Cardiology
`Cardiology
`
`Direct Thrombin Inhibitors for Anticoagulation
`Direct Thrombin Inhibitors for Anticoagulation
`
`Edith A Nutescu and Ann K Wittkowsky
`Edith A Nutescu and Ann K Wittkowsky
`
`OBJECTIVE: To review the progress in developing direct thrombin inhibitors (DTIs) for anticoagulation within the context of existing
`OBJECTIVE: To review the progress in developing direct thrombin inhibitors (DT's) for anticoagulation within the context of existing
`anticoagulation therapies.
`anticoagulation therapies.
`DATA SOURCES: Searches of MEDLINE (1993–June 2003) were conducted.
`DATA SOURCES: Searches of MEDLINE (1993—June 2003) were conducted.
`STUDY SELECTION AND DATA EXTRACTION: We examined English-language articles, human studies, and relevant animal studies,
`STUDY SELECTION AND DATA EXTRACTION: We examined English-language articles, human studies, and relevant animal studies,
`and obtained additional citations from the references of these articles.
`and obtained additional citations from the references of these articles.
`DATA SYNTHESIS: Because of its pivotal role in hemostasis, thrombin is a key therapeutic target in the treatment and prevention of
`DATA SYNTHESIS: Because of its pivotal role in hemostasis, thrombin is a key therapeutic target in the treatment and prevention of
`thromboembolic disorders. Conventional anticoagulant therapies, such as warfarin, unfractionated heparin, and low-molecular-
`thromboembolic disorders. Conventional anticoagulant therapies, such as warfarin, unfractionated heparin, and low-molecular-
`weight heparin, exert their pharmacologic action by indirect thrombin inhibition. Although these agents are effective, each has
`weight heparin, exert their pharmacologic action by indirect thrombin inhibition. Although these agents are effective, each has
`limitations, prompting a search for more effective, specific, better-tolerated, and convenient anticoagulants. The efficacy and safety
`limitations, prompting a search for more effective, specific, better-tolerated, and convenient anticoagulants. The efficacy and safety
`of factor Xa inhibitors are being investigated. Furthermore, the development of DTIs such as recombinant hirudin (lepirudin),
`of factor Xa inhibitors are being investigated. Furthermore, the development of DT's such as recombinant hirudin (lepirudin),
`bivalirudin, and argatroban continues. Challenges in the development of DT's include establishing a binding affinity for thrombin that
`bivalirudin, and argatroban continues. Challenges in the development of DTIs include establishing a binding affinity for thrombin that
`is not associated with excessive bleeding, attaining high thrombin specificity, achieving inhibition of both unbound and clot-bound
`is not associated with excessive bleeding, attaining high thrombin specificity, achieving inhibition of both unbound and clot-bound
`thrombin, and producing an effective, fixed-dose oral anticoagulant to improve the practicality of anticoagulation therapy.
`thrombin, and producing an effective, fixed-dose oral anticoagulant to improve the practicality of anticoagulation therapy.
`Ximelagatran, an oral DTI designed to meet these standards, is currently in Phase III clinical trials.
`Ximelagatran, an oral DTI designed to meet these standards, is currently in Phase III clinical trials.
`CONCLUSIONS: Significant progress has been made in developing DTIs. The recent emergence of orally administered DTIs may
`CONCLUSIONS: Significant progress has been made in developing DT's. The recent emergence of orally administered DT's may
`simplify the prevention and treatment of thrombosis.
`simplify the prevention and treatment of thrombosis.
`KEY WORDS: anticoagulants, direct thrombin inhibitors, thrombosis.
`KEY WORDS: anticoagulants, direct thrombin inhibitors, thrombosis.
`Ann Pharmacother 2004;38:99-109.
`Ann Pharmacother 2004;38:99-109.
