FDA Approves MULPLETA (Lusutrombopag) for the Treatment of Thrombocytopenia in Adult Patients with Chronic Liver Disease who are Scheduled to Undergo a Procedure

On July 31, 2018, the U.S. Food and Drug Administration (FDA) approved MULPLETA (lusutrombopag) for the treatment of thrombocytopenia in adult patients with chronic liver disease (CLD) who are scheduled to undergo a procedure.

The approved recommended dosage of MULPLETA is 3 mg orally once daily with or without food for 7 days. Begin MULPLETA dosing 8 to 14 days prior to a scheduled procedure. Obtain a platelet count prior to initiation of MULPLETA therapy and not more than 2 days before the procedure. Patients should undergo their procedure 2 to 8 days after the last dose. Consider the potential increased thrombotic risk when administering MULPLETA to patients with known risk factors for thromboembolism, including genetic pro-thrombotic conditions. MULPLETA should not be administered to patients with CLD in an attempt to normalize platelet counts.

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)

• MOA: Lusutrombopag is a thrombopoietin (TPO) receptor agonist.
• General PK: The pharmacokinetics of lusutrombopag were similar in both healthy subjects and the CLD population. Lusutrombopag demonstrated dose-proportional pharmacokinetics after single doses ranging from 1 mg (0.33 times the recommended dosage) to 50 mg (16.7 times the recommended dosage). C_max and AUC accumulation ratios were approximately 2 and steady-state plasma concentrations were achieved after Day 5.
• Absorption: The time to peak concentration was 6 to 8 hours.
• Food Effect: A high-fat meal did not affect lusutrombopag AUC and C_max.
• Distribution: The mean (%CV) apparent volume of distribution was 39.5 (23.5) L. Plasma protein binding is > 99.9%.
• Elimination: The terminal elimination half-life was approximately 27 hours. The estimated mean (%CV) clearance in patients with CLD is 1.1 (36.1) L/hr.
• Metabolism: Lusutrombopag is primarily metabolized by CYP4 enzymes, including CYP4A11.
• Excretion: Eighty-three percent (16% unchanged) of the administered lusutrombopag dose was excreted in feces and approximately 1% in urine.
• PD: The effect of lusutrombopag on platelet count increase was correlated with the AUC across the studied dose range of 0.25 mg (0.08 times the recommended dosage) to 4 mg (1.3 times the recommended dosage) in thrombocytopenic patients with CLD. With the 3 mg daily dose, the median time to reach the maximum platelet count was 12.0 (5 to 35) days.
• Cardiac Electrophysiology: At a dose 8 times the recommended dosage, MULPLETA does not prolong QT interval to any clinically relevant extent. 

Use in Specific Populations

No clinically significant differences in the pharmacokinetics of lusutrombopag were observed based on age, race/ethnicity, body weight, mild to moderate renal impairment (CLcr ≥ 30 mL/min to < 90 mL/min), or hepatic impairment. Data in patients with severe renal impairment (CLcr < 30 mL/min) are limited.

Drug Interactions

No clinically significant changes in lusutrombopag exposure were observed when co-administered with cyclosporine (an inhibitor of P-gp and BCRP) or an antacid containing a multivalent cation (calcium carbonate). No clinically significant changes in midazolam (a CYP3A substrate) exposure were observed when co-administered with lusutrombopag.

Efficacy and Safety

The efficacy of MULPLETA for the treatment of thrombocytopenia in patients with CLD who are scheduled to undergo a procedure was demonstrated at the recommended dosage in two randomized, double-blind, placebo-controlled trials (Studies L-PLUS 1 and 2). Primary efficacy endpoints were the proportion of patients who require no platelet transfusion prior to the primary invasive procedure (Study L-PLUS 1) and the proportion of patients who require no platelet transfusion prior to the primary invasive procedure and no rescue therapy for bleeding (i.e., platelet preparations, other blood preparations, including red blood cells and plasma, volume expanders) from randomization through 7 days after the primary invasive procedure (Study L-PLUS 2). Additional information regarding efficacy trials can be found in the full prescribing information linked below.

The safety of MULPLETA was evaluated in three randomized, double-blind, placebo-controlled trials. The most common serious adverse reaction reported with MULPLETA was portal vein thrombosis. The most common adverse reaction (≥ 3%) was headache. 
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Full prescribing information is available at https://go.usa.gov/xU7Vp. 

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.