Peringatan Keamanan

The acute toxicity of intravenous lepirudin was evaluated in mice (0.1-1000 mg/kg), rats (1-1000 mg/kg), and monkeys (1-100 mg/kg), and toxicity was not detected at the doses investigated.^L41539 The acute toxicity of lepirudin administered subcutaneously was also evaluated in mice (1-1250 mg/kg) and rats (1-500 mg/kg), and no toxicity was detected.^L41539 One rat (100 mg/kg) died of rapid blood loss after the subcutaneous administration of lepirudin. Reactions to local injections such as hemorrhages, hematomas and/or nodules were detected in mice and rats given subcutaneous doses of lepirudin equal or higher than 500 mg/kg and 10 mg/kg, respectively.^L41539

Chronic toxicity was evaluated in rats and monkeys given lepirudin for up to 3 months. Most of the effects observed were due to the antithrombotic action of lepirudin. After 3 months, hemosiderin deposits in the spleen and moderate sinus histiocytosis in the lymph node were observed in rats. In monkeys, external and internal hemorrhages and hematomas were detected.^L41539 Lepidurin was reported as not mutagenic.^L41539

Relative overdose may occur in patients with renal impairment, therefore, bolus dose and rate of infusion must be reduced in case of known or suspected renal insufficiency.^L41539 Excessively high activated partial thromboplastin time (aPTT) values suggest an overdose and a risk of bleeding. Lepirudin has no known antidote. In case of life-threatening bleeding and if excessive plasma levels of lepirudin are suspected: 1)stop the administration of lepirudin immediately, 2) determine aPTT and coagulation parameters, 3) determine hemoglobin, and prepare for a transfusion, 4) follow the treatment guidelines for patients with shock.^L41539 Hemofiltration or hemodialysis may be useful in case of overdose, based in single case reports and animal data.^L41539

Lepirudin

DB00001

biotech approved withdrawn

Deskripsi

Lepirudin is a recombinant hirudin formed by 65 amino acids that acts as a highly specific and direct thrombin inhibitor.L41539,L41569 Natural hirudin is an endogenous anticoagulant found in Hirudo medicinalis leeches.^L41539 Lepirudin is produced in yeast cells and is identical to natural hirudin except for the absence of sulfate on the tyrosine residue at position 63 and the substitution of leucine for isoleucine at position 1 (N-terminal end).^A246609

Lepirudin is used as an anticoagulant in patients with heparin-induced thrombocytopenia (HIT), an immune reaction associated with a high risk of thromboembolic complications.A3, L41539 HIT is caused by the expression of immunoglobulin G (IgG) antibodies that bind to the complex formed by heparin and platelet factor 4. This activates endothelial cells and platelets and enhances the formation of thrombi.^A246609 Bayer ceased the production of lepirudin (Refludan) effective May 31, 2012.^L41574

Struktur Molekul 2D

Struktur tidak tersedia

Peta Jejaring Molekuler

Obat Target Gen Interaksi Enzim Transporter Carrier

Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

1. Pendahuluan & Konsep

Fitur visualisasi ini dikembangkan menggunakan pendekatan Graph Theory untuk memetakan hubungan polifarmasi dan molekuler. Entitas (Obat, Target, Gen) direpresentasikan sebagai Simpul (Nodes), sedangkan hubungan biologisnya sebagai Sisi (Edges).

2. Sumber Data (Validasi)

Data Obat: Diekstraksi dari elemen drugbank-id dan name pada skema XML DrugBank.
Target Protein: Diambil dari elemen targets/target yang memuat polipeptida sasaran.
Genetik: Disinkronisasi dari sub-elemen gene-name dan varian snp-effects.
Genetik: Jumlah titik node dibatasi pada maksimal 10 (Slice=10) interaksi untuk menghindari tumpukan data.

3. Algoritma Visualisasi

Tata letak grafik menggunakan algoritma Force-Directed Graph (Barnes-Hut). Model fisika ini menerapkan gaya tolak-menolak antar simpul (Gravitasi: -3000) agar tidak tumpang tindih, serta gaya pegas (Spring: 0.04) pada garis penghubung untuk fleksibilitas interaksi.

4. Legenda Visual

Obat Utama (Pusat Analisis)

Target Protein (Mekanisme)

Gen (Faktor Genetik)

Metode ini mendukung analisis Precision Medicine dan evaluasi risiko Drug-Drug Interaction (DDI).

