Cardiovascular and Metabolic Diseases Research

Cambridge, United Kingdom

Cardiovascular and Metabolic Diseases Research

Cambridge, United Kingdom
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Almquist J.,Fraunhofer Chalmers Center | Almquist J.,Chalmers University of Technology | Almquist J.,Astrazeneca | Penney M.,Clinical Pharmacology | And 8 more authors.
CPT: Pharmacometrics and Systems Pharmacology | Year: 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. © 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc.


Crombie A.L.,Pfizer | Antrilli T.M.,Cardiovascular and Metabolic Diseases Research | Campbell B.A.,Collegeville | Crandall D.L.,Cardiovascular and Metabolic Diseases Research | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

A series of biaryl amides containing an azabicyclooctane amine headpiece were synthesized and evaluated as mixed arginine vasopressin (AVP) receptor antagonists. Several analogues, including 8g, 12g, 13d, and 13g, were shown to have excellent V 1a- and good V 2-receptor binding affinities. Compound 13d was further profiled for drug-like properties and for an in vitro comparison with conivaptan, the program's mixed V 1a/V 2-receptor antagonist standard. © 2010 Elsevier Ltd.


PubMed | Fraunhofer Chalmers Center, Clinical Pharmacology and DMPK, Cardiovascular and Metabolic Diseases Research and Astrazeneca
Type: Journal Article | Journal: CPT: pharmacometrics & systems pharmacology | Year: 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.

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