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Introduction. As a result of portal hypertension (sequestration of platelets in an enlarged spleen) and liver failure (decreased production of thrombopoietin in the liver) in liver cirrhosis, thrombocytopenia develops, which is associated with the risk of periprocedural/perioperative bleeding complications. There are still unresolved questions regarding risk stratification of bleeding complications, the prognostic role of thrombocytopenia, as well as the need for treatment of thrombocytopenia and its methods.Materials and methods. The Russian Scientific Liver Society selected a panel of experts in the field of therapeutic and surgical hepatology, hematology, transfusion medicine to make reasoned statements and recommendations on the issue of treatment of thrombocytopenia before elective surgery / invasive procedures in patients with liver cirrhosis.Results. Relevant clinical issues were determined based on the PICO principle (patient or population, intervention, comparison, outcome). The Delphi panel made five questions and gave reasoned answers, framed as ‘clinical practice recommendations and statements’ with evidence-based comments. The questions and statements were based on the results of search and critical analysis of medical literature using keywords in English- and Russian-language databases. The formulated questions could be combined into four categories: bleeding risk stratification, the prognostic value of thrombocytopenia, the necessity and methods of thrombocytopenia drug correction, and bleeding risk reduction.Conclusions. The results of experts' work are directly related to high-quality management of patients with liver cirrhosis and thrombocytopenia, who have scheduled invasive procedures/surgery. Thus, this recommendations and statements can be used in clinical practice.

(S)-1-(3′-Bromo-2′-methoxyphenyl)ethanol ((S)-1b) is the key precursor for the synthesis of Lusutrombopag. The bioreduction of 1-(3′-bromo-2′-methoxyphenyl)ethanone (1a) offers an attractive method to access this important compound. Through screening the available carbonyl reductases, we obtained a carbonyl reductase from Novosphingobium aromaticivorans (CBR), which could completely convert 100 ​g/L of 1a to (S)-1b. Furthermore, a carbonyl reductase from Novosphingobium sp. Leaf2 (NoCR) was identified to completely convert 200 ​g/L of 1a to (S)-1b with excellent enantioselectivity (>99% ee) and 77% isolated yield using FDH/formate system for NADH regeneration. The Km and kcat of recombinant NoCR towards 1a were 0.66 ​mmol/L and 7.5 s-1, and the catalytic efficiency kcat/Km was 11.3 ​mmol/s.L. Meanwhile, NoCR showed high catalytic activity and stereoselectivity towards acetophenone derivatives with halogen or methoxy substitution on the benzene ring, indicating that NoCR is a valuable biocatalyst with potential practical applications.

Abstract Background Platelet (PLT) transfusion was the most practical way to increase patients’ PLT counts before invasive hepatic procedures such as radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). A novel drug that raises the PLT count by acting on the thrombopoietin receptor has recently become available. Methods Lusutrombopag 3 mg was administered daily for 7 days to patients who underwent RFA for liver tumors with low PLT counts ( 50,000 PLT µL− 1 had higher PLT counts before lusutrombopag administration. The degree of splenomegaly did not affect the rate of PLT count elevation. There was no specific adverse effect by administrating lusutrombopag for patients with PLT counts of around 50,000 µL− 1 but > 50,000 µL− 1. Conclusions Lusutrombopag administration before RFA was effective and seemed to be relatively safe for hepatocellular carcinoma patients with low PLT counts. Trial registration This study was approved by Japanese Red Cross Medical Center Institutional Reseach Comittie (#862, 07/03/2016), and was registered in a publically accessible primary register (#UMIN000046629, registered date: 14/01/2022).

Aim: Lustrombopag has been approved for the treatment of thrombocytopenia in patients with chronic liver diseases who are scheduled to undergo an invasive procedure. Here, we report the final results of a post‐marketing surveillance assessing the safety and effectiveness of lusutrombopag in Japan. Methods: This multicenter, prospective, real‐world surveillance collected data from case report forms between October 2016 and May 2021. The observation period was 2 months after the first day of lusutrombopag treatment. Safety and effectiveness (proportion of patients avoiding preoperative platelet transfusion and responders who achieved platelet count increase from baseline) were assessed. Results: The safety analysis set included 1033 (100.0%), 130 (12.6%), and 14 (1.4%) patients who received one or more, two or more, and three or more treatment cycle(s), and 482 (48.9%), 457 (46.3%), and 43 (4.4%) patients who were Child–Pugh class A, B, and C, respectively. The most common serious adverse drug reactions were portal vein thrombosis, pancytopenia, and white blood cell count decrease, reported in 14 (1.36%), three (0.29%), and two (0.19%) patients, respectively. The incidence of adverse drug reactions was not higher in patients with Child–Pugh class C or those undergoing retreatment cycles compared with other Child–Pugh classes or the first treatment cycle, respectively. During the observation period of the first treatment cycle, 94.7% (889/939) of patients avoided preoperative platelet transfusion and 82.8% (741/895) of the patients met the responder criteria. Conclusions: This surveillance study further supports the safety and effectiveness of lusutrombopag in a broad range of patients with chronic liver diseases undergoing planned invasive procedures. Clinical Trial Registration: JapicCTI‐163432. [ABSTRACT FROM AUTHOR]

