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A Priori Identifiability of Target-Mediated Drug Disposition Models and Approximations.

ABSTRACT: A priori identifiability of mathematical models assures that for a given input/output experiment, the parameter set has one unique solution within a defined space, independent of the experimental design. Many biologic therapeutics exhibit target-mediated drug disposition (TMDD), and use of the full compartmental model describing this system is well documented. In practice, estimation of the full parameter set for TMDD models, given real-world clinical data, is characterized by convergence difficulties and unstable solutions. Still, the formal assessment of the a priori identifiability of these systems has yet to be reported. The exact arithmetic rank (EAR) approach was used to test the a priori identifiability of a TMDD model as well as model approximations. The full TMDD and quasi-equilibrium/rapid binding (QE/RB), quasi-steady state (QSS), and Michaelis-Menten (MM) approximations were fully identifiable, a priori, regardless of whether observations were taken from a single or multiple compartments. The results of these identifiability analyses indicated that the difficulty with TMDD model convergence, a posteriori, lies in the experimental design, not in the mathematical identifiability in the lack of samples from several compartments. Experiments can be tailored to resolve these structurally non-identifiable parameters, notwithstanding practical implementation challenges. This work highlights the importance of identifiability analyses, specifically how they can influence experimental design and selection of the appropriate model structure to describe a dynamic biological system.

SUBMITTER: Eudy RJ

PROVIDER: S-EPMC4540726 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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A Priori Identifiability of Target-Mediated Drug Disposition Models and Approximations.

Eudy Rena J RJ Riggs Matthew M MM Gastonguay Marc R MR

The AAPS journal 20150616 5

A priori identifiability of mathematical models assures that for a given input/output experiment, the parameter set has one unique solution within a defined space, independent of the experimental design. Many biologic therapeutics exhibit target-mediated drug disposition (TMDD), and use of the full compartmental model describing this system is well documented. In practice, estimation of the full parameter set for TMDD models, given real-world clinical data, is characterized by convergence diffic ...[more]

PMID: 26077506

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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

A Priori Identifiability of Target-Mediated Drug Disposition Models and Approximations.

Publications

A Priori Identifiability of Target-Mediated Drug Disposition Models and Approximations.

Similar Datasets

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