lusutrombopag and Thrombocytopenia

The thrombopoietin receptor agonists (TPO-RAs) romiplostim, eltrombopag, avatrombopag, and lusutrombopag carry unique US Food and Drug Administration (US FDA)- and European Medicines Agency (EMA)-approved indications and may be used to increase platelet counts in a variety of conditions. Current indications for available TPO-RAs include treatment of chronic immune thrombocytopenia (ITP) in cases of insufficient response to prior treatment (avatrombopag, eltrombopag, romiplostim), management of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure (avatrombopag, lusutrombopag), management of severe aplastic anemia (eltrombopag), and management of thrombocytopenia associated with interferon-based therapy for hepatitis C (eltrombopag). Across current indications, pharmacists can assist in stabilizing platelet counts and help to reduce large undulations commonly seen when starting, stopping, or transitioning between these agents. If therapy modifications may benefit the patient, pharmacists should discuss possible changes with the patient's treatment team or treating physician. When used for ITP, romiplostim, eltrombopag, and avatrombopag stimulate TPO receptors on hematopoietic stem cells (also known as c-Mpl, or CD110) to promote platelet production; however, romiplostim is the only TPO-RA that binds at the same site as endogenous TPO. These subtle mechanistic differences may explain why switching TPO-RA may be clinically advantageous in some situations. As pharmacists are called to counsel patients on TPO-RA use, a deep understanding of potential adverse events and management strategies, as well as appropriate monitoring, will increase the likelihood that patients meet their goals of therapy in the shortest timeframe. Other uses of TPO-RAs are also discussed in this review, including use following hematopoietic stem cell transplant, use in myelodysplastic syndrome, and use in chemotherapy-induced thrombocytopenia.

Topics: Benzoates; Cinnamates; Dose-Response Relationship, Drug; Drug Monitoring; Health Knowledge, Attitudes, Practice; Humans; Hydrazines; Pharmacists; Platelet Count; Pyrazoles; Receptors, Fc; Receptors, Thrombopoietin; Recombinant Fusion Proteins; Thiazoles; Thiophenes; Thrombocytopenia; Thrombopoietin

Patients with hepatocellular carcinoma (HCC) secondary to chronic liver disease often require invasive procedures but frequently have thrombocytopenia. Lusutrombopag is an agonist of the thrombopoietin receptor that activates platelet production.. The per-protocol population included 270 patients (95 with HCC). A significantly higher proportion of patients with HCC who received lusutrombopag achieved the primary end point (68.0%) vs patients who received placebo (8.9%) (P < .0001); in patients without HCC, these proportions were 77.0% vs 21.6% (P < .0001). Lusutrombopag reduced the need for platelet transfusions, increased platelet counts for 3 weeks, and reduced the number of bleeding events in patients with and without HCC compared with placebo. Risk of thrombosis was similar to that of placebo.. Patients with and without HCC receiving lusutrombopag had a reduction in the number of platelet transfusions before invasive procedures compared with patients receiving placebo, with no increase in thrombosis or bleeding. L-PLUS 1: JapicCTI-132323; L-PLUS 2: ClinicalTrials.gov number no: NCT02389621.

Topics: Carcinoma, Hepatocellular; Cinnamates; Humans; Liver Neoplasms; Thiazoles; Thrombocytopenia

Thrombocytopenia is common in advanced liver disease, and such patients frequently need invasive procedures. Numerous mechanisms for thrombocytopenia exist, including splenic sequestration and reduction of levels of the platelet growth factor thrombopoietin. Traditionally, platelet transfusions have been used to increase platelet counts before elective procedures, usually to a threshold of greater than or equal to 50,000/μL, but levels vary by provider, procedure, and specific patient. Recently, the thrombopoietin receptor agonists avatrombopag and lusutrombopag were studied and found efficacious for increasing platelet count in the outpatient setting for select patients with advanced liver disease who need a procedure.