Background: Platelet (PLT) transfusion was the most practical way to increase patients’ PLT counts before invasive hepatic procedures such as radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). A novel drug that raises the PLT count by acting on the thrombopoietin receptor has recently become available. Methods: Lusutrombopag 3 mg was administered daily for 7 days to patients who underwent RFA for liver tumors with low PLT counts (< 50,000 PLT µL− 1). We collected demographic data concerning the patients’ liver function and PLT counts. Results: Lusutrombopag was administered to 91 patients, with a median age of 71 years (range 51–86). Forty-two patients had hepatitis C, 12 had hepatitis B, 21 had alcoholic liver disease, 11 had nonalcoholic steatohepatitis, and five had other diseases. The median Child-Pugh score was 7 (range 5–11). Thirty-seven patients had stage I tumors, 41 had Stage II, 12 had stage III, and one had stage IV. PLT count was elevated from 4.4 × 104 ± 1.4 × 104 to 8.6 × 104 ± 2.5 × 104 PLT µL− 1. Lusutrombopag administration prevented PLT transfusions in 84/91 patients (92%). No patient had bleeding complications after RFA. One had portal thrombosis after lusutrombopag administration. Patients who achieved PLT counts of > 50,000 PLT µL− 1 had higher PLT counts before lusutrombopag administration. The degree of splenomegaly did not affect the rate of PLT count elevation. There was no specific adverse effect by administrating lusutrombopag for patients with PLT counts of around 50,000 µL− 1 but > 50,000 µL− 1. Conclusions: Lusutrombopag administration before RFA was effective and seemed to be relatively safe for hepatocellular carcinoma patients with low PLT counts. Trial registration: This study was approved by Japanese Red Cross Medical Center Institutional Reseach Comittie (#862, 07/03/2016), and was registered in a publically accessible primary register (#UMIN000046629, registered date: 14/01/2022). [ABSTRACT FROM AUTHOR]

Introduction: Patients with thrombocytopenia and chronic liver disease are at increased risk of bleeding during invasive procedures due to low platelet counts. Lusutrombopag, an orally active thrombopoietin receptor agonist, increases platelet count and reduces the need for platelet transfusion in chronic liver disease patients with thrombocytopenia undergoing a planned invasive procedure. The safety of lusutrombopag in patients with Child-Pugh class C chronic liver disease is not known. The present analysis was performed to determine the pharmacokinetics, efficacy, and safety of lusutrombopag in patients with Child-Pugh class C chronic liver disease.Methods: Data for patients with Child-Pugh class C chronic liver disease were collected from three data sets: a phase 1/2 Child-Pugh class C study (n = 5) (JapicCTI-163289 [Japan Pharmaceutical Information Center]), a phase 3 pivotal study (L-PLUS 2, n = 3) (NCT02389621 [Clinicaltrials.gov]), and ongoing post-marketing surveillance (n = 27) (JapicCTI-163432 [Japan Pharmaceutical Information Center]). Patients received lusutrombopag at 3 mg for up to 7 days. Safety and efficacy assessments were collected from two clinical studies and the post-marketing surveillance; pharmacokinetic data were collected from the phase 1/2 study.Results: Mean Cmax and AUC0-τ were lower in Child-Pugh class C patients than Child-Pugh class A and B; individual patients' Cmax and AUC0-τ values overlapped among Child-Pugh classes. In lusutrombopag patients who did not receive platelet transfusion (n = 4 in phase 1/2, n = 1 in phase 3, n = 24 in post-marketing surveillance), the median (range) maximum platelet count was 88.5 × 109/L (54-105 × 109/L), 80 × 109/L, and 91 × 109/L (41-186 × 109/L; n = 23), respectively. There were no treatment-related adverse events or treatment-related serious adverse events. One patient from the phase 1/2 study had a non-serious portal vein thrombosis, which was not considered treatment-related.Conclusions: The analysis presented in this study suggests that lusutrombopag increases platelet counts in Child-Pugh class C patients and is safe and well tolerated in this patient population.Trial Registration: L-PLUS 2: NCT02389621 (Clinicaltrials.gov). Phase 1/2: JapicCTI-163289 (Japan Pharmaceutical Information Center [JAPIC]). Post-marketing surveillance: JapicCTI-163432 (JAPIC). [ABSTRACT FROM AUTHOR]

