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Objective Lusutrombopag is a thrombopoietin receptor agonist that improves thrombocytopenia in patients with chronic liver disease scheduled to undergo invasive procedures. However, information on the efficacy of repeated lusutrombopag treatment and factors associated with the treatment is scarce. We analyzed the efficacy of repeated lusutrombopag treatment and the factors associated with a response to lusutrombopag. Methods Thirty-nine patients with chronic liver disease who received lusutrombopag treatment before undergoing invasive procedures were enrolled in this retrospective study. Of the 39 patients, 10 received lusutrombopag treatment multiple times for a total of 53 regimens of lusutrombopag treatment. Changes in platelet counts, the effects of repeated lusutrombopag treatment, and factors associated with response to lusutrombopag were analyzed. Results The median platelet count increased significantly from 4.5×104/μL before lusutrombopag treatment to 7.2×104/μL before the invasive procedure (p

We describe the development of a one-pot preparation process of (E)-3,5-dichloro-4-(3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl)benzoic acid (3), which is a key carboxylic acid intermediate of lusutrombo...

Background/Aims: Lusutrombopag, a small-molecule thrombopoietin receptor agonist, is used to treat thrombocytopenia based on the results of a phase 3 trial, including data for single-use administration in patients with chronic liver disease (CLD) undergoing invasive procedures. We aimed to evaluate the efficacy and safety of repeated lusutrombopag use. Methods: Lusutrombopag was administered repeatedly in patients undergoing multi-cycle invasive procedures at intervals >1 month. Results: Data from 8 patients (median platelet count at baseline, 44.0 [range, 35–49] × 109/L) and 25 cycles of invasive procedures, including 2 cycles in 3 patients, 3 cycles in 4 patients, and 7 cycles in 1 patient, were retrospectively evaluated. The procedures included 18 transarterial chemoembolizations, 5 radiofrequency ablations, and 2 liver needle biopsies. Platelet counts increased significantly compared with baseline, and median changes in platelet counts were 46.0 × 109/L (p = 0.012) in cycle 1, 44.0 × 109/L (p = 0.012) in cycle 2, and 42.0 × 109/L (p = 0.008) in cycles 3–7. No severe adverse events, including portal vein thrombus or bleeding, were observed. Conclusions: Repeated use of lusutrombopag might be safe and effective against thrombocytopenia in patients with CLD undergoing multi-cycle invasive procedures, although long-term data from more patients are required.

A novel, simple and sensitive method for the determination of Lusutrombopag in rat plasma using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was developed and validated. The determination was performed on an API4000 triple quadrupole mass spectrometry in the multiple reaction monitoring mode using the respective [M+H]+ ions m/z 593.1 → 272.3 for Lusutrombopag. The limit of detection was 0.5 ng/mL, and the lower limit of quantification was 2.0 ng/mL in rat plasma. Good linearity was obtained over the range of 2.0–150.0 ng/mL and the correlation coefficient was found to be 0.9998. The intra and inter-day precisions were found to be 3.8–6.9% and 6.8–10.5%, respectively. The intra and inter-day accuracy derived from QC samples was found to be 2.5–4.9% and 5.5–7.2%, respectively. The analyte was stable under various conditions (at room temperature, during freeze-thaw, in the autosampler and under deep-freeze conditions). The F-test and t-test at 95% confidence level were subjected on data for statistical analysis. The developed method was successfully applied to the pharmacokinetic study in rats. Keywords: Development and validation, Novel LC-MS/MS method, Lusutrombopag, Pharmacokinetic studies, ICH

