Rivaroxaban

Biological Activity

Rivaroxaban (Xarelto, BAY 59-7939) is oral direct factor Xa inhibitor with an IC50 value of 2.1nM. Rivaroxaban (Xarelto,BAY 59-7939) inhibits endogenous FXa more potently in human and rabbit plasma (IC50 = 21 nM) than in rat plasma (IC50 = 290 nM).Rivaroxaban (Xarelto,BAY 59-7939) also shows a similar affinity to purified human and rabbit FXa (IC50=0.7 nM and 0.8 nM, respectively), but a lesser potency against purified rat FXa (IC50 3.4 nM).

Protocol

Cell Experiment
Cell lines	L-MDR1 and Caco-2 cells line
Preparation method	Calculation of the Apparent Permeability Coefficient Values for Rivaroxaban. The apparent permeability coefficient (Papp) was calculated using eq. 1:where Papp is the apparent permeability, Vr is the volume of medium in the receiver chamber, C0 is the concentration of the test drug in the donor chamber at t = 0 h, S is the surface area of the monolayer, C2 is the concentration of the test drug in the acceptor chamber after 2 h of incubation, and t is the incubation time. For reference compounds, peak heights were used instead of concentrations.where Papp(B–A) and Papp(A–B) represent the apparent permeability of the test compound from the basolateral to apical and apical to basolateral sides of the cellular monolayer, respectively. The S.D. for the efflux ratio was calculated using eq. 3:where SD Papp(B–A) and SD Papp(A–B) represent the standard deviations of the apparent permeability of test compound from the basolateral to apical and apical to basolateral side of the cellular monolayer, respectively.
Concentrations	2 μM
Incubation time	2 h

Animal Experiment
Animal models	Rat venous stasis model
Formulation	dissolved in polyethylene glycol/H2O/ glycerol (996 g/100 g/60 g)
Dosages	0.03, 0.1 and 0.3mg/kg
Administration	intravenous (i.v.) bolus injection into a tail vein

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information

References

Rivaroxaban for stroke prevention in atrial fibrillation: a critical review of the ROCKET AF trial.
Paikin JS, et al. Expert Rev Cardiovasc Ther. 2012 Aug;10(8):965-72. PMID: 23030284.

Rivaroxaban Delivery and Reversal at a Venous Flow Rate.
Haynes LM, et al. Arterioscler Thromb Vasc Biol. 2012 Sep 27. PMID: 23023369.

Management consensus guidance for the use of rivaroxaban - an oral, direct factor Xa inhibitor.
Turpie AG, et al. Thromb Haemost. 2012 Sep 26;108(5). PMID: 23014816.

Assessment of the impact of rivaroxaban on coagulation assays: Laboratory recommendations for the monitoring of rivaroxaban and review of the literature.
Douxfils J, et al. Thromb Res. 2012 Sep 21. PMID: 23006523.

In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban.
Gnoth MJ, et al. J Pharmacol Exp Ther. 2011 Jul;338(1):372-80. PMID: 21515813.

In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939--an oral, direct Factor Xa inhibitor.
Perzborn E, et al. J Thromb Haemost. 2005 Mar;3(3):514-21. PMID: 15748242.