Topics: Chronic Disease; Cinnamates; Hemorrhage; Humans; Liver Diseases; Platelet Count; Platelet Transfusion; Receptors, Thrombopoietin; Risk Factors; Surgical Procedures, Operative; Thiazoles; Thiophenes; Thrombocytopenia; Thrombopoiesis

There have been no licensed treatment options in the UK for treating thrombocytopenia in people with chronic liver disease requiring surgery. Established management largely involves platelet transfusion prior to the procedure or as rescue therapy for bleeding due to the procedure.. To assess the clinical effectiveness and cost-effectiveness of two thrombopoietin receptor agonists, avatrombopag (Doptelet. Systematic review and cost-effectiveness analysis.. Secondary care.. Severe thrombocytopenia (platelet count of < 50,000/µl) in people with chronic liver disease requiring surgery.. Lusutrombopag 3 mg and avatrombopag (60 mg if the baseline platelet count is < 40,000/µl and 40 mg if it is 40,000-< 50,000/µl).. Risk of platelet transfusion and rescue therapy or risk of rescue therapy only.. Systematic review including meta-analysis. English-language and non-English-language articles were obtained from several databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials, all searched from inception to 29 May 2019.. Model-based cost-effectiveness analysis.. From a comprehensive search retrieving 11,305 records, six studies were included. Analysis showed that avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy or rescue therapy only, and mostly with a statistically significant difference (i.e. 95% confidence intervals not overlapping the point of no difference). However, only avatrombopag seemed to be superior to no thrombopoietin receptor agonist in reducing the risk of rescue therapy, although far fewer patients in the lusutrombopag trials than in the avatrombopag trials received rescue therapy. When assessing the cost-effectiveness of lusutrombopag and avatrombopag, it was found that, despite the success of these in avoiding platelet transfusions prior to surgery, the additional long-term gain in quality-adjusted life-years was very small. No thrombopoietin receptor agonist was clearly cheaper than both lusutrombopag and avatrombopag, as the cost savings from avoiding platelet transfusions were more than offset by the drug cost. The probabilistic sensitivity analysis showed that, for all thresholds below £100,000, no thrombopoietin receptor agonist had 100% probability of being cost-effective.. Some of the rescue therapy data for lusutrombopag were not available. There were inconsistencies in the avatrombopag data. From the cost-effectiveness point of view, there were several additional important gaps in the evidence required, including the lack of a price for avatrombopag.. Avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy, but they were not cost-effective given the lack of benefit and increase in cost.. A head-to-head trial is warranted.. This study is registered as PROSPERO CRD42019125311.. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in

Topics: Bayes Theorem; Cinnamates; Clinical Trials as Topic; Cost-Benefit Analysis; End Stage Liver Disease; Humans; Models, Economic; Platelet Transfusion; Quality-Adjusted Life Years; Receptors, Thrombopoietin; Secondary Care; Technology Assessment, Biomedical; Thiazoles; Thiophenes; Thrombocytopenia

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.

Topics: Aminopyridines; Animals; Cinnamates; Drug Development; Humans; Morpholines; Oxazines; Pyridines; Pyrimidines; Receptors, Thrombopoietin; Small Molecule Libraries; Syk Kinase; Thiazoles; Thiophenes; Thrombocytopenia

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.. 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.. 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).. Anti-GPIIb/IIIa antibody-producing B cells may be a predictor for TPO receptor agonists in patients with chronic liver disease.

Topics: Aged; Aged, 80 and over; Autoantibodies; B-Lymphocytes; Blood Platelets; Cinnamates; Female; Humans; Liver Diseases; Male; Middle Aged; Multivariate Analysis; Organ Size; Platelet Count; Platelet Glycoprotein GPIIb-IIIa Complex; Prospective Studies; Spleen; Thiazoles; Thrombocytopenia

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.. 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.. 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.. 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.