`Published Online, 5 Dec 2003, www.theannals.com, DOI 10.1345/aph.1D066
`Published Online, 5 Dec 2003, www.theannals.com, DOI 10.1345/aph.1D066
`ACPE UNIVERSAL PROGRAM NUMBER: 407-000-04-003-H01
`ACPE UNIVERSAL PROGRAM NUMBER: 407-000-04-003-H01
`THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREW THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT
`
`
`
`Coagulation and platelet aggregation are the body’s pri-
`Coagulation and platelet aggregation are the body's pri-
`
`mary defenses against bleeding from vascular injury.
`mary defenses against bleeding from vascular injury.
`Coordinated responses by coagulation enzymes and platelets
`Coordinated responses by coagulation enzymes and platelets
`form an insoluble clot. However, inappropriate thrombosis
`form an insoluble clot. However, inappropriate thrombosis
`results in significant morbidity and mortality from disor-
`results in significant morbidity and mortality from disor-
`ders including venous thrombosis, pulmonary embolism,
`ders including venous thrombosis, pulmonary embolism,
`myocardial infarction (MI), and stroke. Anticoagulation
`myocardial infarction (MI), and stroke. Anticoagulation
`therapies indicated for the prevention and/or treatment of
`therapies indicated for the prevention and/or treatment of
`these conditions modify the coagulation system. Thrombin
`these conditions modify the coagulation system. Thrombin
`is the key effector enzyme responsible for the final step in
`is the key effector enzyme responsible for the final step in
`
`Author information provided at the end of the text.
`Author information provided at the end of the text.
`
`thrombus formation,1 and most anticoagulant medications
`thrombus formation,' and most anticoagulant medications
`inhibit thrombin generation or activity.
`inhibit thrombin generation or activity.
`The coagulation system is closely regulated, and throm-
`The coagulation system is closely regulated, and throm-
`bin generation is limited under basal conditions.2 However,
`bin generation is limited under basal conditions.2 However,
`after the coagulation system is triggered, the amount of
`after the coagulation system is triggered, the amount of
`thrombin present at the injury site increases rapidly. The
`thrombin present at the injury site increases rapidly. The
`extrinsic pathway of the coagulation system is triggered by
`extrinsic pathway of the coagulation system is triggered by
`the exposure of tissue factor released from injured tissues
`the exposure of tissue factor released from injured tissues
`to blood. Following binding with factor VIIa, the tissue
`to blood. Following binding with factor VIIa, the tissue
`factor/factor VIIa complex converts factor X to factor Xa
`factor/factor Vila complex converts factor X to factor Xa
`(Figure 1).2 In the presence of calcium ions and a phospho-
`(Figure 1).2 In the presence of calcium ions and a phospho-
`lipid surface (provided by activated platelets), factor Xa
`lipid surface (provided by activated platelets), factor Xa
`binds with factor Va to form the prothrombinase complex,
`binds with factor Va to form the prothrombinase complex,
`
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`The Annals of Pharmacotherapy • 2004 January, Volume 38 • 99
`The Annals of Pharmacotherapy I 2004 January, Volume 38 I 99
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`MYLAN - EXHIBIT 1029
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`

`

`EA Nutescu and AK Wittkowsky
`EA Nutescu and AK Wittkowsky
`
`which converts prothrombin to thrombin. Thrombin cat-
`which converts prothrombin to thrombin. Thrombin cat-
`alyzes the proteolytic cleavage of fibrinogen to form fibrin
`alyzes the proteolytic cleavage of fibrinogen to form fibrin
`monomers, which subsequently polymerize. Stabilization
`monomers, which subsequently polymerize. Stabilization
`of the resultant fibrin polymers is facilitated by the throm-
`of the resultant fibrin polymers is facilitated by the throm-
`bin-mediated activation of factor XIIIa, forming an insolu-
`bin-mediated activation of factor XIlla, forming an insolu-
`ble gel, which, together with aggregated platelets, compris-
`ble gel, which, together with aggregated platelets, compris-
`es the hemostatic plug.
`es the hemostatic plug.