Profil Farmakokinetik

Waktu Paruh (Half-Life) Lepirudin has an initial half-life of approximately 10 minutes, and in young healthy volunteers, it has a terminal half-time of 1.3 hours.[L41539] Lepirudin has a first-order elimination kinetic; plasma concentration increases proportionally as the lepirudin intravenous dose is increased. Elimination half-life values of up to 2 days were detected in patients with marked renal insufficiency (creatinine clearance < 15 mL/min).[L41539]

Volume Distribusi The volume of distribution of lepirudin at steady state was 12.2 L in healthy young subjects (n=18, 18-60 years), 18.7 L in healthy elderly subjects (n=10, 65-80 years), 18.0 L in renally impaired subjects (n=16, creatinine clearance < 80 mL/min, and 32.1 L in heparin-induced thrombocytopenia patients (n=73).[L41539] The distribution of lepirudin is mainly restricted to extracellular fluids.[L41539]

Klirens (Clearance) The clearance of lepirudin is proportional to the glomerular filtration rate. On average, lepirudin clearance was 164 mL/min in healthy young subjects (n=18, 18-60 years) and 25% lower in women than in men. In healthy elderly subjects (n=10, 65-80 years), clearance was 139 mL/min, about 20% lower than in younger patients.[L41539] This is possibly due to the lower creatinine clearance in elderly patients. In renally impaired subjects (n=16, creatinine clearance < 80 mL/min), clearance was 61 mL/min, and in heparin-induced thrombocytopenia patients (n=73), it was 114 mL/min.[L41539]

Absorpsi

Lepirudin administered as a single intravenous bolus injection of 0.4 mg/kg in 9 healthy volunteers (male and female) resulted in a C_max of 2924 ng/mL, a t_max of 0.17 h and an AUC_0-? of 2500 ng•h/mL.^L41539 When 0.1, 0.15 and 0.2 mg/kg of lepirudin was administered as a single intravenous infusion over 6 hours in healthy male volunteers, lepirudin had a corresponding C_max of 111, 203, and 2446 ng/mL and a corresponding AUC of 612, 1184, and 1446 ng•h/mL.^L41544 Bioavailability is 100% following injection. Also, it has been reported that following subcutaneous (sc) administration, the bioavailability of lepirudin is almost 100%.^A246609

Metabolisme

As a polypeptide, lepirudin is expected to be metabolized by the sequential cleavage of amino acids by kidney exoproteases, which have carboxypeptidase and dipeptidase-like activity.L41539,L41544 The C-terminal cleavage of lepirudin aminoacids (aminoacids 1 to 65) produces four metabolites with anti-thrombotic activity: M1 (aminoacids 1 to 64), M2 (aminoacids 1 to 63), M3 (aminoacids 1 to 62), and M4 (aminoacids 1 to 61).^L41544

Rute Eliminasi

Lepirudin is mostly excreted through urine (48.3%). About 35% of lepirudin is excreted unchanged, while metabolites are found in a smaller proportion (2.5% of M1, 5.4% of M2, 3.9% of M3 and 1.6% of M4).^L41544

Interaksi Makanan

1 Data

1. Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include chamomile, garlic, ginger, ginkgo and ginseng.

Interaksi Obat

653 Data

Apixaban	Apixaban may increase the anticoagulant activities of Lepirudin.
Dabigatran etexilate	Dabigatran etexilate may increase the anticoagulant activities of Lepirudin.
Dasatinib	The risk or severity of bleeding and hemorrhage can be increased when Dasatinib is combined with Lepirudin.
Deferasirox	The risk or severity of gastrointestinal bleeding can be increased when Lepirudin is combined with Deferasirox.
Ursodeoxycholic acid	The risk or severity of bleeding and bruising can be increased when Lepirudin is combined with Ursodeoxycholic acid.
Glycochenodeoxycholic Acid	The risk or severity of bleeding and bruising can be increased when Lepirudin is combined with Glycochenodeoxycholic Acid.
Cholic Acid	The risk or severity of bleeding and bruising can be increased when Lepirudin is combined with Cholic Acid.
Glycocholic acid	The risk or severity of bleeding and bruising can be increased when Lepirudin is combined with Glycocholic acid.
Deoxycholic acid	The risk or severity of bleeding and bruising can be increased when Lepirudin is combined with Deoxycholic acid.
Taurocholic acid	The risk or severity of bleeding and bruising can be increased when Lepirudin is combined with Taurocholic acid.
Obeticholic acid	The risk or severity of bleeding and bruising can be increased when Lepirudin is combined with Obeticholic acid.
Chenodeoxycholic acid	The risk or severity of bleeding and bruising can be increased when Lepirudin is combined with Chenodeoxycholic acid.
Taurochenodeoxycholic acid	The risk or severity of bleeding and bruising can be increased when Lepirudin is combined with Taurochenodeoxycholic acid.
Tauroursodeoxycholic acid	The risk or severity of bleeding and bruising can be increased when Lepirudin is combined with Tauroursodeoxycholic acid.
Bamet-UD2	The risk or severity of bleeding and bruising can be increased when Lepirudin is combined with Bamet-UD2.
Dehydrocholic acid	The risk or severity of bleeding and bruising can be increased when Lepirudin is combined with Dehydrocholic acid.
Hyodeoxycholic Acid	The risk or severity of bleeding and bruising can be increased when Lepirudin is combined with Hyodeoxycholic Acid.
Edoxaban	The risk or severity of bleeding can be increased when Edoxaban is combined with Lepirudin.
Ibrutinib	The risk or severity of bleeding and hemorrhage can be increased when Ibrutinib is combined with Lepirudin.
Obinutuzumab	The risk or severity of bleeding and hemorrhage can be increased when Lepirudin is combined with Obinutuzumab.
Rivaroxaban	Lepirudin may increase the anticoagulant activities of Rivaroxaban.
Sugammadex	The risk or severity of bleeding and hemorrhage can be increased when Lepirudin is combined with Sugammadex.
Tibolone	Tibolone may increase the anticoagulant activities of Lepirudin.
Tipranavir	The risk or severity of bleeding and hemorrhage can be increased when Tipranavir is combined with Lepirudin.
Urokinase	Urokinase may increase the anticoagulant activities of Lepirudin.
Vitamin E	Vitamin E may increase the anticoagulant activities of Lepirudin.
Vorapaxar	The risk or severity of bleeding and hemorrhage can be increased when Vorapaxar is combined with Lepirudin.
Ginkgo biloba	Ginkgo biloba may increase the anticoagulant activities of Lepirudin.
Ifosfamide	The risk or severity of bleeding can be increased when Ifosfamide is combined with Lepirudin.
Quinine	The therapeutic efficacy of Lepirudin can be increased when used in combination with Quinine.
Quinidine	The therapeutic efficacy of Lepirudin can be increased when used in combination with Quinidine.
Tamoxifen	The risk or severity of bleeding can be increased when Tamoxifen is combined with Lepirudin.
Toremifene	The risk or severity of bleeding can be increased when Toremifene is combined with Lepirudin.
Pentoxifylline	The therapeutic efficacy of Lepirudin can be increased when used in combination with Pentoxifylline.
Pentosan polysulfate	Pentosan polysulfate may increase the anticoagulant activities of Lepirudin.
Levocarnitine	The therapeutic efficacy of Lepirudin can be increased when used in combination with Levocarnitine.
Diethylstilbestrol	Diethylstilbestrol may decrease the anticoagulant activities of Lepirudin.
Chlorotrianisene	Chlorotrianisene may decrease the anticoagulant activities of Lepirudin.
Conjugated estrogens	Conjugated estrogens may decrease the anticoagulant activities of Lepirudin.
Mestranol	The risk or severity of adverse effects can be increased when Mestranol is combined with Lepirudin.
Estrone sulfate	Estrone sulfate may decrease the anticoagulant activities of Lepirudin.
Quinestrol	Quinestrol may decrease the anticoagulant activities of Lepirudin.
Hexestrol	Hexestrol may decrease the anticoagulant activities of Lepirudin.
Synthetic Conjugated Estrogens, A	Synthetic Conjugated Estrogens, A may decrease the anticoagulant activities of Lepirudin.
Synthetic Conjugated Estrogens, B	Synthetic Conjugated Estrogens, B may decrease the anticoagulant activities of Lepirudin.
Polyestradiol phosphate	Polyestradiol phosphate may decrease the anticoagulant activities of Lepirudin.
Esterified estrogens	Esterified estrogens may decrease the anticoagulant activities of Lepirudin.
Zeranol	Zeranol may decrease the anticoagulant activities of Lepirudin.
Equol	Equol may decrease the anticoagulant activities of Lepirudin.
Methallenestril	Methallenestril may decrease the anticoagulant activities of Lepirudin.
Epimestrol	Epimestrol may decrease the anticoagulant activities of Lepirudin.
Moxestrol	Moxestrol may decrease the anticoagulant activities of Lepirudin.
Estradiol acetate	Estradiol acetate may decrease the anticoagulant activities of Lepirudin.
Estradiol benzoate	Estradiol benzoate may decrease the anticoagulant activities of Lepirudin.
Estradiol cypionate	Estradiol cypionate may decrease the anticoagulant activities of Lepirudin.
Estradiol valerate	Estradiol valerate may decrease the anticoagulant activities of Lepirudin.
Biochanin A	Biochanin A may decrease the anticoagulant activities of Lepirudin.
Formononetin	Formononetin may decrease the anticoagulant activities of Lepirudin.
Estriol	Estriol may decrease the anticoagulant activities of Lepirudin.
Limaprost	The risk or severity of bleeding can be increased when Limaprost is combined with Lepirudin.
Icosapent	The risk or severity of bleeding and hemorrhage can be increased when Icosapent is combined with Lepirudin.
Mesalazine	The risk or severity of bleeding can be increased when Mesalazine is combined with Lepirudin.
Indomethacin	The risk or severity of bleeding and hemorrhage can be increased when Indomethacin is combined with Lepirudin.
Nabumetone	The risk or severity of bleeding and hemorrhage can be increased when Nabumetone is combined with Lepirudin.
Ketorolac	The risk or severity of bleeding and hemorrhage can be increased when Ketorolac is combined with Lepirudin.
Tenoxicam	The risk or severity of bleeding and hemorrhage can be increased when Tenoxicam is combined with Lepirudin.
Celecoxib	The risk or severity of bleeding and hemorrhage can be increased when Celecoxib is combined with Lepirudin.
Tolmetin	The risk or severity of bleeding and hemorrhage can be increased when Tolmetin is combined with Lepirudin.
Rofecoxib	The risk or severity of bleeding and hemorrhage can be increased when Rofecoxib is combined with Lepirudin.
Piroxicam	The risk or severity of bleeding and hemorrhage can be increased when Piroxicam is combined with Lepirudin.
Fenoprofen	The risk or severity of bleeding and hemorrhage can be increased when Fenoprofen is combined with Lepirudin.
Valdecoxib	The risk or severity of bleeding and hemorrhage can be increased when Valdecoxib is combined with Lepirudin.
Diclofenac	The risk or severity of bleeding and hemorrhage can be increased when Diclofenac is combined with Lepirudin.
Sulindac	The risk or severity of bleeding and hemorrhage can be increased when Sulindac is combined with Lepirudin.
Flurbiprofen	The risk or severity of bleeding and hemorrhage can be increased when Flurbiprofen is combined with Lepirudin.
Etodolac	The risk or severity of bleeding and hemorrhage can be increased when Etodolac is combined with Lepirudin.
Mefenamic acid	The risk or severity of bleeding and hemorrhage can be increased when Mefenamic acid is combined with Lepirudin.
Naproxen	The risk or severity of bleeding and hemorrhage can be increased when Naproxen is combined with Lepirudin.
Sulfasalazine	The risk or severity of bleeding and hemorrhage can be increased when Sulfasalazine is combined with Lepirudin.
Phenylbutazone	The risk or severity of bleeding and hemorrhage can be increased when Phenylbutazone is combined with Lepirudin.
Meloxicam	The risk or severity of bleeding and hemorrhage can be increased when Meloxicam is combined with Lepirudin.
Carprofen	The risk or severity of bleeding and hemorrhage can be increased when Carprofen is combined with Lepirudin.
Diflunisal	The risk or severity of bleeding and hemorrhage can be increased when Diflunisal is combined with Lepirudin.
Salicylic acid	The risk or severity of bleeding and hemorrhage can be increased when Salicylic acid is combined with Lepirudin.
Meclofenamic acid	The risk or severity of bleeding and hemorrhage can be increased when Meclofenamic acid is combined with Lepirudin.
Oxaprozin	The risk or severity of bleeding and hemorrhage can be increased when Oxaprozin is combined with Lepirudin.
Ketoprofen	The risk or severity of bleeding and hemorrhage can be increased when Ketoprofen is combined with Lepirudin.
Balsalazide	The risk or severity of bleeding and hemorrhage can be increased when Balsalazide is combined with Lepirudin.
Olsalazine	The risk or severity of bleeding can be increased when Olsalazine is combined with Lepirudin.
Lumiracoxib	The risk or severity of bleeding and hemorrhage can be increased when Lumiracoxib is combined with Lepirudin.
Magnesium salicylate	The risk or severity of bleeding and hemorrhage can be increased when Magnesium salicylate is combined with Lepirudin.
Salsalate	The risk or severity of bleeding and hemorrhage can be increased when Salsalate is combined with Lepirudin.
Choline magnesium trisalicylate	The risk or severity of bleeding and hemorrhage can be increased when Choline magnesium trisalicylate is combined with Lepirudin.
Antrafenine	The risk or severity of bleeding and hemorrhage can be increased when Antrafenine is combined with Lepirudin.
Aminophenazone	The risk or severity of bleeding and hemorrhage can be increased when Aminophenazone is combined with Lepirudin.
Antipyrine	The risk or severity of bleeding and hemorrhage can be increased when Antipyrine is combined with Lepirudin.
Tiaprofenic acid	The risk or severity of bleeding and hemorrhage can be increased when Tiaprofenic acid is combined with Lepirudin.
Etoricoxib	The risk or severity of bleeding and hemorrhage can be increased when Etoricoxib is combined with Lepirudin.
Taxifolin	The risk or severity of bleeding and hemorrhage can be increased when Taxifolin is combined with Lepirudin.
Oxyphenbutazone	The risk or severity of bleeding and hemorrhage can be increased when Oxyphenbutazone is combined with Lepirudin.

Target Protein

Prothrombin F2

Referensi & Sumber

Synthesis reference: Recombinant hirudin expressed by using yeast secretary (China Patent No. CN1371994A, 2001). China National Intellectual Property Administration. https://patents.google.com/patent/CN1371994A/en

Artikel (PubMed)

PMID: 16244762
Smythe MA, Stephens JL, Koerber JM, Mattson JC: A comparison of lepirudin and argatroban outcomes. Clin Appl Thromb Hemost. 2005 Oct;11(4):371-4.
PMID: 16690967
Tardy B, Lecompte T, Boelhen F, Tardy-Poncet B, Elalamy I, Morange P, Gruel Y, Wolf M, Francois D, Racadot E, Camarasa P, Blouch MT, Nguyen F, Doubine S, Dutrillaux F, Alhenc-Gelas M, Martin-Toutain I, Bauters A, Ffrench P, de Maistre E, Grunebaum L, Mouton C, Huisse MG, Gouault-Heilmann M, Lucke V: Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparin-induced thrombocytopenia treated with lepirudin. Blood. 2006 Sep 1;108(5):1492-6. Epub 2006 May 11.
PMID: 16241940
Lubenow N, Eichler P, Lietz T, Greinacher A: Lepirudin in patients with heparin-induced thrombocytopenia - results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3. J Thromb Haemost. 2005 Nov;3(11):2428-36.
PMID: 19707378
Petros S: Lepirudin in the management of patients with heparin-induced thrombocytopenia. Biologics. 2008 Sep;2(3):481-90. doi: 10.2147/btt.s3415.
PMID: 25294122
Chapin JC, Hajjar KA: Fibrinolysis and the control of blood coagulation. Blood Rev. 2015 Jan;29(1):17-24. doi: 10.1016/j.blre.2014.09.003. Epub 2014 Sep 16.

Link

Contoh Produk & Brand

Produk: 6 • International brands: 0

Produk

Refludan

Powder • 50 mg/1mL • Intravenous • US • Approved
Refludan

Powder, for solution • 50 mg / vial • Intravenous • Canada • Approved
Refludan

Injection, solution, concentrate • 50 mg • Intravenous • EU
Refludan

Injection, solution, concentrate • 50 mg • Intravenous • EU
Refludan

Injection, solution, concentrate • 20 mg • Intravenous • EU
Refludan

Injection, solution, concentrate • 20 mg • Intravenous • EU

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.