Introduction: Lusutrombopag is an oral thrombopoietin receptor agonist (TPO-RA). Clinical trials have shown lusutrombopag's efficacy in reducing need for preoperative platelet transfusion in patients with chronic liver disease (CLD) and severe thrombocytopenia. This analysis assessed efficacy and safety of lusutrombopag in patients with severe thrombocytopenia and CLD undergoing planned invasive procedures.Methods: An electronic database search (through 1 December 2020) identified three randomised, placebo-controlled, double-blind clinical trials comparing lusutrombopag with placebo in patients with CLD and platelet count below 50 × 109/L scheduled to undergo a procedure with a perioperative bleeding risk. A random-effects meta-analysis examined treatment effect, with Cochrane Collaboration's tool assessing risk of bias.Results: The meta-analysis included 343 (lusutrombopag 3 mg, n = 173; placebo, n = 170) patients. More patients met the criteria for treatment response (platelet count at least 50 × 109/L and increase of at least 20 × 109/L from baseline anytime during the study) with lusutrombopag versus placebo (risk ratio [RR] 6.39; 95% confidence interval [CI] 3.69, 11.07; p < 0.0001). The primary efficacy outcome, proportion of patients requiring no platelet transfusion and no rescue therapy for bleeding for at least 7 days post procedure, was achieved by more patients treated with lusutrombopag versus placebo (RR 3.42; 95% CI 1.86, 6.26; p = 0.0001). The risk of any bleeding event was significantly lower with lusutrombopag compared to placebo (RR 0.55; 95% CI 0.32, 0.95; p = 0.03); conversely, thrombosis event rates were similar between lusutrombopag and placebo (RR 0.79; 95% CI 0.19, 3.24; p = 0.74).Conclusion: This meta-analysis showed that treatment of severe thrombocytopenia with lusutrombopag in patients with CLD prior to a planned invasive procedure was efficacious and safe in increasing platelet counts, avoiding the need for platelet transfusions, and reducing risk of bleeding, thereby enhancing the certainty of evidence supporting the efficacy and safety of lusutrombopag. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aim Thrombocytopenia is a frequent hematological condition in chronic liver disease (CLD) patients increasing the risk of bleeding in patients undergoing invasive procedures. Without an alternative, clinical guidelines recommended the use of platelet transfusion (PT) prior to procedure to prevent this bleeding risk. Lusutrombopag (LUSU), an orally active, small‐molecule thrombopoietin receptor agonist, was developed as an alternative to PT. The objective of this study was to evaluate a cost‐effectiveness of LUSU as a potential alternative to PT in Japan. Methods A cost‐effectiveness analysis of LUSU relative to PT was conducted by a simulation model consisting of a decision tree combined to Markov model. Quality‐adjusted life years (QALYs) were used as an indicator of efficacy, and the analysis was conducted from the Japanese public healthcare payer's perspective. The time horizon of the analysis was 50 years (a lifetime) and the discount rate was set at 2%. Results LUSU gained 6.1803 QALYs with an expected lifetime costs of 2 380 219 JPY compared to PT with 6.1712 QALYs gained and expected lifetime costs of 2 382 908 JPY. Thus, LUSU was deemed dominant compared with PT. Based on probabilistic analyses, the chance of LUSU being dominant and the incremental cost‐effectiveness ratio being below 5 million JPY/QALY was estimated at 51.8% and 78.3%, respectively, demonstrating the robustness of the results. Conclusions LUSU was evaluated as an efficacious and cost‐saving treatment option for Japanese CLD patients with thrombocytopenia who required a planned invasive procedure compared with PT and economically should be considered as an alternative treatment.

Background: Lusutrombopag effectively increases platelet count in patients with severe thrombocytopenia. However, no multicenter studies analyzing the effects of Lusutrombopag on patients with mild thrombocytopenia (platelet count > 50 000/µL) have been performed. In this study, we aimed to clarify the efficacy of Lusutrombopag on these patients by unifying background factors by propensity score matching. Methods: A total of 139 patients with thrombocytopenia were enrolled, and matched for age, sex, etiology, disease, treatment, liver function, renal function, peripheral blood count, and spleen index. The primary endpoint was to compare the increase in platelet count from baseline between the high‐platelet group (>50 000/µL) and the low‐platelet group (<50 000/µL) after Lusutrombopag treatment, using propensity score matching. The secondary endpoint was to clarify platelet transfusion avoidance rate and adverse events, moreover, to identify independent predictors associated with the increase in platelet count. Results: The mean increase in platelet count was 67 000/μL vs 48 000/μL in all patients (high‐ vs low‐platelet group, P =.024), and 64 000/μL vs 48 000/μL (P =.12) after propensity score matching. The increase in platelet count and the platelet transfusion avoidance rate tended to be higher in the high‐platelet group. There was no significant difference between adverse events. Predictors associated with an increase in platelet count were sex, estimated glomerular filtration rate, and spleen index by multivariate analysis. Conclusion: Lusutrombopag has a little stronger effect in patients with mild thrombocytopenia than those with severe thrombocytopenia and showed a more substantial effect in patients with impaired renal function and small spleen. [ABSTRACT FROM AUTHOR]

Lusutrombopag is a thrombopoietin receptor agonist approved to treat thrombocytopenia in patients with chronic liver disease (CLD). This post hoc analysis of the Japanese L-PLUS 1 and global L-PLUS 2 trials aimed to clarify factors related to platelet count increase after lusutrombopag treatment. In L-PLUS 1, Pearson's correlation coefficients were used to evaluate correlations between platelet count and spleen index, thrombopoietin concentration, white blood cell (WBC) counts, and red blood cell counts (intent-to-treat [ITT] population). Associations between platelet count increase after lusutrombopag treatment and each parameter were assessed by regression analysis and mixed-effect model for repeated measures (MMRM). Associations between time-dependent changes in platelet count increase and each parameter were also examined in the L-PLUS 2 lusutrombopag ITT population by MMRM. In L-PLUS 1, the baseline platelet count was correlated with pretreatment spleen index (r = −0.23, 95% confidence interval [CI] −0.41 to −0.03) and WBC count (r = 0.26, 95% CI 0.06 to 0.43). No selected parameters were associated with the maximum platelet count increase from baseline. Patients with WBC counts below the normal range showed smaller platelet count increases after lusutrombopag treatment than patients with WBC counts within the normal range (p =.0028). In L-PLUS 2 (p =.0533), findings were similar and confirmed by larger pooled data of L-PLUS 1/L-PLUS 2 (p =.0021). This post hoc analysis revealed a possible association between baseline WBC count and platelet count increase after lusutrombopag treatment. WBC count could be a relevant factor for lusutrombopag efficacy. [ABSTRACT FROM AUTHOR]