`Thrombin amplifies its own generation, resulting in a
`Thrombin amplifies its own generation, resulting in a
`burst of thrombin activity. Once a small amount of throm-
`burst of thrombin activity. Once a small amount of throm-
`bin is present, more is produced via the intrinsic pathway
`bin is present, more is produced via the intrinsic pathway
`by thrombin activation of factors XI and VIII, leading to
`by thrombin activation of factors XI and VIII, leading to
`formation of the tenase complex. Thrombin also stimulates
`formation of the tenase complex. Thrombin also stimulates
`the extrinsic pathway by activating factor V and accelerat-
`the extrinsic pathway by activating factor V and accelerat-
`ing formation of the prothrombinase complex (Figure 1).1
`ing formation of the prothrombinase complex (Figure 1).'
`It also potently activates platelets,3 thereby creating the
`It also potently activates platelets,3 thereby creating the
`phospholipid surface on which these reactions occur.
`phospholipid surface on which these reactions occur.
`Once present, thrombin has several antifibrinolytic func-
`Once present, thrombin has several antifibrinolytic func-
`tions, including activation of factor XIII, which crosslinks
`tions, including activation of factor XIII, which crosslinks
`fibrin strands and contributes to crosslinking of α-2 an-
`fibrin strands and contributes to crosslinking of a-2 an-
`tiplasmin (the principal inhibitor of plasmin) to fibrin, and
`tiplasmin (the principal inhibitor of plasmin) to fibrin, and
`activation of thrombin-activatable fibrinolysis inhibitor.
`activation of thrombin-activatable fibrinolysis inhibitor.
`Additionally, thrombin participates in negative feedback
`Additionally, thrombin participates in negative feedback
`loops to maintain hemostasis by activating protein C,
`loops to maintain hemostasis by activating protein C,
`which inactivates factors Va and VIIIa.4
`which inactivates factors Va and VIlla.4
`
`Traditional Anticoagulant Therapies
`Traditional Anticoagulant Therapies
`
`Traditional anticoagulants are indirect thrombin in-
`Traditional anticoagulants are indirect thrombin in-
`hibitors: warfarin, unfractionated heparin (UFH), and low-
`hibitors: warfarin, unfractionated heparin (UFH), and low-
`molecular-weight heparins (LMWHs). The Food and Drug
`molecular-weight heparins (LMWHs). The Food and Drug
`Administration–approved indications for these medica-
`Administration-approved indications for these medica-
`tions are described in Appendix I.5
`tions are described in Appendix I.
`
`WARFARIN
`WARFARIN
`
`Warfarin interferes with vitamin K– dependent carboxy-
`Warfarin interferes with vitamin K- dependent carboxy-
`lation of several coagulation factors including prothrombin
`lation of several coagulation factors including prothrombin
`(factor II), VII, IX, and X, as well as the anticoagulant pro-
`(factor II), VII, IX, and X, as well as the anticoagulant pro-
`teins C and S.6 Warfarin’s full anticoagulant effect may not
`teins C and S.° Warfarin's full anticoagulant effect may not
`be achieved until >5 days after treatment initiation or any
`be achieved until >5 days after treatment initiation or any
`change in dose because depletion of the active coagulation
`change in dose because depletion of the active coagulation
`factors is gradual. Therefore, additional anticoagulant ther-
`factors is gradual. Therefore, additional anticoagulant ther-
`apy, typically UFH or an LMWH, is required during the
`apy, typically UFH or an LMWH, is required during the
`initiation of therapy and periods of significant underantico-
`initiation of therapy and periods of significant underantico-
`agulation.7
`agulation.7
`Patient response to warfarin varies considerably. The av-
`Patient response to warfarin varies considerably. The av-
`erage daily dose to maintain patients within the appropriate
`erage daily dose to maintain patients within the appropriate
`therapeutic range is 4–5 mg, but can range from <1 to >20
`therapeutic range is 4-5 mg, but can range from <1 to >20
`mg/day. Age, hepatic function, underlying disease states,
`mg/day. Age, hepatic function, underlying disease states,
`and patient-specific metabolic characteristics (ie, cyto-
`and patient-specific metabolic characteristics (ie, cyto-
`chrome P450 isoenzymes) influence dosing requirements.8
`chrome P450 isoenzymes) influence dosing requirements .°
`Interactions with dietary vitamin K, numerous medications
`Interactions with dietary vitamin K, numerous medications
`including herbal and other natural products, and lifestyle is-
`including herbal and other natural products, and lifestyle is-
`sues also influence patient response to warfarin.
