A. Hutchaleelaha, G. Lu, FR. Deguzman, MJ. Karbarz, M. Inagaki, S. Yau, PB. Conley, U. Sinha, SJ. Hollenbach
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1 Recombinant factor Xa inhibitor antidote (PRT064445) mediates reversal of anticoagulation through reduction of free drug concentration: A common mechanism for direct factor Xa inhibitors A. Hutchaleelaha, G. Lu, FR. Deguzman, MJ. Karbarz, M. Inagaki, S. Yau, PB. Conley, U. Sinha, SJ. Hollenbach Portola Pharmaceuticals, Inc, South San Francisco, United States of America
2 Disclosures for Hutchaleelaha et al All authors are employees of Portola Pharmaceuticals, Inc. 2
3 r-antidote: a recombinant human fxa variant lacking the membrane binding Gla-domain and active site serine Light Chain Heavy Chain S419A S419A Gla EGF1,2 S S Inactive Catalytic Domain EGF1,2 S S fxai PRT PRT (r-antidote) Unable to assemble into the prothrombinase complex and cleave prothrombin Retained binding ability for all fxa inhibitors 3
4 r-antidote has a high affinity for fxa inhibitors FXa activity (mod/min) Control 2.5nM Rivaroxaban 5.0nM Rivaroxaban 7.5nM Rivaroxaban PRT (nm) Inhibitor r-antidote Kd (nm) fxa Ki (nm) Rivaroxaban * Apixaban * Betrixaban *Perzborn at al J Thromb Haemost 2005;3:514, 4 Pinto et al J Med Chem 2007; 50:5339
5 r-antidote completely reverses the activity of rivaroxaban in vitro and ex vivo In vitro in plasma Ex vivo in rat model 125 Human plasma+rivaroxaban (230nM) 5.0 Infusion of Rivaroxaban (0.25 mg/kg/hr) Bolus + Infusion of PRT (4 mg + 4 mg/hr) Anti-fXa (%) Rat plasma +rivaroxaban (230nM) Whole Blood PT (INR) + SD * Vehicle+Vehicle (n=4) Rivaroxaban+Vehicle (n=4) Rivaroxaban+PRT (n=4) * PRT ( M) Time (min) *P-value 0.01 (PRT vs. Rivaroxaban Alone) 5 ISTH 2009
6 Free drug concentration of rivaroxaban was well correlated with reversal of PD parameter 5.0 Infusion of Rivaroxaban (0.25 mg/kg/hr) Bolus + Infusion of PRT (4 mg + 4 mg/hr) Whole Blood PT (INR) + SD * Vehicle+Vehicle (n=4) Rivaroxaban+Vehicle (n=4) Rivaroxaban+PRT (n=4) * Time (min) *P-value 0.01 (PRT vs. Rivaroxaban Alone) Total and Unbound Rivaroxaban Plasma Conc (ng/ml) 1400 Rivaroxaban Alone: Total Rivaroxaban + (4+4) mg PRT064445: Total 1200 Rivaroxaban Alone : Unbound Rivaroxaban + (4+4) mg PRT064445: Unbound Infusion of Rivaroxaban Infusion of PRT Time (min)
7 Has free drug concentration been used as a surrogate marker for pharmacodynamic activity? Reversal of digoxin toxicity by decreasing free digoxin concentration with digoxin-specific Fab antibodies 7
8 Pharmacokinetic Aspects of Digoxin-Specific Fab Therapy in the Management of Digitalis Toxicity Michael R Ujhelyi 1 and Sylvie Robert 2 Clin Pharmacokinet 28(6): Within minutes of Fab dosing, there is a 10- to 30-fold increase in total digoxin conc and free digoxin conc decreases from 75-90% to 0-5% When free concentration rebounds beyond 0.8 ug/ml, signs and symptoms of digoxin reintoxication return in some patients 8
9 Apixaban 4.0 Infusion of Apixaban (0.5 mg/kg/hr) Bolus + Infusion of PRT (6 mg + 6 mg/hr) Whole Blood PT (INR) SD * * Apixaban + Vehicle (n=5) Vehicle + Vehicle (n=5) Apixaban + PRT (n=5) * Time (min) * p-value < 0.01 Apixaban + PRT vs Apixaban alone Apixaban Alone: Total Apixaban Alone: Unbound Apixaban + (6+6) mg PRT : Total Apixaban + (6+6) mg PRT064445: Unbound Infusion of PRT Total and Unbound Apixaban Plasma Conc (ng/ml) Infusion of Apixaban Time (min)
10 Betrixaban Betrixaban Alone: Total Betrixaban Alone: Unbound Betrixaban + (6+9) mg PRT064445: Total Betrixaban+ (6+9) mg PRT064445: Unbound Infusion of PRT Total and Unbound Betrixaban Plasma Conc (ng/ml) Infusion of Betrixaban Time (min)
11 Is free drug concentration correlated with correction of blood loss in animal model? Rabbit model of liver laceration* Anesthetized rabbits were treated with vehicle or rivaroxaban via IV bolus. After 30 minutes, PRT or vehicle was administered as a bolus injection Two liver lobes were lacerated (5X each lobe 1-cm long, 3-mm deep incisions) Lost blood was collected on pre-weighed gauze over 15 minutes Non-protein bound free fraction of rivaroxaban was separated by equilibrium dialysis and quantitated by LC- MS/MS Anti-fXa activity was measured by modified LMWH kit *Adapted from Godier et al, Anesthesiology 2012:116, 94 11
12 Free drug concentration correlated with correction of blood loss in animal model 40 *** * Blood Loss (gm) Unbound Rivaroxaban Conc (ng/ml) Vehicle Riva Riva+PRT Vehicle+PRT ***P (Riv a vs. Vehicle) = * P (Riv a+prt vs. Riv a) = P (Riv a+prt vs. Vehicle) = ns P (PRT vs. Vehicle) = ns Time (min) Rivaroxaban Rivaroxaban + PRT correction of peak anti-fxa units = 98% 12
13 Summary PRT (r-antidote) is a factor Xa derivative which reverses the anticoagulant activity of fxa inhibitors Reversal of anticoagulation in rats correlates to reversal of pharmacodynamic markers (anti-fxa units, PT/INR) Reversal is mediated through reduction of free fraction of fxa inhibitor in plasma Rivaroxaban mediated blood loss in rabbit liver laceration model was reduced by 85% upon administration of r-antidote Maximal reduction of free fraction of rivaroxaban ~ 98% Reduction of Anti-fXa activity = 98% Reversal of Prothrombin time = 74% r-antidote is currently in Phase 1 studies in healthy volunteers 13
14 Back Up 14
15 Blood Loss ± SD (gm) Reduction of Blood Loss in Rivaroxaban Anticoagulated Rabbits with PRT but not rfviia using Rabbit Liver Laceration Model P<0.01 P< P<0.001 P< Vehicle Rivaroxaban Rivaroxaban + PRT PRT alone Rivaroxaban + rviia rviia alone 15
16 Time (min) % Free Rivaroxaban Rivaroxaban alone Rivaroxaban + PRT
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