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TMDD Workshop at ACOP-2015

From: Leonid Gibiansky <lgibiansky>
Date: Mon, 24 Aug 2015 12:30:41 -0400

Dear All,
We plan to present a TMDD workshop at ACoP (October 8th, 2015, see
below) but the current enrollment is near the low boundary of workshop
acceptance limit. If you plan to attend, could you please register at
ACoP web site or let me know (by replying to me, not to nmusers group)
if you plan to attend.


A one day workshop on Modeling Biologics with Target-Mediated Disposition

The 1-day workshop is intended for PK scientists with or without prior
experience in population PK modeling of therapeutic proteins. It will
provide an overview of the PK of biologics, introduce target-mediated
drug disposition (TMDD) modeling concepts, and discuss some applications
of TMDD modeling to drug development of biologics. We will start with
the detailed introduction of the TMDD system. Equations that describe
the TMDD process will be introduced and implicit and explicit
assumptions of these equations will be reviewed. Characteristic features
of the TMDD system will be demonstrated on the simulated examples. Data
that are typically available for the analysis and assay properties will
be reviewed. It will be demonstrated why TMDD models are often
overparameterized and poorly identifiable. The hierarchy of TMDD
approximations (rapid binding, quasi-steady-state, irreversible binding,
and Michaelis-Menten) will be derived and discussed. Extensions of the
TMDD equations to more general systems, including antibody-drug
conjugates will be demonstrated. Experience-based recommendations for
modeling of TMDD systems will be discussed and demonstrated on case
studies. Nonmem control streams that implement TMDD equations and its
approximations will be provided. Biological considerations for choice of
TMDD approximations will be introduced. We will review allometric
scaling for FIH exposure predictions, covariates that may influence PK
properties of biologics, and possible drug-drug interactions. Methods
for detection, evaluation and modeling of immunogenicity will be
discussed. Use of different Nonmem estimation methods and
parallelization for TMDD models will be reviewed.

Part I: TMDD Model and Equations

Short introduction to biologics;
PK properties of biologics as related to their binding to targets;
Characteristic features of the target-mediated drug disposition;
Introduction of a target-mediated drug disposition (TMDD) system of
Implicit and explicit assumptions and how they translate into the TMDD
Assay properties; importance and difficulties in assessing drug and
target concentrations; free versus total drug and target concentration
Difficulties and possible solutions in application of TMDD;
Part II: TMDD Model Approximations: Derivations, Selection and Applications

Review and derivation of the TMDD model approximations;
TMDD and equations with Michaelis-Menten elimination;
Hierarchy of approximations of the TMDD system;
Identifiability of TMDD model parameters;
Modeling of drugs with TMDD: how to select correct approximation;
Biological considerations for choice of TMDD approximations;
Case study that demonstrates application of the introduced concepts on
the example of a population PK model development for a monoclonal
antibody with soluble target;
Part III: Applications to Drug Development of Biologics

TMDD approximations and indirect response model;
TMDD model for drugs that bind to more than one target;
Immunogenicity: detection, evaluation, and modeling;
Modeling of antibody-drug conjugates;
Subcutaneous absorption: modeling of absorption rate and bioavailability;
Prediction of human PK from animal data;
Covariates that could be important for PK of biologics;
Drug-drug interactions for biologics;
PK-PD modeling of biologics;
Part IV: Nonmem Implementation of the TMDD Equations

PK-PD case study: tocilizumab example.
Nonmem control streams for the full TMDD system and various approximations;
Nonmem control streams for possible generalizations of the TMDD equations:
- binding in tissues;
-TMDD system for drugs that bind to two targets;
Brief summary of experience using new estimation methods and
parallelization for TMDD models;
Brief review of the recent literature on TMDD modeling of biologics.
Questions and answers session.
Received on Mon Aug 24 2015 - 12:30:41 EDT

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