`sues also influence patient response to warfarin.
`Warfarin treatment is associated with a significant risk
`Warfarin treatment is associated with a significant risk
`for bleeding, with a cumulative incidence at 48 months
`for bleeding, with a cumulative incidence at 48 months
`ranging from 3% in low-risk patients to 53% in highest-
`ranging from 3% in low-risk patients to 53% in highest-
`risk patients.9 A portion of this risk is due to the narrow
`risk patients.9 A portion of this risk is due to the narrow
`therapeutic window associated with warfarin, which re-
`therapeutic window associated with warfarin, which re-
`quires that therapy be carefully maintained within an appro-
`quires that therapy be carefully maintained within an appro-
`priate therapeutic range, monitored using the international
`priate therapeutic range, monitored using the international
`normalized ratio (INR). The need for frequent testing and
`normalized ratio (INR). The need for frequent testing and
`dose adjustments detracts from warfarin’s ease of use in clin-
`dose adjustments detracts from warfarin's ease of use in clin-
`ical practice.7,8 Warfarin activity can be reversed by admin-
`ical practice.7,8 Warfarin activity can be reversed by admin-
`istration of vitamin K or infusion of coagulation factors.
`istration of vitamin K or infusion of coagulation factors.
`
`TF + FVIla
`
`FX
`
`•
`
`FV
`
`FXI
`
`FIX
`
`FXIa
`)
`
`FVIII
`
`)
`
`FIXa + FVIlla
`(Ca", phospholipid)
`
`Tenase complex
`
`FXa + FVa
`(Ca", phospholipid)
`Prothrombinase complex
`
`Prothrombin
`
`THROMBIN
`
`FXIII
`41/4 FXIIIa
`
`Fibrinogen
`
`Fibrin
`(soluble)
`
`I. Fibrin
`(insoluble)
`
`Hemostatic
`plug
`
`EXTRINSIC PATHWAY
`
`INTRINSIC PATHWAY
`
`Figure 1. The coagulation system. F = factor; T = tissue. Adapted with permission.2
`Figure 1. The coagulation system. F = factor; T = tissue. Adapted with permission.2
`
`HEPARINS
`HEPARINS
`
`UFH is a heterogeneous mixture of gly-
`UFH is a heterogeneous mixture of gly-
`cosaminoglycans. Because of the size hetero-
`cosaminoglycans. Because of the size hetero-
`geneity of heparin preparations (3000–30 000
`geneity of heparin preparations (3000-30 000
`Da; mean 15 000), only one-third of the hep-
`Da; mean 15 000), only one-third of the hep-
`arin molecules in a given preparation exhibit
`arin molecules in a given preparation exhibit
`anticoagulant activity.10 UFH exerts its antico-
`anticoagulant activity.'° UFH exerts its antico-
`agulant effect via antithrombin. Heparin binds
`agulant effect via antithrombin. Heparin binds
`to and produces a conformational change in an-
`to and produces a conformational change in an-
`tithrombin, converting it into a rapid inhibitor
`tithrombin, converting it into a rapid inhibitor
`of thrombin (factor IIA) and factor Xa.
`of thrombin (factor HA) and factor Xa.
