seven mAbs from digitized literature data. When the target is in plasma, the cTMDD model performed similarly to the 2CM and TMDD models, but with one less system parameter. When the target exists in ISF, the pTMDD functioned well in analyzing only plasma data to reflect interstitial target binding properties. Assigning TMDD consistent with target-expressing tissues is important to obtain reliable characterizations of receptors and receptor binding. The mPBPK model exhibits excellent feasibility in integrating TMDD not only in plasma but also in ISF.

Dataset Information

FG-3019, a Human Monoclonal Antibody Recognizing Connective Tissue Growth Factor, is Subject to Target-Mediated Drug Disposition.

Publications

FG-3019, a Human Monoclonal Antibody Recognizing Connective Tissue Growth Factor, is Subject to Target-Mediated Drug Disposition.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets