Lusutrombopag
Lusutrombopag Uses, Dosage, Side Effects, Food Interaction and all others data.
Lusutrombopag is an orally bioavailable thrombopoietin receptor (TPOR) agonist developed by Shionogi & Company (Osaka, Japan). TPOR is a regulatory target site for endogenous thrombopoietin, which acts as a primary cytokine to promote megakaryocyte proliferation and differentiation, and affect other hematopoietic lineages as well, including erythroid, granulocytic and lymphoid lineages . Thrombocytopenia, which indicates abnormally low levels of platelets, is a common complication related to chronic liver disease. This hematological abnormality, especially in cases of severe thrombocytopenia (platelet count 4. Lusutrombopag binds to the transmembrane domain of TPOR expressed on megakaryocytes, and causes the proliferation and differentiation of megakaryocytic progenitor cells from hematopoietic stem cells .
In September 2015, lusutrombopag received its first global approval in Japan to reduce the need for platelet transfusion in adults with chronic liver disease and thrombocytopenia who are schedule to undergo an invasive medical procedure . Lusutrombopag was approved by the FDA on July 31st, 2018 for the same therapeutic indication under the market name Mulpleta. In two randomized, double-blind, placebo-controlled trials, patients with chronic liver disease and severe thrombocytopenia who were undergoing an invasive procedure with a platelet count less than 50 x 10^9/L were administered lusutrombopag orally . Higher percentages (65-78%) of the patients receiving lusutrombopag required no platelet transfusion prior to the primary invasive procedure compared to those receiving placebo . Lusutrombopag is currently in phase III development in various European countries including Austria, Belgium, Germany, and the UK .
The AUC of lusutrombopag was found to correlate the increased platelet counts. Following administration of 3 mg daily dose in patients with chronic liver disease and thrombocytopenia, the mean (standard deviation) maximum platelet count in patients (N=74) without platelet transfusion was 86.9 (27.2) × 10^9/L, and the median time to reach the maximum platelet count was 12.0 (5 to 35) days . Lusutrombopag was not shown to induce any clinically significant QTc prolongation at a dose 8 times the recommended dosage .
| Trade Name | Lusutrombopag |
| Availability | Prescription only |
| Generic | Lusutrombopag |
| Lusutrombopag Other Names | Lusutrombopag |
| Related Drugs | prednisone, dexamethasone, Decadron, Deltasone, Promacta |
| Weight | 3mg |
| Type | Oral tablet |
| Formula | C29H32Cl2N2O5S |
| Weight | Average: 591.54 Monoisotopic: 590.1408987 |
| Protein binding | The plasma protein binding of lusutrombopag is more than 99.9% . |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Lusutrombopag is a medication used to treat thrombocytopenia in patients with chronic liver disease scheduled to have a procedure.
Lusutrombopag is indicated for the treatment of thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure.
Lusutrombopag is also used to associated treatment for these conditions: Chronic immune thrombocytopenia
How Lusutrombopag works
Lusutrombopag mimics the biological actions of endogenous thrombopoietin (TPO) by acting as an agonist for the thrombopoietin receptor (TPOR) expressed on megakaryocytes. It binds to the transmembrane domain of the receptor and induces thrombocytopoiesis by targeting the same signal transduction system as that of endogenous TPO, which involves the activation of JAK and STAT pathways . It stimulates the proliferation and differentiation of bone marrow progenitor cells into megakaryocytes, which undergoes maturation to act as precursor cells for platelets . A single megakaryocyte produces and releases thousands of platelets upon maturation and series of remodeling events . Lusutrombopag displays high specificity towards human TPORs when compared to murine TPORs . Lusutrombopag may affect other hematopoietic lineages as well, including erythroid, granulocytic and lymphoid lineages. One case of increased leukocyte and erythrocyte counts that prolonged for over 120 days was reported following administration in a patient with liver cirrhosis (LC) due to hepatitis C virus .
Toxicity
There is no known antidote for lusutrombopag: hemodialysis is not expected to enhance the elimination of lusutrombopag from the plasma as there is high protein binding. Overdose may be characterized by excessive platelet counts that may result in thrombotic and thromboembolic complications. In the event of overdose, closely monitor patients and platelet count and treat thrombotic complications in accordance with standard of care .
In animal and in vitro studies, lusutrombopag did not display any carcinogenicity, genotoxicity, or reproductive toxicity .
Food Interaction
- Take with or without food.
Lusutrombopag Disease Interaction
Moderate: severe renal impairment, thrombotic / thromboembolic complications
Volume of Distribution
The mean (%CV) lusutrombopag apparent volume of distribution in healthy adult subjects was 39.5 (23.5) L .
Elimination Route
Lusutrombopag is rapidly absorbed following oral administration . It exhibited a dose‐proportional pharmacokinetic profile over the single dose range of 1 mg to 50 mg, which was similar in both healthy subjects and those with chronic liver disease. A geometric mean (%CV) maximal concentration (Cmax) and area under the curve (AUC) in healthy subjects receiving 3 mg of lusutrombopag were 111 (20.4) ng/mL and 2931 (23.4) ng.hr/mL . The accumulation ratios of Cmax and AUC were approximately 2 with once‐daily multiple‐dose administration, and steady‐state plasma lusutrombopag concentrations were achieved after Day 5. The time to reach peak plasma concentrations (Tmax) were approximately 6 to 8 hours after oral administration in patients with chronic liver disease . Food consumption is not reported to affect the absorption and bioavailability of lusutrombopag .
Half Life
In healthy adult subjects, the terminal elimination half‐life (t1/2) was approximately 27 hours .
Clearance
The approximate mean (%CV) clearance of lusutrombopag in patients with chronic liver disease is estimated to be 1.1 (36.1) L/hr .
Elimination Route
About 1% of the administered dose of lusutrombopag undergoes urinary excretion. Fecal excretion accounted for 83% of the total dose, where 16% of the dose was excreted as unchanged parent compound .
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