`UFH has a short half-life (~1 h) and must be
`UFH has a short half-life (-1 h) and must be
`administered either subcutaneously or via con-
`administered either subcutaneously or via con-
`tinuous infusion.10 It is heavily sulfated and
`tinuous infusion.'° It is heavily sulfated and
`therefore has a high negative-charge density
`therefore has a high negative-charge density
`that promotes nonspecific binding to several
`that promotes nonspecific binding to several
`plasma and cellular proteins. This results in de-
`plasma and cellular proteins. This results in de-
`creased bioavailability, substantial interpatient
`creased bioavailability, substantial interpatient
`variability in anticoagulant response, and an
`variability in anticoagulant response, and an
`increased potential for bleeding and thrombotic
`increased potential for bleeding and thrombotic
`complications due to heparin–platelet interac-
`complications due to heparin-platelet interac-
`tions. Therefore, when given in therapeutic dos-
`tions. Therefore, when given in therapeutic dos-
`es, UFH requires frequent laboratory monitoring
`es, UFH requires frequent laboratory monitoring
`to assess the anticoagulation level, as measured
`to assess the anticoagulation level, as measured
`
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`

`

`by activated partial thromboplastin time (aPTT). Heparin re-
`by activated partial thromboplastin time (aPTT). Heparin re-
`quires frequent dosage adjustments, limiting its ease of use
`quires frequent dosage adjustments, limiting its ease of use
`in clinical practice.
`in clinical practice.
`Although heparin can be reversed by protamine, its use
`Although heparin can be reversed by protamine, its use
`is complicated by the potential for bleeding. In addition,
`is complicated by the potential for bleeding. In addition,
`heparin-induced thrombocytopenia (HIT), which may oc-
`heparin-induced thrombocytopenia (HIT), which may oc-
`cur in up to 5% of exposed patients, causes significant ve-
`cur in up to 5% of exposed patients, causes significant ve-
`nous and arterial thrombosis and is associated with a high
`nous and arterial thrombosis and is associated with a high
`mortality rate.10 Osteoporosis can also develop in long-
`mortality rate.'° Osteoporosis can also develop in long-
`term users.
`term users.
`The development of LMWHs in the late 1970s resulted
`The development of LMWHs in the late 1970s resulted
`from the discovery that shorter heparin chains (3800–5000
`from the discovery that shorter heparin chains (3800-5000
`Da) sufficiently enhance the anti-factor Xa activity of an-
`Da) sufficiently enhance the anti-factor Xa activity of an-
`tithrombin. LMWHs are derived by the chemical or enzy-
`tithrombin. LMWHs are derived by the chemical or enzy-
`matic depolymerization of UFH and inactivate thrombin to
`matic depolymerization of UFH and inactivate thrombin to
`a lesser extent than UFH because smaller molecular frag-
`a lesser extent than UFH because smaller molecular frag-
`ments cannot bind thrombin and antithrombin simultane-
`ments cannot bind thrombin and antithrombin simultane-
`ously. Therefore, LMWHs inhibit factor Xa more than
`ously. Therefore, LMWHs inhibit factor Xa more than
`they inhibit thrombin.10 They have better bioavailability
`they inhibit thrombin.'° They have better bioavailability
`and a longer half-life than UFH and are administered sub-
`and a longer half-life than UFH and are administered sub-
`cutaneously either once or twice daily, which is convenient
`cutaneously either once or twice daily, which is convenient
`in clinical practice. LMWHs display reduced binding to
`in clinical practice. LMWHs display reduced binding to
`plasma and cellular proteins and have a more predictable
`plasma and cellular proteins and have a more predictable
`dose response than UFH. Thus, monitoring anticoagula-
`dose response than UFH. Thus, monitoring anticoagula-
`tion intensity and dose adjustments are generally unneces-
`tion intensity and dose adjustments are generally unneces-
`sary. Protamine cannot be used for adequate reversal be-
`sary. Protamine cannot be used for adequate reversal be-
`cause it only partially reverses LMWH. HIT type II occurs
`cause it only partially reverses LMWH. HIT type II occurs
`much less often with LMWH than with UFH. However,
`much less often with LMWH than with UFH. However,
`LMWH crossreacts with antibodies against UFH and should
`LMWH crossreacts with antibodies against UFH and should
`not be given as an alternative anticoagulant in patients with
`not be given as an alternative anticoagulant in patients with
`new-onset HIT or a history of HIT.
`new-onset HIT or a history of HIT.