Aims: Thrombocytopenia is a common complication among patients with chronic liver disease (CLD). To increase platelet counts, lusutrombopag, a small-molecule, second-generation thrombopoietin receptor agonist, was developed in September 2015. Lusutrombopag is mainly used in patients with platelet counts Methods: We evaluated 36 patients who received lusutrombopag for CLD. Changes in platelet counts were evaluated. A treatment response was defined as an increasing platelet count ≥20,000/µL from baseline after drug administration. The differences related to these changes between platelet counts ≥50,000 and Results: Of the patients, 25 had platelet counts ≥50,000/µL. The increase in platelet count and the date in which it reached a maximum did not significantly differ between the groups. The effectiveness of lusutrombopag did not significantly differ between the groups. In both groups, no adverse reaction was observed during lusutrombopag administration. Conclusion: In this study, we showed the effectiveness of lusutrombopag, which had no complications. This study is the first to report that the effectiveness of lusutrombopag was the same for patients with platelet counts ≥50,000/µL and

Background Chronic liver disease (CLD) is often complicated by severe thrombocytopenia (platelet count 50,000/µL at baseline: the proportions of patients who did not require platelet transfusion were 84–96%, which might be overestimated. Methods The efficacy and safety of lusutrombopag were retrospectively investigated in CLD patients with platelet count of Results Among 31 patients who received lusutrombopag, 23 patients (74.2%) patients showed a platelet count of ≥ 50,000/µL (Group A) and did not require platelet transfusion. The remaining 8 patients (25.8%) did not reached platelet ≥ 50,000/µL (Group B). The means of platelet increase were 38,000/µL and 12,000/µL in groups A and B, respectively. A low platelet count at baseline was a characteristic of patients in group B. Among 13 patients who repeatedly used lusutrombopag, lusutrombopag significantly increased the platelet count as the initial treatment. When all repeated uses of lusutrombopag were counted among these 13 patients, platelet transfusion was not required in 82.1% (23/28) of treatments. Although one patient showed portal thrombosis after lusutrombopag treatment, the thrombosis was disappeared by anticoagulant treatment for 35 days. The degree of platelet increase with lusutrombopag was larger than that in their previous platelet transfusion. Conclusions The proportion of patients who did not require platelet transfusion was 74.2%, which is smaller than that in former studies which included CLD patients with a platelet count of > 50,000/µL. However, lusutrombopag is effective and safe for CLD patients with a platelet count of

Background and Aims Thrombocytopenia complicates management of chronic liver disease (CLD), and may interfere with the performance of invasive procedures. Lusutrombopag (LUSU), an oral, small molecule thrombopoietin receptor agonist, has been studied for the treatment of thrombocytopenia in patients with CLD who are scheduled for invasive procedures. Aiming to further assess its efficacy and safety, a meta-analysis of LUSU randomised controlled trial (RCT) data is presented. Method A direct random-effects meta-analysis was conducted in Stata 14.2MP, using the method of DerSimonian and Laird, with data from three RCTs enrolling pre-procedure CLD patients with a platelet count (PC) Results LUSU is statistically significantly better than PBO in reducing the need for platelet transfusions (PT) prior to and after an invasive procedure (No PT during study: Odds ratio 11.24 (95% CI: 2.83, 44.64); p = 0.001). During the procedure window, patients who received LUSU and no PT had a statistically significant higher increase in PC than patients who received PBO and a PT (mean difference between LUSU and no PT versus PBO with PT at day 12: 34.18 × 109/L (95% CI: 30.31, 38.06; p Conclusion Lusutrombopag is well tolerated and can increase platelet count in thrombocytopenic CLD patients prior to an invasive procedure, reducing the need for platelet transfusions and lowering the risk of bleeding.

Background Thrombocytopenia represents an obstacle for invasive procedures in chronic liver disease (CLD) patients. We aimed to estimate the appropriate dose and evaluate the efficacy and safety of lusutrombopag for the treatment of thrombocytopenia before percutaneous liver radiofrequency ablation (RFA) for primary hepatic cancer in patients with CLD. Methods In this multicenter, randomized, double-blind, placebo-controlled study conducted in Japan, 61 CLD patients with platelet count