Background and aims: Management of severe thrombocytopenia poses significant challenges in patients with chronic liver disease. Here, we aimed to evaluate the first real-world European post-marketing cohort of cirrhotic patients treated with lusutrombopag, a thrombopoietin receptor agonist, verifying the efficacy and safety of the drug. Methods: In the REAl-world Lusutrombopag treatment in ITalY (REALITY) study, we collected data from consecutive cirrhotic patients treated with lusutrombopag in 19 Italian hepatology centers, mostly joined to the "Club Epatologi Ospedalieri" (CLEO). Primary and secondary efficacy endpoints were the ability of lusutrombopag to avoid platelet transfusions and to raise the platelet count to ≥50,000/μL, respectively. Treatment-associated adverse events were also collected. Results: A total of 66 patients and 73 cycles of treatment were included in the study, since 5 patients received multiple doses of lusutrombopag over time for different invasive procedures. Fourteen patients (19%) had a history of portal vein thrombosis (PVT). Lusutrombopag determined a significant increase in platelet count [from 37,000 (33,000-44,000/μL) to 58,000 (49,000-82,000), p < 0.001]. The primary endpoint was met in 84% of patients and the secondary endpoint in 74% of patients. Baseline platelet count was the only independent factor associated with response in multivariate logistic regression analysis (OR for any 1000 uL of 1.13, CI95% 1.04-1.26, p 0.01), with a good discrimination power (AUROC: 0.78). Notably, a baseline platelet count ≤ 29,000/μL was identified as the threshold for identifying patients unlikely to respond to the drug (sensitivity of 91%). Finally, de novo PVT was observed in four patients (5%), none of whom had undergone repeated treatment, and no other safety or hemorrhagic events were recorded in the entire population analyzed. Conclusions: In this first European real-world series, lusutrombopag demonstrated efficacy and safety consistent with the results of registrational studies. According to our results, patients with baseline platelet counts ≤29,000/μL are unlikely to respond to the drug.

Background and Aim: Thrombocytopenia is a frequent hematological condition in chronic liver disease (CLD) patients increasing the risk of bleeding in patients undergoing invasive procedures. Without an alternative, clinical guidelines recommended the use of platelet transfusion (PT) prior to procedure to prevent this bleeding risk. Lusutrombopag (LUSU), an orally active, small‐molecule thrombopoietin receptor agonist, was developed as an alternative to PT. The objective of this study was to evaluate a cost‐effectiveness of LUSU as a potential alternative to PT in Japan. Methods: A cost‐effectiveness analysis of LUSU relative to PT was conducted by a simulation model consisting of a decision tree combined to Markov model. Quality‐adjusted life years (QALYs) were used as an indicator of efficacy, and the analysis was conducted from the Japanese public healthcare payer's perspective. The time horizon of the analysis was 50 years (a lifetime) and the discount rate was set at 2%. Results: LUSU gained 6.1803 QALYs with an expected lifetime costs of 2 380 219 JPY compared to PT with 6.1712 QALYs gained and expected lifetime costs of 2 382 908 JPY. Thus, LUSU was deemed dominant compared with PT. Based on probabilistic analyses, the chance of LUSU being dominant and the incremental cost‐effectiveness ratio being below 5 million JPY/QALY was estimated at 51.8% and 78.3%, respectively, demonstrating the robustness of the results. Conclusions: LUSU was evaluated as an efficacious and cost‐saving treatment option for Japanese CLD patients with thrombocytopenia who required a planned invasive procedure compared with PT and economically should be considered as an alternative treatment. [ABSTRACT FROM AUTHOR]

Lusutrombopag is an oral platelet production promoter for thrombocytopenia in patients with chronic liver disease (CLD) that is usually administered before an invasive procedure. However, not all patients showed adequate platelet elevation. To the best of our knowledge, there is only one case report published so far on patients treated with lusutrombopag before tooth extraction. Here, we reported three cases of CLD complicated by thrombocytopenia treated with lusutrombopag before tooth extraction, whose platelet count (PLC) increased appropriately in two cases but did not rise in the third case, necessitating platelet transfusion. Case 1 was that of a 72-year-old male with cirrhosis, hepatocellular carcinoma, hypertension, chronic renal failure, and low PLC (4.7 × 104/μL). Case 2 was that of a 67-year-old female with cirrhosis, diabetes, and chronic renal failure, low PLC (3.6 × 104/μL). Both the PLCs of cases 1 and 2 increased appropriately after the administration of lusutrombopag, and we were able to perform extraction without platelet transfusion. Case 3 was that of a 56-year-old female with idiopathic portal hypertension, giant spleen, portal vein embolism, and systemic lupus erythematosus, whose PLC was reduced at 2.9 × 104/μL. Abdominal ultrasonography revealed an abnormal enlargement of the spleen. The PLC did not increase after lusutrombopag administration, and platelet transfusion was required during surgery in this case. Furthermore, PLC did not increase on the day after platelet transfusion. Therefore, this suggested that PLC did not increase by lusutrombopag or platelet transfusion because of splenomegaly caused by idiopathic portal hypertension. [ABSTRACT FROM AUTHOR]

