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General Description:

Lusutrombopag, identified by CAS number 1110766-97-6, is a notable compound with significant therapeutic applications. 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 <50,000/μL), creates challenges to patients requiring invasive medical procedures where there is a significant risk for spontaneous bleeding . 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 .

Indications:

This drug is primarily indicated for: Lusutrombopag is indicated for the treatment of thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Lusutrombopag undergoes metabolic processing primarily in: CYP4 enzymes predominantly contribute to the metabolism of lusutrombopag, especially CYP4A11 . Lusutrombopag is reported to mainly undergo ω- and β-oxidation, as well as glucuronidation . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Lusutrombopag are crucial for its therapeutic efficacy: 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 . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Lusutrombopag is an important consideration for its dosing schedule: In healthy adult subjects, the terminal elimination half‐life (t1/2) was approximately 27 hours . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Lusutrombopag exhibits a strong affinity for binding with plasma proteins: The plasma protein binding of lusutrombopag is more than 99.9% . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Lusutrombopag from the body primarily occurs through: 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 . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Lusutrombopag is distributed throughout the body with a volume of distribution of: The mean (%CV) lusutrombopag apparent volume of distribution in healthy adult subjects was 39.5 (23.5) L . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Lusutrombopag is a critical factor in determining its safe and effective dosage: The approximate mean (%CV) clearance of lusutrombopag in patients with chronic liver disease is estimated to be 1.1 (36.1) L/hr . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Lusutrombopag exerts its therapeutic effects through: 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 . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Lusutrombopag functions by: 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 . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Lusutrombopag belongs to the class of organic compounds known as cinnamic acids. These are organic aromatic compounds containing a benzene and a carboxylic acid group forming 3-phenylprop-2-enoic acid, classified under the direct parent group Cinnamic acids. This compound is a part of the Organic compounds, falling under the Phenylpropanoids and polyketides superclass, and categorized within the Cinnamic acids and derivatives class, specifically within the Cinnamic acids subclass.

Categories:

Lusutrombopag is categorized under the following therapeutic classes: Acids, Carbocyclic, BCRP/ABCG2 Substrates, Blood and Blood Forming Organs, Hemostatics, P-glycoprotein substrates, Sulfur Compounds, Thrombopoietin Receptor Agonist. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Lusutrombopag include:

• Water Solubility: Practically insoluble