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| {{Drugbox
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| | Verifiedfields = changed
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| | verifiedrevid = 461744356
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| | IUPAC_name = N-(5-chloropyridin-2-yl)-2-([4-(N,N-dimethylcarbamimidoyl)benzoyl]amino)-5-methoxybenzamide
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| | image = Betrixaban_structure.png
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| | width = 200
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| <!--Clinical data-->
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| | tradename =
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| | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
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| | pregnancy_US = <!-- A / B / C / D / X -->
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| | pregnancy_category =
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| | legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
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| | legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
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| | legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
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| | legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
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| | legal_status =
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| | routes_of_administration =
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| <!--Pharmacokinetic data-->
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| | bioavailability =
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| | protein_bound =
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| | metabolism =
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| | elimination_half-life =
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| | excretion =
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| <!--Identifiers-->
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| | CAS_number_Ref = {{cascite|changed|??}}
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| | CAS_number = 330942-05-7
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| | ATC_prefix = none
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| | ChEMBL_Ref = {{ebicite|correct|EBI}}
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| | ChEMBL = 512351
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| | PubChem = 10275777
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| | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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| | DrugBank =
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| | UNII_Ref = {{fdacite|correct|FDA}}
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| | UNII = 74RWP7W0J9
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| | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
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| | ChemSpiderID = 18981107
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| | InChI = 1/C23H22ClN5O3/c1-29(2)21(25)14-4-6-15(7-5-14)22(30)27-19-10-9-17(32-3)12-18(19)23(31)28-20-11-8-16(24)13-26-20/h4-13,25H,1-3H3,(H,27,30)(H,26,28,31)
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| | InChIKey = XHOLNRLADUSQLD-UHFFFAOYAK
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| | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
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| | StdInChI = 1S/C23H22ClN5O3/c1-29(2)21(25)14-4-6-15(7-5-14)22(30)27-19-10-9-17(32-3)12-18(19)23(31)28-20-11-8-16(24)13-26-20/h4-13,25H,1-3H3,(H,27,30)(H,26,28,31)
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| | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
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| | StdInChIKey = XHOLNRLADUSQLD-UHFFFAOYSA-N
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|
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| <!--Chemical data-->
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| | C=23 | H=22 | Cl=1 | N=5 | O=3
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| | molecular_weight = 451.905 g/mol
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| | smiles = CN(C)C(=N)C1=CC=C(C=C1)C(=O)NC2=C(C=C(C=C2)OC)C(=O)NC3=NC=C(C=C3)Cl
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| }}
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| __NOTOC__
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| {{SI}}
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| {{CMG}}
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| ==Overview==
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| '''Betrixaban''' ([[International Nonproprietary Name|INN]], codenamed '''PRT-054,021''') is an [[anticoagulant]] drug which acts as a direct [[factor Xa]] inhibitor.<ref name="pmid19071881">{{cite journal |author=Eriksson BI, Quinlan DJ, Weitz JI |title=Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development |journal=Clinical Pharmacokinetics |volume=48 |issue=1 |pages=1–22 |year=2009 |pmid=19071881 |doi= |url=}}</ref> It is potent, orally active and highly selective for factor Xa, being selected from a group of similar compounds for its low [[hERG]] affinity.