title: 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.
authors.affiliation: Metrum Institute, 2 Tunxis Road, Suite 112, Tariffville, Connecticut, 06081, USA, renae@metrumrg.com.
authors.forename: Rena J
authors.initials: RJ
authors.lastname: Eudy
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Riggs
authors.forename: Marc R
authors.initials: MR
authors.lastname: Gastonguay
mesh_terms: D016503:Drug Delivery Systems; D006801:Humans; D008954:Models, Biological; D008962:Models, Theoretical; D014018:Tissue Distribution