Background & Aims: Despite limitations, platelet transfusion has been used to minimise bleeding risk in patients with thrombocytopaenia. Lusutrombopag is an oral, thrombopoietin receptor agonist approved for treatment of thrombocytopaenia associated with chronic liver disease in patients undergoing planned invasive procedures. This post-hoc analysis assessed the magnitude of platelet count change based on the integrated per-protocol population from 2 similar phase III multicentre, randomised, double-blind, placebo-controlled trials. Methods: Adults with chronic liver disease-induced thrombocytopaenia and platelet count

Background: To make an accurate estimate of the response to thrombopoietin (TPO) receptor agonists for thrombocytopenia associated with chronic liver disease, we evaluated the influence of antiplatelet autoantibodies on the response to lusutrombopag in thrombocytopenic patients with liver disease. Methods: A prospective study was conducted at 2 hospitals. Thrombocytopenic patients with liver disease received oral lusutrombopag 3.0 mg once daily for up to 7 days. We analyzed changes in platelet counts from baseline to the maximum platelet count on days 9–14. The definition of clinical response was a platelet count of ≥5 × 104/μL with an increased platelet count of ≥2 × 104/μL from baseline. We assessed the correlation between the response to treatment drug and antiplatelet autoantibodies measured by anti-GPIIb/IIIa antibody-producing B cells. Results: Thirty patients received the trial drug. There were 25 responders and 5 nonresponders. The median change in platelet counts was 3.9 × 104/μL (95% CI 2.8–4.6, p < 0.0001). The correlation between change in platelet counts and the frequency of the anti-glycoprotein IIb/IIIa antibody-producing B cells was moderate (r = 0.414, 95% CI 0.064–0.674, p = 0.023). In multivariate analysis of factors affecting the change in platelet counts, the anti-GPIIb/IIIa antibody-producing B cells were identified as an independent factor (regression coefficient [B] = 0.089; CI 0.021–0.157, p = 0.013). Conclusion: Anti-GPIIb/IIIa antibody-producing B cells may be a predictor for TPO receptor agonists in patients with chronic liver disease. [ABSTRACT FROM AUTHOR]

The human mass balance of lusutrombopag, an orally bioavailable thrombopoietin (TPO) receptor agonist, was characterised in seven healthy male subjects after a single oral dose of [14C]-lusutrombopag (2 mg, 100 μCi) in solution. Lusutrombopag was the main component in plasma, accounting for 56% of plasma radioactivity AUC0-∞. In plasma, the half-life of radioactivity (70.7 h) was longer than that of lusutrombopag (25.7 h), suggesting the presence of long circulating metabolites. The main excretion pathway of lusutorombopag was feces, with a radioactivity recovery of approximately 83% within 336 h post-dose. M6 (lusutrombopag-O-propanol or lusutrombopag-O-acetic acid) and M7 (lusutrombopag-O-ethane-1,2-diol) were also identified as main components in feces, accounting for at most 17.9%, and 16.9% of the dose, respectively, and were β-oxidation related metabolites. Our in vitro metabolism study of lusutrombopag indicated that β-oxidation was a subsequent metabolism of ω-oxidation and CYP4 enzymes, including CYP4A11, were the major isozymes contributing to ω-oxidation. In conclusion, lusutrombopag is primarily eliminated via ω-oxidation and excreted in the feces, where CYP4 enzymes play an important role. [ABSTRACT FROM AUTHOR]

Due to the widespread abuse of antibiotics, drug resistance in Enterococcus has been increasing. However, the speed of antibiotic discovery cannot keep pace with the acquisition of bacterial resistance. Thus, drug repurposing is a proposed strategy to solve the crises. Lusutrombopag (LP) has been approved as a thrombopoietin receptor agonist by the Food and Drug Administration. This study demonstrated that LP exhibited significant antimicrobial activities against vancomycin-resistant Enterococcus in vitro with rare resistance occurrence. Further, LP combined with tobramycin exhibited synergistic antimicrobial effects in vitro and in vivo against Enterococcus. No in vitro or in vivo detectable toxicity was observed when using LP. Mechanism studies indicated that the disrupted proton motive force may account for LP's antimicrobial activity. In summary, these results demonstrate that LP has the previously undocumented potential to serve as an antibacterial agent against refractory infections caused by Enterococcus.

Abstract 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.