<ref name="pmid19297154">{{cite journal |author=Zhang P, Huang W, Wang L, Bao L, Jia ZJ, Bauer SM, Goldman EA, Probst GD, Song Y, Su T, Fan J, Wu Y, Li W, Woolfrey J, Sinha U, Wong PW, Edwards ST, Arfsten AE, Clizbe LA, Kanter J, Pandey A, Park G, Hutchaleelaha A, Lambing JL, Hollenbach SJ, Scarborough RM, Zhu BY |title=Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor |journal=Bioorganic & Medicinal Chemistry Letters |volume=19 |issue=8 |pages=2179–85 |year=2009 |month=April |pmid=19297154 |doi=10.1016/j.bmcl.2009.02.111 |url=}}</ref> Betrixaban has undergone human phase 1 and 2 [[clinical trials]] for prevention of [[pulmonary embolism]] after knee surgery,<ref name="pmid19132191">{{cite journal |author=Turpie AG, Bauer KA, Davidson BL, Fisher WD, Gent M, Huo MH, Sinha U, Gretler DD |title=A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT) |journal=Thrombosis and Haemostasis |volume=101 |issue=1 |pages=68–76 |year=2009 |month=January |pmid=19132191 |doi= |url=}}</ref> and prevention of [[stroke]] following [[atrial fibrillation]],<ref name="pmid20520539">{{cite journal |author=Piccini JP, Lopes RD, Mahaffey KW |title=Oral factor Xa inhibitors for the prevention of stroke in atrial fibrillation |journal=[[Curr. Opin. Cardiol.]] |volume=25 |issue=4 |pages=312–20 |year=2010 |month=July |pmid=20520539 |doi=10.1097/HCO.0b013e32833a524f |url=}}</ref>.<ref name="pmid19739042">{{cite journal |author=Sobieraj-Teague M, O'Donnell M, Eikelboom J |title=New anticoagulants for atrial fibrillation |journal=[[Semin. Thromb. Hemost.]] |volume=35 |issue=5 |pages=515–24 |year=2009 |month=July |pmid=19739042 |doi=10.1055/s-0029-1234147 |url=}}</ref>
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| ==Chemical Properties==
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| Betrixaban is a potent and specific inhibitor of human factor Xa (fXa) activity which acts by binding to the active site of fXa. Betrixaban as the maleate salt has a molecular weight (MW) of 567.98
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| ==Pharmacokinetics==
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| Betrixaban is available for oral administration as an immediate release capsule. It is rapidly absorbed with mean peak concentrations occurring 3-4 hours after oral administration. Oral bioavailability of an 80 mg dose is approximately 34% and protein binding is approximately 60%. The drug exhibits nonlinear kinetics within the expected therapeutic dosing range with greater than proportional increases in plasma concentrations occurring with increased dose; maximum plasma concentration (Cmax) and area under the curve (AUC) at steady-state increased approximately 3-fold when the dose was doubled from 40 mg to 80 mg. Excretion is mostly unchanged through the bile with renal clearance approximately 7-10% of the absorbed dose. When administered after a high-fat, high-calorie breakfast, Cmax and AUC were reduced by approximately 50% as compared to the fasting state.
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| Betrixaban is not a substrate for major cytochrome P450 enzymes. It is a substrate for efflux proteins including permeability glycoprotein (P-glycoprotein or P-gp). When co-administered with the potent P-gp inhibitor, ketoconazole, betrixaban concentrations were increased approximately 2-fold. Based on population pharmacokinetic (PK) analysis from the Phase II EXPLORE Xa study, a similar effect was observed when betrixaban was given concomitantly with amiodarone. A drug interaction study with the P-gp substrate, digoxin, showed no significant interaction, and one with the inhibitor verapamil suggests that co-administration in fasted state increases both Cmax and exposure to betrixaban.
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| ==Phase 1 and 2 Studies==
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| To date betrixaban has been studied in 22 Phase I and II studies performed in 1,411 normal healthy volunteers and patients (1,200 of whom received betrixaban). Of these, nineteen Phase I studies were conducted in 499 normal healthy volunteers (459 received betrixaban) and three Phase II studies were conducted in 697 patients with atrial fibrillation (AF) (570 received betrixaban and 127 received comparator drug) and in 215 post-surgical patients after knee replacement (171 received betrixaban and 43 received comparator drug, 1 patient did not receive study drug).
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| In Phase I studies enrolling healthy subjects, single doses between 5 and 550 mg were well tolerated, as were 10-day regimens of 40, 80 and 120 mg every 12 hours (H). In the EXPERT study <ref name="Cohen">Cohen A, Spiro TE, Buller HR et al. Rivaroxaban versus enoxaparin for the prevention of venous thromboembolism in acutely ill medical patients: analysis of factors contributing to benefit and risk in MAGELLAN. J Thromb Haemost 2011;9(Suppl s2):960.</ref> , betrixaban doses of 15 and 40 mg twice daily (BID) showed activity in the prevention of VTE after total knee replacement (TKR) when compared to historical control and a small concurrent enoxaparin control group. Major and minor bleeding rates were low and comparable between the betrixaban and enoxaparin treated groups. The results of the EXPERT study indicate that prophylaxis with betrixaban appeared comparable to optimal use of enoxaparin. Results of the EXPLORE Xa study (<ref name ="Collett">Collett A, Tanianis-Hughes J, Warhurst G. Rapid induction on P-glycoprotein expression by high permeability compounds in colonic cells in vitro: a possible source of transporter mediated drug interactions. Biochemical Pharmacology 2004;68:783-790.</ref>,<ref name="Haslam">Haslam I, Jones K, Coleman T, Simmons NL. Induction of P-glycoprotein expression and function in human intestinal epithelial cells (T84). Biochemical Pharmacology 2008;76:850-861.</ref>) demonstrate that once daily doses of 40, 60 and 80 mg for stroke prevention in patients with non-valvular AF were well tolerated with all doses of betrixaban having a favorable bleeding profile compared to warfarin. Very low rates of stroke in all treatment groups that were observed in this study suggests active anticoagulant effect.
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| ==References==
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| {{reflist|2}}
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| {{Antithrombotics}}
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| [[Category:Drug]]
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Anticoagulants]]
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