Topics: Aged; Cinnamates; Female; Humans; Male; Platelet Count; Postoperative Complications; Receptors, Thrombopoietin; Thiazoles; Thrombocytopenia; Time Factors; Treatment Outcome

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.. 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.. Lusutrombopag 3 mg once daily for 7 days was effective without raising concerns about excessive increases in platelet count.. The study is registered at JapicCTI-121944.

Topics: Aged; Aged, 80 and over; Carcinoma, Hepatocellular; Chronic Disease; Cinnamates; Double-Blind Method; Female; Half-Life; Humans; Japan; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Platelet Count; Platelet Transfusion; Preoperative Care; Radiofrequency Ablation; Receptors, Thrombopoietin; Thiazoles; Thrombocytopenia; Thrombosis

Platelet transfusion is used to prevent hemorrhagic events in patients with thrombocytopenia undergoing invasive procedures, but there are many disadvantages. We evaluated the efficacy and safety of lusutrombopag in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures.. We performed a double-blind, parallel-group, phase 3 study of 96 patients with chronic liver disease and thrombocytopenia (platelet counts below 50,000/μL) undergoing invasive procedures from October 2013 to May 2014 at 81 centers in Japan. Patients were randomly assigned (1:1) to groups given once-daily lusutrombopag (3 mg) or placebo for up to 7 days. The primary efficacy endpoint was the proportion of patients not requiring platelet transfusion before the invasive procedure. The protocol-defined response (platelet count 50,000/μL or more with an increase of 20,000/μL or more from baseline) and the time course of the change in platelet count were also evaluated. Adverse events were recorded.. The proportions of patients who did not require preoperative platelet transfusion were 79.2% (38/48) in the lusutrombopag group and 12.5% (6/48) in the placebo group (P < .0001). A response was observed in 77.1% (37/48) of patients in the lusutrombopag group and 6.3% (3/48) of patients in the placebo group (P < .0001). In the lusutrombopag group without platelet transfusion, the median platelet count was 50,000/μL or more after 5 days; the mean time to reach the maximum platelet count was 13.4 days; and the number of days (adjusted mean) during which the platelet count was 50,000/μL or more was 21.09 days. Adverse drug reactions were reported in 8.3% of patients in the lusutrombopag group and 2.1% of patients in the placebo group. Two patients (1 per group) had a thrombotic event, but neither were associated with an excessive increase in platelet count (200,000/μL or more).. In a placebo-controlled trial, lusutrombopag was effective in achieving and maintaining the target platelet count in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures. No significant safety concerns were raised. Japanese clinical trial registration no: JapicCTI-132323.

Topics: Aged; Catheter Ablation; Cinnamates; Double-Blind Method; Female; Follow-Up Studies; Humans; Incidence; Japan; Liver Cirrhosis; Male; Platelet Transfusion; Postoperative Hemorrhage; Retrospective Studies; Thiazoles; Thrombocytopenia; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Cinnamates; Humans; Propensity Score; Receptors, Thrombopoietin; Thiazoles; Thrombocytopenia

Lusutrombopag is a thrombopoietin receptor agonist which reduces the need for platelet transfusions before planned invasive procedures. A post hoc analysis of data from the registration trials observed that lusutrombopag-treated patients who achieved a platelet count > 50 × 109/L (responder patients) did so in a median of 6 days and the effect on platelet count lasted for nearly 3 weeks in total. Since patients with cirrhosis often require repeat invasive procedures, this kind of response-time trend sheds light on the possibility of placing more than one invasive procedure within a single course of lusutrombopag treatment.. Platelet transfusion represents the gold standard in this setting, but is limited by the risk of adverse events and limited availability.. We describe our experience with lusutrombopag in three patients with severe cirrhosis-associated thrombocytopenia who underwent multiple invasive procedures after a single course of treatment.. The treatment schedule is lusutrombopag orally 3 mg/daily for 7 days and then a time window of 6 days (day 9-14) for the elective invasive procedure.. All three patients achieved good response to lusutrombopag treatment and were able to undergone more invasive procedures in the same course of treatment without need of platelet transfusion.. our preliminary experience supports the safety and the effectiveness of lusutrombopag in patients with severe cirrhosis-associated thrombocytopenia who underwent multiple invasive elective procedures after a single course.