Background: The thrombopoietin (TPO) receptor agonist lusutrombopag was developed to treat thrombocytopenia in chronic liver disease (CLD). However, its effectiveness remains unclear. The purpose of this study was to assess the efficacy of lusutrombopag and identify predictors associated with increase in platelet count. Methods: Eighty CLD patients with thrombocytopenia were enrolled. The primary endpoint was a satisfactory increase in platelets (greater than 1.0 × 104/μL from baseline) in the absence of platelet transfusion. The secondary endpoints were response rate (an increase of greater than 1.0 × 104/μL from baseline), independent predictors of increase in platelets, and the superiority of lusutrombopag over platelet transfusion. Results: The primary endpoint was achieved in 93.8% (75 of 80) patients. The response rate was 96.2% (77 of 80). Renal function parameters (blood urea nitrogen, creatinine, eGFR) were significantly negatively associated with platelet count (p = 0.033, 0.049, and 0.0014, respectively) and were identified as independent predictors by multiple regression analysis (p = 0.049, 0.0023, and 0.0016, respectively). The median increase in platelet count was significantly higher after lusutrombopag than after platelet transfusion (41,000 vs. 12,000/μL, p = 0.015). Conclusion: Lusutrombopag was more effective than platelet transfusion for CLD patients, and renal function independently predicted increase in platelet count. Renal function parameters were significantly associated with platelet count. [ABSTRACT FROM AUTHOR]

Purpose: Drug-drug interaction (DDI) potentials of lusutrombopag, a thrombopoietin receptor agonist, on the activity of cytochrome P450 (CYP) 3A and of cyclosporine, which inhibits P-glycoprotein and breast cancer resistance protein, on lusutrombopag pharmacokinetics were assessed via clinical studies and physiologically based pharmacokinetic (PBPK) modeling. Methods: The effect of lusutrombopag on midazolam (a CYP3A probe substrate) pharmacokinetics was assessed in 15 healthy subjects receiving a single midazolam 5-mg dose with or without coadministration of lusutrombopag 0.75 mg for 6 days (first dose: 1.5-mg dose). The effect of cyclosporine on lusutrombopag pharmacokinetics was assessed in 16 healthy subjects receiving a single lusutrombopag 3-mg dose with or without a single cyclosporine 400- to 600-mg dose. PBPK modeling was employed to extrapolate the effect of lusutrombopag at the clinical dose (3 mg once daily) on midazolam pharmacokinetics. Results: In the clinical study, mean ratios (90% confidence intervals [CIs]) of with/without lusutrombopag for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of midazolam were 1.01 (0.908–1.13) and 1.04 (0.967–1.11), respectively, indicating no effect of lusutrombopag on midazolam pharmacokinetics. PBPK modeling suggested no effect of lusutrombopag at the clinical dose on midazolam pharmacokinetics. Mean ratios (90% CIs) of with/without cyclosporine for lusutrombopag Cmax and AUC were 1.18 (1.11–1.24) and 1.19 (1.13–1.25), respectively, indicating a slight increase in lusutrombopag exposure. Conclusions: In consideration with in vitro data, the in vivo and in silico results suggested no clinically significant DDI potential of lusutrombopag with other medical products via metabolic enzymes and transporters. [ABSTRACT FROM AUTHOR]

Aim: Lusutrombopag is approved for thrombocytopenia in chronic liver disease patients planned to undergo invasive procedures. In previous clinical studies, lusutrombopag treatment was stopped in patients with an increase in platelet count (PC) of ≥20 × 109/L from baseline and whose PC was ≥50 × 109/L (discontinuation criteria). We assessed the influence of platelet monitoring during lusutrombopag treatment in lusutrombopag‐naïve patients. Methods: In this open‐label study, Child–Pugh class A and B (A/B) patients were enrolled and treated with lusutrombopag (3 mg/day) for 7 days. In the treatment‐naïve A/B‐1 group, the discontinuation criteria were applied on day 6. In the treatment‐naïve A/B‐2 group, the criteria were not applied. In a non‐naïve A/B group, the criteria were applied on days 3 and 5–7. The main efficacy end‐point was the proportion of patients without platelet transfusion (PT) before the primary invasive procedure. Results: In the A/B‐1, A/B‐2, and non‐naïve A/B groups, the proportions of patients without PT were 80.9% (38/47), 83.0% (39/47), and 75.0% (6/8), respectively. The mean durations of PC ≥ 50 × 109/L without PT were 20.7, 20.3, and 22.8 days, respectively. Excessive PC increases (≥200 × 109/L) were not detected in any group. Treatment‐related adverse events occurred in 4.3%, 6.4%, and 0% of A/B‐1, A/B‐2, and non‐naïve A/B patients, respectively. Severe portal vein thrombosis occurred in one A/B‐2 patient (PC 75 × 109/L at onset). Conclusions: No meaningful efficacy and safety differences were observed among the groups with or without discontinuation criteria and the non‐naïve group. These findings support lusutrombopag treatment without platelet monitoring and retreatment with lusutrombopag. [ABSTRACT FROM AUTHOR]

Aims: Thrombocytopenia is a common complication among patients with chronic liver disease (CLD). Lusutrombopag, an oral thrombopoietin receptor agonist, is used to reduce the risk of hemorrhage in patients with thrombocytopenia who are undergoing invasive procedures. Platelet transfusion was the standard treatment for thrombocytopenia; however, multiple platelet transfusions lead to the production of antiplatelet antibody. The effect of giving lusutrombopag three times or more has not been previously reported. In this study, we investigated the effect of lusutrombopag readministration in patients with thrombocytopenia. Methods: This study included 14 patients (total, 24 readministrations) who received lusutrombopag two times or more. Changes in platelet counts were evaluated. Treatment response was defined as an increased platelet count of ≥20 000/μL after lusutrombopag treatment. Results: Lusutrombopag was given twice in nine patients, three times in three patients, five times in one patient, and six times in one patient. An elevated platelet count of <20 000/μL was noted in only one of the 24 readministrations. There were no postoperative hemorrhagic complications, and no patient had an increased platelet count of >200 000/μL. One patient had a portal venous mural thrombus; however, he was asymptomatic, and the thrombus resolved after anticoagulant treatment, without recurrence. The comparison between the first, second, and third or more treatments showed there was no significant difference in platelet increase. Conclusion: Repeated treatment of lusutrombopag is effective for CLD patients with thrombocytopenia. Moreover, three or more treatments with lusutrombopag showed equal effect compared with one and two treatments with the medication. [ABSTRACT FROM AUTHOR]

