Unraveling the Pharmacokinetic Interaction of Ticagrelor and MEDI2452 (Ticagrelor Antidote) by Mathematical Modeling
Artikel i vetenskaplig tidskrift, 2016

The investigational ticagrelor-neutralizing antibody fragment, MEDI2452, is developed to rapidly and specifically reverse the antiplatelet effects of ticagrelor. However, the dynamic interaction of ticagrelor, the ticagrelor active metabolite (TAM), and MEDI2452, makes pharmacokinetic (PK) analysis nontrivial and mathematical modeling becomes essential to unravel the complex behavior of this system. We propose a mechanistic PK model, including a special observation model for post-sampling equilibration, which is validated and refined using mouse in vivo data from four studies of combined ticagrelor-MEDI2452 treatment. Model predictions of free ticagrelor and TAM plasma concentrations are subsequently used to drive a pharmacodynamic (PD) model that successfully describes platelet aggregation data. Furthermore, the model indicates that MEDI2452-bound ticagrelor is primarily eliminated together with MEDI2452 in the kidneys, and not recycled to the plasma, thereby providing a possible scenario for the extrapolation to humans. We anticipate the modeling work to improve PK and PD understanding, experimental design, and translational confidence.

Författare

Joachim Almquist

Chalmers, Biologi och bioteknik, Systembiologi

M. Penney

DMPK

S. Pehrsson

AstraZeneca AB

A. S. Sandinge

AstraZeneca AB

A. Janefeldt

AstraZeneca AB

S. Maqbool

DMPK

S. Madalli

MedImmune, Inc.

J. Goodman

DMPK

S. Nylander

AstraZeneca AB

Peter Gennemark

AstraZeneca AB

CPT: Pharmacometrics and Systems Pharmacology

2163-8306 (ISSN)

Vol. 5 6 313-323

Ämneskategorier

Farmakologi och toxikologi

DOI

10.1002/psp4.12089

Mer information

Senast uppdaterat

2018-03-21