`Recent research has investigated the feasibility of deliver-
`Recent research has investigated the feasibility of deliver-
`ing UFH or LMWH orally via a delivery agent, such as sodi-
`ing UFH or LMWH orally via a delivery agent, such as sodi-
`um N-[8(-2-hydroxybenzoyl) amino] caprylate (SNAC)11 or
`um N-[8(-2-hydroxybenzoyl) amino] caprylate (SNAC)" or
`conjugates of deoxycholic acid (DOCA).12 SNAC-heparin
`conjugates of deoxycholic acid (DOCA)." SNAC-heparin
`recently failed to show better efficacy than enoxaparin in a
`recently failed to show better efficacy than enoxaparin in a
`Phase III trial of 2264 patients.13 Poor adherence in the
`Phase III trial of 2264 patients.'3 Poor adherence in the
`SNAC-heparin group due to the poor taste of the liquid
`SNAC-heparin group due to the poor taste of the liquid
`preparation may have affected these results. Current re-
`preparation may have affected these results. Current re-
`search is directed at developing improved oral formula-
`search is directed at developing improved oral formula-
`tions.
`tions.
`
`Targeted Anticoagulation
`Targeted Anticoagulation
`
`Potential targets within the coagulation system are being
`Potential targets within the coagulation system are being
`explored to develop anticoagulant therapies with improved
`explored to develop anticoagulant therapies with improved
`effectiveness, safety, and ease of use. The anticoagulants in
`effectiveness, safety, and ease of use. The anticoagulants in
`development generally seek specific molecular targets for
`development generally seek specific molecular targets for
`a predictable anticoagulant effect. This mechanism may
`a predictable anticoagulant effect. This mechanism may
`avoid the need for monitoring and dose adjustment. Signif-
`avoid the need for monitoring and dose adjustment. Signif-
`icant progress has recently been made in the development
`icant progress has recently been made in the development
`of factor Xa inhibitors and direct thrombin inhibitors (DTIs),
`of factor Xa inhibitors and direct thrombin inhibitors (DTIs),
`both of which ultimately prevent thrombin production.
`both of which ultimately prevent thrombin production.
`
`FACTOR XA INHIBITION
`FACTOR XA INHIBITION
`
`Fondaparinux is a synthetic version of the pentasaccha-
`Fondaparinux is a synthetic version of the pentasaccha-
`ride sequence of UFH and LMWH that binds to antithrom-
`ride sequence of UFH and LMWH that binds to antithrom-
`
`Direct Thrombin Inhibitors for Anticoagulation
`Direct Thrombin Inhibitors for Anticoagulation
`
`bin and modifies its conformation, inhibiting factor Xa.14
`bin and modifies its conformation, inhibiting factor Xa."
`Fondaparinux is administered by subcutaneous injection
`Fondaparinux is administered by subcutaneous injection
`and does not require anticoagulation monitoring due to its
`and does not require anticoagulation monitoring due to its
`predictable pharmacokinetic profile and stable dose re-
`predictable pharmacokinetic profile and stable dose re-
`sponse. It has a long half-life (17–21 h), allowing once-
`sponse. It has a long half-life (17-21 h), allowing once-
`daily administration,14-16 and is renally excreted. It has no
`daily administration,'446 and is renally excreted. It has no
`known antidote. Due to the lack of hepatic metabolism,
`known antidote. Due to the lack of hepatic metabolism,
`fondaparinux is not responsible for drug interactions medi-
`fondaparinux is not responsible for drug interactions medi-
`ated by cytochrome P450.17 Unlike the heparins, fonda-
`ated by cytochrome P450.'7 Unlike the heparins, fonda-
`parinux does not affect platelet function, nor does it inhibit
`parinux does not affect platelet function, nor does it inhibit
`platelet aggregation stimulated by various agonists.16,18,19 In
`platelet aggregation stimulated by various agonists.1648" In
`vitro studies suggest that fondaparinux does not react with
`vitro studies suggest that fondaparinux does not react with
`heparin platelet factor 4 antibodies, thus potentially elimi-
`heparin platelet factor 4 antibodies, thus potentially elimi-
`nating the risk of HIT.18,19 This observation has not been
`nating the risk of HIT."'" This observation has not been
`confirmed in vivo; additional studies are needed to eluci-
`confirmed in vivo; additional studies are needed to eluci-
`date the potential of using fondaparinux in patients with
`date the potential of using fondaparinux in patients with
`HIT.