Aim: The thrombopoietin receptor agonist, lusutrombopag, was recently adapted for treatment of thrombocytopenia in chronic liver disease. However, no studies have compared the effects of lusutorombopag and platelet transfusion. Therefore, we aimed to clarify the efficacy and proportion of responders of lusutrombopag compared with platelet transfusion, by propensity score matching. Methods: A total of 200 patients (90 lusutrombopag, 110 platelet transfusion) with thrombocytopenia were enrolled, and matched for age, liver function, renal function, platelet count, peripheral blood count, and spleen size, using the propensity score‐matching method. Finally, 52 patients (26 lusutrombopag, 26 platelet transfusion) were included. The primary end‐point was an increase in platelet count. Secondary end‐points were the proportion of responders, duration of the sustained effect, incidence of adverse events, and predictors associated with an increase in platelet count. Results: The median increase in platelets from baseline was 48 × 103/μL versus 9.5 × 103/μL (lusutrombopag vs. transfusion, P < 0.0001). The proportion of responders (increase of >10 × 103/μL) was 100% versus 50.0% (P < 0.0001). Median duration of the sustained effect (increase of >50 × 103/μL) was 10 versus 2 days (P < 0.0001). The incidence of adverse events was 7.7% versus 50.0% (P = 0.036). Predictors associated with an increase in platelets were hemoglobin and spleen size by multiple regression analysis. Conclusion: Lusutrombopag was more effective in chronic liver disease patients than platelet transfusion. The proportion of responders, effect duration, and non‐incidence rate of adverse events were higher in the lusutrombopag group. [ABSTRACT FROM AUTHOR]

Thrombocytopenia is one of the most common hematologic complications in cirrhosis. Despite limited data linking platelet count and bleeding risk in patients with cirrhosis, the use of platelets transfusions for invasive procedures has been a common practice. Recently, thrombopoietin (TPO) receptor agonists have been approved for use in patients with chronic liver disease (CLD) undergoing invasive procedures. The aim of this study was to review current literature on bleeding risk in patients with cirrhosis and the use of platelet transfusions and TPO receptor agonists in the context of invasive procedures. PubMed search was conducted to find articles relating to cirrhosis, thrombocytopenia, and new novel treatments for this condition. Search terms included CLD, cirrhosis, thrombocytopenia, bleeding, thrombosis, coagulopathy, hemostasis, and TPO receptor agonists. Romiplostim, eltrombopag, avatrombopag, and lusutrombopag are approved TPO receptor agonists, with avatrombopag and lusutrombopag specifically approved for use in patients with CLD undergoing invasive procedures. In patients with platelet counts < 50,000/mm 3 , avatrombopag and lusutrombopag increased the platelet counts above this threshold in the majority of treated patients and reduced the frequency of platelet transfusions. At the approved doses, incidence of thrombosis was not increased and therapies were well tolerated. Studies were not powered to assess whether risk of bleeding complications was reduced and the fundamental question of whether correction of thrombocytopenia is warranted in patients undergoing invasive procedures remains unanswered. The use of TPO receptor agonists has resulted in less requirement for platelet transfusions. In patients with cirrhosis undergoing invasive procedures for whom platelet transfusion is planned, TPO receptor agonists are an alternative and avoid the risks associated with transfusions. However, there is need for a thoughtful approach to manage bleeding risk in patients with cirrhosis undergoing procedures, with the consideration of a comprehensive hemostatic profile, the severity of portal hypertension, and the complexity of the invasive procedure to guide decisions regarding transfusions or use of TPO receptor agonists. [ABSTRACT FROM AUTHOR]

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 <50,000/µL. However, its usefulness in patients with platelet counts ≥50,000/µL remains unknown. We studied the effectiveness of lusutrombopag administration in patients with platelet counts of ≥50,000/µL. 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 <50,000/µL were evaluated. 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 <50,000/µL. [ABSTRACT FROM AUTHOR]

