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Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor

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Abstract

Apixaban is a potent, highly selective, reversible, oral, direct factor Xa (fXa) inhibitor in development for thrombosis prevention and treatment. The preclinical pharmacokinetic (PK) attributes of apixaban feature small volume of distribution (Vd), low systemic clearance (CL), and good oral bioavailability. Apixaban is well absorbed in rat, dog, and chimpanzee, with absolute oral bioavailability of approximately 50% or greater. The steady-state Vd of apixaban is approximately 0.5, 0.2, and 0.17 l/kg in rats, dogs, and chimpanzees, while CL is approximately 0.9, 0.04, and 0.018 l/h/kg, respectively. In vitro metabolic clearance of apixaban is also low. Renal clearance comprises approximately 10–30% of systemic clearance in rat, dog, and chimpanzee. Anti-fXa activity, prothrombin time (PT), and HEPTEST® clotting time (HCT) prolongation correlated well with plasma apixaban concentration in rat, dog and chimpanzee. There was no lag time between apixaban plasma concentration and the pharmacodynamic (PD) markers, suggesting a rapid onset of action of apixaban. The PK/PD analyses were performed using an inhibitory E max model for anti-fXa assay and a linear model for PT and HCT assays. The IC50 values for anti-fXa activity were 0.73 ± 0.03 and 1.5 ± 0.15 μM for rat and dog, respectively. The apparent K i values for PT were approximately 1.7, 6.6, and 4.8 μM for rat, dog and chimpanzee, respectively. The apparent K i for HCT was approximately 1.3 μM for dog. Apixaban exhibits desirable PK and PD properties for clinical development with good oral bioavailability, small Vd, low CL, and direct, predictable, concentration-dependent PD responses.

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Abbreviations

α1-AGP:

α1-Acid glycoprotein

AUCinf :

Area under concentration–time curve from 0 to infinity

AUC(0–24h) :

Area under concentration–time curve from 0 to 24 h

CL:

Clearance

CLint :

Intrinsic clearance

C max :

Maximum concentration

F :

Absolute bioavailability

fXa:

Factor Xa

HCT:

HEPTEST® clotting time

HSA:

Human serum albumin

IC50 :

Concentration required for 50% inhibition

K i :

Inhibition constant

LC–MS/MS:

Liquid chromatography–tandem mass spectrometry

MRT:

Mean residence time

PD:

Pharmacodynamics

PK:

Pharmacokinetics

PT:

Prothrombin time

t 1/2 :

Half-life

T max :

Time to maximum concentration

Vdss :

Volume of distribution at steady state

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Conflict of interest

The authors are current or former employees of Bristol-Myers Squibb. This study was sponsored by Bristol-Myers Squibb and Pfizer Inc.

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Authors and Affiliations

  1. Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, NJ, USA

    Kan He, Donglu Zhang, Bing He, James E. Grace Jr., Baomin Xin & Scott J. Grossman

  2. Discovery Chemistry, Bristol-Myers Squibb Company, Princeton, NJ, USA

    Donald J. P. Pinto, Patrick Y. S. Lam & Ruth R. Wexler

  3. Discovery Biology, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ, 08543, USA

    Joseph M. Luettgen, Pancras C. Wong & Robert M. Knabb

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  1. Kan He
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  2. Joseph M. Luettgen
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  4. Bing He
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Correspondence to Joseph M. Luettgen.

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He, K., Luettgen, J.M., Zhang, D. et al. Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor. Eur J Drug Metab Pharmacokinet 36, 129–139 (2011). https://doi.org/10.1007/s13318-011-0037-x

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