`HIT.
`Fondaparinux was approved in the US for the preven-
`Fondaparinux was approved in the US for the preven-
`tion of venous thromboembolism (VTE) following hip and
`tion of venous thromboembolism (VTE) following hip and
`knee replacement and hip fracture surgeries (Appendix I).
`knee replacement and hip fracture surgeries (Appendix I).
`Ongoing studies may support its use for additional indica-
`Ongoing studies may support its use for additional indica-
`tions.20,21
`tions."'"
`Additional factor Xa inhibitors are in development.
`Additional factor Xa inhibitors are in development.
`Idraparinux, a compound closely related to fondaparinux
`Idraparinux, a compound closely related to fondaparinux
`that can be given by injection once weekly, has completed
`that can be given by injection once weekly, has completed
`Phase II trials in patients with proximal deep vein throm-
`Phase II trials in patients with proximal deep vein throm-
`bosis (DVT).21 Direct factor Xa inhibitors for parenteral de-
`bosis (DVT)." Direct factor Xa inhibitors for parenteral de-
`livery in early development include FXV673, RPR130737,22
`livery in early development include FXV673, RPR130737,22
`ZK807834 (CI-1031),23 M55113,24 SF303, and SK509.25
`ZK807834 (CI-1031),23 M55113," SF303, and SK509."
`Oral direct factor Xa inhibitors, such as DX-9065A,26
`Oral direct factor Xa inhibitors, such as DX-9065A,26
`DPC423,27 and JTV-803,28 are also being investigated.
`DPC423,27 and JTV-803,28 are also being investigated.
`
`DIRECT THROMBIN INHIBITION
`DIRECT THROMBIN INHIBITION
`
`As thrombin is the central effector of coagulation and
`As thrombin is the central effector of coagulation and
`amplifies its own production (Figure 1), it is a natural tar-
`amplifies its own production (Figure 1), it is a natural tar-
`get for pharmacologic intervention. Several DTIs are in
`get for pharmacologic intervention. Several DTIs are in
`clinical use (Appendix I). Acronyms for clinical trials are
`clinical use (Appendix I). Acronyms for clinical trials are
`defined in Appendix II.
`defined in Appendix II.
`DTIs target sites on the thrombin molecule responsible
`DTIs target sites on the thrombin molecule responsible
`for substrate recognition and/or cleavage (Figure 2).29 The
`for substrate recognition and/or cleavage (Figure 2).29 The
`substrate recognition site (exosite 1) acts as a docking sta-
`substrate recognition site (exosite 1) acts as a docking sta-
`tion, binding thrombin to fibrinogen prior to its enzymatic
`tion, binding thrombin to fibrinogen prior to its enzymatic
`actions. The catalytic site (active site) is responsible for the
`actions. The catalytic site (active site) is responsible for the
`enzymatic actions of thrombin, including activation of
`enzymatic actions of thrombin, including activation of
`platelets and cleavage of fibrinogen for thrombus forma-
`platelets and cleavage of fibrinogen for thrombus forma-
`tion.30 By blocking either the active site alone or both the
`tion." By blocking either the active site alone or both the
`active site and exosite 1, DTIs specifically inhibit thrombin
`active site and exosite 1, DTIs specifically inhibit thrombin
`activity.
`activity.
