Dataset Information

Physiologically-based modeling to predict the clinical behavior of monoclonal antibodies directed against lymphocyte antigens.

ABSTRACT: Many clinically approved and investigational monoclonal antibody (mAb)-based therapeutics are directed against proteins located in the systemic circulation, including cytokines, growth factors, lymphocyte proteins, and shed antigens. Interaction between mAb and target may lead to non-linear pharmacokinetics (PK), characterized by rapid, target-mediated elimination. Several groups have reported that determinants of target-mediated elimination could include mAb-target binding, target expression, and target turnover. Recently, we scaled a physiologically-based pharmacokinetic model for mAb disposition to man and used it to predict the non-linear PK of mAbs directed against tumor epithelial proteins. In this work, we extended the previously described model to account for the influence of lymphocyte proteins on mAb PK in man. To account for the dynamic behavior of lymphocytes in the circulation, lymphocyte cycling between blood and lymphoid organs was described using first-order transfer rate constants. Use of lymphocyte cycling and reported target turnover rates in the model allowed the accurate prediction of the pharmacokinetics and pharmacodynamics (PD) of 4 mAbs (TRX1, MTRX1011a, rituximab, daclizumab) directed against 3 lymphocyte targets (CD4, CD20, CD25). The results described here suggest that the proposed model structure may be useful in the a priori prediction of the PK/PD properties of mAbs directed against antigens in the circulation.

SUBMITTER: Glassman PM

PROVIDER: S-EPMC5297519 | biostudies-literature | 2017 Feb/Mar

REPOSITORIES: biostudies-literature

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Physiologically-based modeling to predict the clinical behavior of monoclonal antibodies directed against lymphocyte antigens.

Glassman Patrick M PM Balthasar Joseph P JP

mAbs 20161128 2

Many clinically approved and investigational monoclonal antibody (mAb)-based therapeutics are directed against proteins located in the systemic circulation, including cytokines, growth factors, lymphocyte proteins, and shed antigens. Interaction between mAb and target may lead to non-linear pharmacokinetics (PK), characterized by rapid, target-mediated elimination. Several groups have reported that determinants of target-mediated elimination could include mAb-target binding, target expression, a ...[more]

PMID: 27892793

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Project description:Minimal physiologically-based pharmacokinetic (mPBPK) models provide a sensible modeling approach when fitting only plasma (or blood) data yielding physiologically-relevant PK parameters that may provide more practical value than parameters of mammillary models. We propose a second-generation mPBPK model specifically for monoclonal antibodies (mAb) by including (lumping) several essential components of mAb PK used in full PBPK models. These components include convection as the primary mechanism of antibody movement from plasma into tissues and return to plasma with interstitial fluid as the major extravascular distribution space. The model divides tissue spaces into two groups according to their vascular endothelial structure, leaky and tight, which consequently allows discernment of two types and general sites of distribution. This mPBPK model was applied to two mAbs in mice and ten mAbs with linear kinetics in humans. The model captured their plasma PK profiles well with predictions of concentrations in interstitial fluid for two types of tissues. Predictions of tissue concentrations for mAb 7E3 and 8C2 were consistent with actual measurements in mice, indicating the feasibility of this model in assessing extravascular distribution in the two categories of tissues. The vascular reflection coefficients (??) of tight tissues (V(tight)) ranged 0.883-0.987 and coefficients (??) for leaky tissues (V(leaky)) ranged 0.311 to 0.837. The plasma clearance (CL(p)) varied among the mAbs in humans from 0.0054 to 0.03 L/h. In addition, applying this model generates parameters for mAb transcapillary escape rates and assesses major sites of elimination. Four of ten mAbs exhibited better fitting statistics premised on elimination from interstitial fluid than from plasma. This approach allows comparisons of mAb PK when only plasma data are available, provides more realistic parameters and predictions than mammillary models, and may provide an intermediate step towards utilizing full PBPK models for mAbs.

Dataset Information

Physiologically-based modeling to predict the clinical behavior of monoclonal antibodies directed against lymphocyte antigens.

Publications

Physiologically-based modeling to predict the clinical behavior of monoclonal antibodies directed against lymphocyte antigens.

Similar Datasets

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