Key result
A mechanistic pharmacokinetic model successfully described platelet aggregation data and indicated that MEDI2452-bound ticagrelor is primarily eliminated in the kidneys without recycling to the plasma.
Mathematical modeling of ticagrelor and its antidote MEDI2452 clarifies their complex pharmacokinetic interaction and suggests renal elimination of the bound complex, aiding future translational studies.
May aid PK-guided development of ticagrelor reversal; leaves open clinical validation and translation.
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.
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Almquist et al. (2016) studied this question. MEDI2452 (Ticagrelor antidote) was evaluated on Pharmacokinetic and pharmacodynamic modeling of free ticagrelor and TAM plasma concentrations and platelet aggregation. A mechanistic pharmacokinetic model successfully described platelet aggregation data and indicated that MEDI2452-bound ticagrelor is primarily eliminated in the kidneys without recycling to the plasma.
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