`Conversely, heparin-activated antithrombin binds to the
`Conversely, heparin-activated antithrombin binds to the
`active site of thrombin, but also blocks the fibrin-binding
`active site of thrombin, but also blocks the fibrin-binding
`site (Figure 1). Thus, when thrombin and fibrin are already
`site (Figure 1). Thus, when thrombin and fibrin are already
`bound, which occurs within a fibrin clot, heparin is unable
`bound, which occurs within a fibrin clot, heparin is unable
`to inactivate thrombin.31 Because DTIs do not bind to the
`to inactivate thrombin.3' Because DTIs do not bind to the
`fibrin-binding site, they can bind both unbound and fibrin-
`fibrin-binding site, they can bind both unbound and fibrin-
`bound thrombin, preventing the dual processes of throm-
`bound thrombin, preventing the dual processes of throm-
`bus initiation and propagation. Based on these pharmaco-
`bus initiation and propagation. Based on these pharmaco-
`logic properties, DTIs may be more potent than traditional
`logic properties, DTIs may be more potent than traditional
`
`www.theannals.com
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`The Annals of Pharmacotherapy n 2004 January, Volume 38 n 101
`The Annals of Pharmacotherapy I 2004 January, Volume 38 I 101
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`EA Nutescu and AK Wittkowsky
`EA Nutescu and AK Wiaktnvsky
`
`anticoagulants. In addition, they are not inhibited by platelet
`anticoagulants. In addition, they are not inhibited by platelet
`factor 4 or associated with the development of HIT.
`factor 4 or associated with the development of HIT.
`Properties of an ideal DTI include high selectivity for
`Properties of an ideal DTI include high selectivity for
`thrombin, rapid onset/offset of action, predictable pharma-
`thrombin, rapid onset/offset of action, predictable pharma-
`cokinetics and pharmacodynamics, lack of drug interac-
`cokinetics and pharmacodynamics, lack of drug interac-
`tions, a wide therapeutic window to prevent thrombosis
`tions, a wide therapeutic window to prevent thrombosis
`while minimizing bleeding, inhibition of unbound and
`while minimizing bleeding, inhibition of unbound and
`clot-bound thrombin, and oral administration.
`clot-bound thrombin, and oral administration.
`
`Hirudins
`Hirudins
`The first DTI to become available was hirudin, a 65-
`The first DTI to become available was hirudin, a 65-
`amino-acid polypeptide (7000 Da) originally obtained
`amino-acid polypeptide (7000 Da) originally obtained
`from the salivary glands of the medicinal leech (Hirudo
`from the salivary glands of the medicinal leech (Hirudo
`rnedicinalis). Although hirudin is not commercially avail-
`medicinalis). Although hirudin is not commercially avail-
`able, derivatives produced by recombinant technology
`able, derivatives produced by recombinant technology
`have been developed. Lepirudin is available in the US (Ap-
`have been developed. Lepirudin is available in the US (Ap-
`pendix I), and desirudin has been investigated in Europe.
`pendix I), and desirudin has been investigated in Europe.
`Hirudins are potent and specific thrombin inhibitors,32
`Hirudins are potent and specific thrombin inhibitors,32
`forming a stoichiometric and very slowly reversible com-
`forming a stoichiometric and very slowly reversible com-
`plex by binding to both the active site and exosite 1 of the
`plex by binding to both the active site and exosite 1 of the
`thrombin molecule (Figure 2). As a result of this bivalent
`thrombin molecule (Figure 2). As a result of this bivalent
`binding, hirudins are the most potent inhibitors of throm-
`binding, hirudins are the most potent inhibitors of throm-
`bin. The potency of inhibition is expressed as the inhibition
`bin. The potency of inhibition is expressed as the inhibition
`constant, which is the dissociation constant for the in-
`constant, which is the dissociation constant for the in-
`hibitor-enzyme complex. Smaller inhibition constants (lit-
`hibitor-enzyme complex. Smaller inhibition constants (lit-
`tle dissociation) are associated with stronger inhibition.
`tle dissociation) are associated with stronger inhibition.
`The inhibition constant for hirudin is 0.1-23 prnol/L.
`The inhibition constant for hirudin is 0.1–2.3 pmol/L.
`Due to the almost irreversible nature of the bond be-
`Due to the almost irreversible nature of the bond be-
`tween lepirudin and thrombin, bleeding problems have
`tween lepirudin and thromb