Topics: Cinnamates; Humans; Liver Cirrhosis; Thiazoles; Thrombocytopenia

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.. Lusutrombopag was administered repeatedly in patients undergoing multi-cycle invasive procedures at intervals >1 month.. 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.. 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.

Topics: Chronic Disease; Cinnamates; Humans; Liver Diseases; Receptors, Thrombopoietin; Retrospective Studies; Thiazoles; Thrombocytopenia

Bleeding may interfere with the visual field and create difficulties in performing the intended treatment, especially in operations involving a small working space such as endoscopic spinal surgery. Therefore, it is important to reduce the risk of bleeding before surgery.. A 76-year-old female presented with a history of right anterior thigh pain along the L3 dermatome for 3-years, following a L3 compression fracture. In addition, the patient had developed autoimmune hepatitis at 50 years of age, and the platelet count on laboratory blood collection was 78 × 109/L.. Magnetic resonance (MR) images showed a narrowed foramen at the L3-4 level. L3 nerve block was effective. L3 foraminal-stenosis was suspected.. Micro-endoscopic laminectomy (MEL) for foraminal decompression was planned due to possible L3 nerve root compression. Lusutrombopag, a thrombopoietin (TPO) receptor agonist, was orally administered for 7 days starting 7 days preoperatively to address the risks of bleeding.. The patient successfully underwent MEL without any adverse events or complications.. The results obtained from the use of lusutrombopag suggested that safety measures could be implemented preoperatively, and that lusutrombopag may be a useful supplemental drug for minimally invasive treatment of patients with cirrhosis and thrombocytopenia.

Topics: Aged; Blood Loss, Surgical; Cinnamates; End Stage Liver Disease; Endoscopy; Female; Humans; Lumbar Vertebrae; Spinal Fractures; Thiazoles; Thrombocytopenia

Topics: Aged; Biopsy; Blood Loss, Surgical; Chemoembolization, Therapeutic; Chronic Disease; Cinnamates; Endoscopy, Digestive System; Female; Humans; Liver Diseases; Male; Middle Aged; Perioperative Care; Platelet Transfusion; Postoperative Hemorrhage; Radiofrequency Ablation; Randomized Controlled Trials as Topic; Receptors, Thrombopoietin; Retrospective Studies; Thiazoles; Thrombocytopenia; Tooth Extraction

Topics: Cinnamates; Endoscopy; Humans; Liver Cirrhosis; Receptors, Thrombopoietin; Surveys and Questionnaires; Thiazoles; Thiophenes; Thrombocytopenia

Chronic liver disease (CLD) is often complicated by severe thrombocytopenia (platelet count < 50,000/µL). Platelet transfusion has been a gold standard for increasing the platelet count to prevent hemorrhagic events in such patients. Lusutrombopag, a thrombopoietin receptor agonist, can increase the platelet count in such patients when invasive procedures are scheduled. Former studies on lusutrombopag included patients with a platelet count of > 50,000/µL at baseline: the proportions of patients who did not require platelet transfusion were 84-96%, which might be overestimated.. The efficacy and safety of lusutrombopag were retrospectively investigated in CLD patients with platelet count of < 50,000/µL, a criterion for platelet transfusion, in real-world settings. We examined the proportion of patients who did not require platelet transfusion in 31 CLD patients, which exceeded a minimum required sample size (21 patients) calculated by 80% power at a significance level of 5%. Lusutrombopag, 3 mg once daily, was administered 8-18 days before scheduled invasive procedures.. 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.. 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 < 50,000/µL.