Thrombocytopenia is common in patients with advanced liver disease. These patients frequently require invasive diagnostic or therapeutic procedures in the setting of thrombocytopenia. A common platelet goal before such procedures is ≥50,000/μL, but target levels vary by provider and the procedure. Platelet transfusion has disadvantages, including safety and cost. No other short‐term options for ameliorating thrombocytopenia before procedures were available until the thrombopoietin receptor agonists were recently approved. Avatrombopag and lusutrombopag can be used in certain patients with thrombocytopenia due to advanced liver disease undergoing elective invasive procedures; these new agents are highly effective in carefully selected patients, and real world data of safety and efficacy are awaited., TPO receptor agonists are an exciting new development that can raise platelet counts in liver patients with thrombocytopenia before elective procedures. We review the strategies to address peri‐procedure thrombocytopenia including data on the most recent trials involving TPO receptor agonists.

Purpose Lusutrombopag is a novel, orally active thrombopoietin receptor agonist. This report describes 3 studies aimed at assessing the effects of food and calcium carbonate on the pharmacokinetic parameters of lusutrombopag in healthy subjects. Methods Three single-dose, open-label crossover studies were conducted. In study 1, eighteen healthy subjects were administered a single 2-mg dose of lusutrombopag as a single tablet in the fasted or fed state or as a 2-mg solution in the fasted state. In study 2, fifteen healthy subjects were administered a single 0.75-mg dose of lusutrombopag as three 0.25-mg tablets in the fasted or fed state, or in the fasted state with coadministration of 4000-mg calcium carbonate. In study 3, fifteen healthy subjects were administered 4-mg lusutrombopag as a single tablet in the fasted or fed state. Pharmacokinetic parameters were estimated from plasma lusutrombopag concentrations. Findings Mean fed versus fasted state ratios (90% CIs) of Cmax and AUC0–∞, respectively, were: 0.904 (0.864–0.945) and 0.920 (0.886–0.956) (study 1); 0.972 (0.864–1.09) and 1.02 (0.945–1.11) (study 2); and 0.917 (0.842–0.999) and 0.908 (0.855–0.964) (study 3). The respective ratios for calcium carbonate versus no calcium carbonate (fasted state) were 1.08 (0.959–1.21) and 0.989 (0.913–1.07) (study 2). Lusutrombopag exposure remained unaffected, except for a slight decrease in exposure with food. Lusutrombopag exposure did not change with the coadministration of calcium carbonate. These findings suggest that there was no clinically significant effect of food or calcium carbonate on the bioavailability of lusutrombopag. Each treatment regimen was well tolerated. Implications According to the present findings, no specific restrictions are required for lusutrombopag administration with regard to meals (including those with dairy products), mineral supplements, or coadministration of antacids. Clinical trial registration: JapicCTI-No.: JapicCTI-194690, JapicCTI-194689. ClinicalTrials.gov identifier: NCT03897413.

Aim Lusutrombopag is approved for the treatment of thrombocytopenia in chronic liver disease patients undergoing invasive procedures. This real-world surveillance assesses the safety and effectiveness of lusutrombopag in Japan. Methods This ongoing, multicenter, prospective, real-world surveillance is collecting data from case report forms between October 2016 and May 2021. Interim data up to September 2018 were used to evaluate safety (adverse events and adverse drug reactions [ADRs]) and effectiveness (proportion of patients avoiding preoperative platelet transfusion and change in platelet count from baseline). Results The safety analysis set included 331 patients. The mean baseline platelet count was 46.2 ± 13.7 × 109 /L. Of 377 invasive procedures, radiofrequency ablation (110 procedures, 29.2%) was the most frequent. The mean time from starting lusutrombopag treatment to invasive procedure was 12.3 days. Incidences of serious adverse events and ADRs were 8.76% and 3.32%, respectively. Six cases (1.81%) of portal vein thrombosis were considered serious adverse events; of these, four cases (1.21%) were classified as serious ADRs. Of 300 patients who underwent an invasive procedure (excluding those with platelet transfusion refractoriness), 282 (94.0%) avoided preoperative platelet transfusion. In patients with platelet measurements before and after lusutrombopag administration who did not undergo platelet transfusion, the mean maximum change in platelet count from baseline was 41.7 ± 31.4 × 109 /L (range, -6 to 276; n = 286). All patients receiving second (n = 20) and third (n = 1) treatments avoided preoperative platelet transfusion without developing any ADRs. Conclusions This real-world surveillance further supports the safety and effectiveness of lusutrombopag in patients with chronic liver disease undergoing invasive procedures.