Background and Aim: Certain thrombocytopenic patients with chronic liver disease have inadequate platelet count recovery after platelet transfusion or lusutrombopag administration. We aimed to identify the reasons for this phenomenon. Methods: We investigated 58 and 86 thrombocytopenic patients with chronic liver disease who received lusutrombopag (3 mg orally for up to 7 days) or underwent blood transfusions, respectively. Thirty patients underwent simultaneous hepatic surgery and splenectomy. Factors preventing platelet count recovery above 50 × 103/μL were identified. Results: The median patient age was 64 years. Eleven, 78, and 55 patients had hepatitis B, hepatitis C, or another etiology, respectively; 59, 69, and 16 had Child–Pugh classes A, B, and C, respectively. The median spleen volume was 432 mL, and a median of 10 blood units were transfused per patient. The median platelet count rose significantly (from 41.5 × 103/μL to 81.0 × 103/μL) after lusutrombopag administration but not after blood transfusion before invasive procedures. However, maximum platelet counts in patients who underwent splenectomy before platelet transfusion were markedly improved over those who did not. Increasing platelet counts above 50 × 103/μL required baseline platelets > 30 × 103/μL and lusutrombopag administration for all patients. Platelet count recovery was dependent on a spleen volume of < 300 mL and baseline platelets of > 40 × 103/μL in patients who underwent platelet transfusions, while a baseline platelet count of > 30 × 103/μL was required for patients administered with lusutrombopag. Conclusion: Neither blood transfusion nor lusutrombopag improves thrombocytopenia in patients with severe conditions; however, the degree of platelet count elevation following lusutrombopag administration is higher than that following blood transfusion. [ABSTRACT FROM AUTHOR]

• A sensitive HPLC-MS/MS assay for analysis of Lusutrombopag in plasma sample. • Recently implemented FDA guideline was followed for method validation. • Successfully applied in metabolic stability and pharmacokinetic study in rats. 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. [ABSTRACT FROM AUTHOR]

This article reviews nine drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Thrombocytopenia is often associated with chronic liver disease. Lusutrombopag is a small molecule thrombopoietin receptor agonist designed to temporarily increase the platelet count in patients with chronic liver disease for whom elective invasive procedures are planned. In the present study, the efficacy and safety of repeated use of lusutrombopag prior to radiofrequency ablation (RFA) for recurrent hepatocellular carcinoma were examined. Methods: Eight patients with hepatocellular carcinoma who had a platelet count <50 000/μL prior to both initial and repeat RFA at the time of recurrence received lusutrombopag (3 mg/day) orally for 7 days between March 2016 and August 2018. The following were compared: the effect of lusutrombopag to increase the platelet count as determined by the platelet count after the initial and repeated use of lusutrombopag, the rate of avoiding platelet transfusion, and the presence of any complications. Results: The platelet count increased to 103 100 ± 22 800/μL 14 days after the first treatment and to 110 700 ± 17 800/μL 14 days after the repeated use. None of the patients required platelet transfusion. None of the patients developed clinical symptoms such as thrombosis, fever, rash, portal vein thrombosis, bleeding, or any other serious adverse events. Conclusions: Repeated use of lusutrombopag increased the platelet count. It did not cause any serious adverse events and led to avoidance of platelet transfusion. Radiofrequency ablation was carried out safely in all patients. Future studies with more cases of repeated use are needed to examine the long‐term efficacy and safety of lusutrombopag. [ABSTRACT FROM AUTHOR]

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 < 50 × 103/µL at screening were randomized to placebo or lusutrombopag 2, 3, or 4 mg once daily for 7 days, followed by a 28-day post-treatment assessment period. The primary efficacy endpoint was the proportion of patients who did not require platelet transfusion before RFA. The pre-specified key secondary efficacy endpoint was the proportion of responders. Adverse events (AEs) and thrombosis-related AEs were evaluated.Results: The proportion of patients who did not require platelet transfusion before RFA and that of responders were significantly higher (p < 0.01) in the 2-mg (80.0, 66.7%), 3-mg (81.3, 68.8%), and 4-mg groups (93.3, 80.0%) compared with the placebo group (20.0, 6.7%) and showed a dose-dependent effect. The incidence of AEs was 97.8 and 100% in the lusutrombopag (all groups) and placebo groups, respectively; no dose-related increase was observed. Four patients experienced thrombosis-related events (one each in the placebo and 2-mg groups, and two in the 4-mg group). A total of 16 (18%) adverse drug reactions occurred in the safety analysis set.Conclusions: Lusutrombopag 3 mg once daily for 7 days was effective without raising concerns about excessive increases in platelet count.Clinical Trial Registration: The study is registered at JapicCTI-121944. [ABSTRACT FROM AUTHOR]

A 56-year-old Japanese man with liver cirrhosis (LC) due to hepatitis C virus was admitted to our hospital for radiofrequency ablation of residual tumor following lusutrombopag administration. Laboratory tests revealed thrombocytopenia and leukopenia. The patient's LC was managed, and he was classified as Child-Pugh A. After admission, lusutrombopag was administered for 7 days. The platelet count increased to over 50,000/mm after 7-14 days and returned to previous levels 50 days after administration. Leukocyte and erythrocyte counts also increased in response to the treatment and stayed elevated for over 120 days. Lusutrombopag acts selectively on human thrombopoietin (TPO) receptors and activates signaling pathways that promote the proliferation and differentiation of bone marrow progenitor cells into megakaryocytes, consequently increasing the blood platelet count. However, the patient treated with lusutrombopag in our case study showed increased blood leukocyte and erythrocyte counts as well. Given that TPO receptors are reportedly expressed in not only megakaryocyte progenitor cells but also hematopoietic progenitors, lusutrombopag may potentially improve pancytopenia caused by LC and can be used for the recovery of blood counts before other treatments. [ABSTRACT FROM AUTHOR]