Dataset Information

Across-Species Scaling of Monoclonal Antibody Pharmacokinetics Using a Minimal PBPK Model.

ABSTRACT: To examine the across-species scalability of monoclonal antibody (mAb) pharmacokinetics (PK) and assess similarities in tissue distribution across species using a recently developed minimal PBPK (mPBPK) model.Twelve sets of antibody PK data from various species were obtained from the literature, which were jointly and individually analyzed. In joint analysis, vascular reflection coefficients for tissues with either tight (? 1 ) or leaky endothelium (? 2 ) were assumed consistent across species with systemic clearance allometrically scaled (CL?=?a?BW (b) ). Four parameters (? 1 , ? 2 , a, and b) were estimated in the joint analysis. In addition, the PK from each species was individually analyzed to assess species similarities in tissue distribution.Twelve mAb PK profiles were well-captured by the mPBPK model in the joint analysis. The estimated ? 1 ranged 0.690 to 0.999 with an average of 0.908; and ? 2 ranged 0.258 to 0.841 with an average of 0.579. Clearance was reasonably scaled and b ranged 0.695 to 1.27 averaging 0.91. Predictions of plasma concentrations for erlizumab and canakinumab in humans using parameters obtained from fitting animal data were consistent with actual measurements.Therapeutic mAbs given IV usually exhibit biexponential kinetics with their distribution properties best captured using physiological concepts. The mPBPK modeling approach may facilitate efforts in translating antibody distribution and overall PK across species.

SUBMITTER: Zhao J

PROVIDER: S-EPMC4580522 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Across-Species Scaling of Monoclonal Antibody Pharmacokinetics Using a Minimal PBPK Model.

Zhao Jie J Cao Yanguang Y Jusko William J WJ

Pharmaceutical research 20150505 10

<h4>Purpose</h4>To examine the across-species scalability of monoclonal antibody (mAb) pharmacokinetics (PK) and assess similarities in tissue distribution across species using a recently developed minimal PBPK (mPBPK) model.<h4>Methods</h4>Twelve sets of antibody PK data from various species were obtained from the literature, which were jointly and individually analyzed. In joint analysis, vascular reflection coefficients for tissues with either tight (σ 1 ) or leaky endothelium (σ 2 ) were ass ...[more]

PMID: 25939552

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Project description:Minimal physiologically based pharmacokinetic (mPBPK) models provide a simple and sensible approach that incorporates physiological elements into pharmacokinetic (PK) analysis when only plasma data are available. With this modeling concept, a second-generation mPBPK model was further developed with specific accommodations for the unique PK properties of monoclonal antibodies (mAb). This study applied this model to extensively survey mAb PK in man in order to seek general perspectives on mAb distributional and elimination features. Profiles for 72 antibodies were successfully analyzed with this model. The model results provide assessment regarding: (1) predominant clearance site, in plasma or interstitial fluid (ISF); (2) mAb ISF concentrations in two groups of lumped tissues with continuous (V(tight)) or fenestrated (V(leaky)) vascular endothelium; (3) Transcapillary escape rate (TER), an indicator of systemic vascular permeability. For 93% of surveyed mAbs, the model assuming clearance from plasma (CL) produced better or at least equivalent model performance than the model with clearance from ISF and yielded most consistent values of vascular reflection coefficients (?1 and ?2) among all antibodies. The average mAb ISF concentration in V(tight) and V(leaky) at equilibrium was predicted to be about 6.8 and 37.9% of that in plasma. A positive correlation was detected between plasma clearance and TER among most mAbs, which could be interpreted as both parameters having common determinants related to ISF tissue distribution in this model context. The mAbs with relative higher plasma clearance (>0.035 L/h/70 kg) did not reveal such positive correlation between clearance and TER, implying that the factors contributing to high clearance may not necessarily increase tissue distribution and penetration. In conclusion, this mPBPK model offers a more mechanistic approach for analyzing plasma mAb PK than compartment models and generates parameters providing useful intrinsic distributional and elimination insights for a large number of mAbs that were examined in man.

Dataset Information

Across-Species Scaling of Monoclonal Antibody Pharmacokinetics Using a Minimal PBPK Model.

Publications

Across-Species Scaling of Monoclonal Antibody Pharmacokinetics Using a Minimal PBPK Model.

Similar Datasets

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