Background The oral thrombopoietin (TPO) receptor agonist lusutrombopag (Mulpleta®) was developed to improve thrombocytopenia in patients with chronic liver disease prior to elective invasive medical procedures. Mulpleta® was first approved for use in Japan in 2015 and in the USA in 2018. In the present report, we discuss a case in which pain management was performed during left renal artery embolization via continuous epidural anesthesia following oral administration of lusutrombopag. To our knowledge, this is the first report to discuss the use of lusutrombopag prior to epidural anesthesia. Case presentation The patient was a 78-year-old woman scheduled to undergo renal artery embolization to address a 3-cm aneurysm of the left renal artery. Fourteen days prior to the scheduled embolization procedure, the urologist was asked to insert an epidural catheter for perioperative and postoperative analgesia. Type C chronic cirrhosis was observed, and platelet count was 5.6 × 104/μL. Eleven days prior to embolization, oral lusutrombopag was initiated at a dosage of 3 mg/day (day 1). Oral lusutrombopag therapy was continued for 5 days, and platelet count on day 11 (i.e., the day prior to surgery) was 12.6 × 104/μL. An epidural catheter was inserted on day 12, following which embolization was performed. Platelet count on day 13 was 11.0 × 104/μL, and the catheter was removed on day 14. No symptoms of epidural hematoma or thrombosis were observed during the patient’s disease course. Conclusions As lusutrombopag is a relatively safe platelet-increasing agent, we believe that this drug can serve as a potential treatment option when performing elective epidural anesthesia in patients with chronic liver disease complicated by thrombocytopenia.

Lusutrombopag was administered to a patient with thrombocytopenia due to chronic liver disease before an invasive procedure. Lusutrombopag, the first drug of its kind, was developed to improve platelet count thereby, avoiding the need for platelet transfusion. Lusutrombopag is potentially effective for the management of haemostasis during invasive procedures, such as tooth extraction. Herein, we present a case of tooth extraction surgery in a patient treated with lusutrombopag. The patient was a 63-year-old woman suffering from thrombocytopenia due to liver cirrhosis. Tooth extraction was indicated by the diagnosis of caries and apical periodontitis of the maxillary left second molar. Mild spontaneous bleeding in the surrounding gum tissue and a reduced platelet count (5.1 × 104 /μL) were observed. Haemostatic difficulties were predicted to accompany tooth extraction surgery. Consultation with a gastroenterology clinic led us to implement lusutrombopag prior to the procedure. The patient’s platelet count had risen to 10.9 × 104 /μL by the day of the surgery. Neither intraoperative nor postoperative bleeding was observed. No adverse events associated with lusutrombopag administration were observed. Lusutrombopag can increase platelet count, suggesting its utility in invasive procedures such as tooth extraction.

This review provides details about three small molecules that were recently approved by the FDA for the treatment of thrombocytopenia. The new treatments include lusutrombopag, avatrombopag, and fostamatinib. The first two drugs are orally active thrombopoietin receptor (TPO-R) agonists which are FDA-approved for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. Fostamatinib is orally active prodrug that, after activation, becomes spleen tyrosine kinase (SYK) inhibitor. Fostamatinib is currently used to treat chronic and refractory immune thrombocytopenia in patients who have had insufficient response to previous treatment. Chemical structures, available dosage forms, recommended dosing, pharmacokinetics, results of toxicity studies in animals, most frequent adverse effects, significant outcomes of the corresponding clinical trials, and their use in specific patient populations are thoroughly described. Described also is a comparative summary of the different aspects of five currently available therapies targeting TPO-R or SYK for the treatment of thrombocytopenia.