Topics: Cinnamates; Humans; Liver Diseases; Receptors, Thrombopoietin; Retrospective Studies; Thiazoles; Thrombocytopenia

The present study aimed to report our real-life experience of the TPO receptor agonist lusutrombopag for cirrhotic patients with low platelet counts.. We studied platelet counts in 1,760 cirrhotic patients undergoing invasive procedures at our hospital between January 2014 and December 2017. In addition, we studied 25 patients who were administered lusutrombopag before invasive procedures between June 2017 and January 2018. Effectiveness of lusutrombopag to raise platelet counts and to avoid transfusion and treatment-related adverse events were analyzed.. In 1,760 cirrhotic patients without lusutrombopag prior to invasive procedures, proportion of patients whose platelet counts <50,000/μL and needed platelet transfusions were 66% (n = 27/41) for radiofrequency ablation, 43% (n = 21/49) for transarterial chemoembolization, and 55% (n = 21/38) for endoscopic injection sclerotherapy / endoscopic variceal ligation, respectively. In 25 cirrhotic patients treated by lusutrombopag prior to the invasive procedures, platelet counts significantly increased compared with baseline (82,000 ± 26,000 vs. 41,000 ± 11,000/μL) (p < 0.01). Out of 25 patients, only 4 patients (16%) needed platelet transfusion before the invasive procedures. The proportion of patients with low platelet count and who needed platelet transfusions was significantly low in patients treated with lusutrombopag compared to those not treated with lusutrombopag (16% (4/25) vs. 54% (69/128), p = 0.001). Platelet counts after lusutrombopag treatment and prior to invasive procedures were lower in patients with a baseline platelet count ≤30,000/μL (n = 8) compared with those with a baseline platelet count >30,000/μL (n = 17) (50,000 ± 20,000 vs 86,000 ± 26,000/μL, p = 0.002). Patients with a baseline platelet count ≤30,000/μL with spleen index (calculated by multiplying the transverse diameter by the vertical diameter measured by ultrasonography) ≥40 cm2 (n = 3) had a lower response rate to lusutrombopag compared to those with spleen index <40 cm2 (n = 5) (0% vs. 100%, p = 0.02). Hemorrhagic complication was not observed. Recurrence of portal thrombosis was observed and thrombolysis therapy was required in one patient who had prior history of thrombosis.. Lusutrombopag is an effective and safe drug for thrombocytopenia in cirrhotic patients, and can reduce the frequency of platelet transfusions.

Topics: Aged; Carcinoma, Hepatocellular; Catheter Ablation; Chemoembolization, Therapeutic; Cinnamates; Esophageal and Gastric Varices; Female; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Platelet Count; Platelet Transfusion; Receptors, Thrombopoietin; Retrospective Studies; Sclerotherapy; Thiazoles; Thrombocytopenia

Patients with thrombocytopenia associated with chronic liver disease (CLD) are at greater risk of bleeding during invasive procedures. This study characterized the pharmacokinetic/pharmacodynamic (PK/PD) profile of lusutrombopag, a novel thrombopoietin-receptor agonist, using modelling and simulation, and evaluated the appropriate dose regimen for treatment of thrombocytopenia in CLD patients undergoing invasive procedures.. A population PK/PD model was developed using plasma lusutrombopag concentrations from 78 healthy subjects and 349 CLD patients, as well as platelet counts from 347 of these 349 patients. Covariates were explored from subject characteristics. Monte-Carlo simulations were performed to assess a dose response for efficacy (platelet counts ≥ 50,000/μL) and a risk for platelet overshooting (platelet counts > 200,000/μL).. Visual predictive checks indicated the developed models described the PK/PD profile of lusutrombopag well. In the simulations, without stopping criteria, lusutrombopag 3 mg once daily for 7 days before scheduled invasive procedures provided effective platelet response (85.2% probability for efficacy). The probability of platelet overshooting was 1.2%, indicating that platelet monitoring is not necessary. Although body weight was an influential covariate on the pharmacokinetics of lusutrombopag, individually estimated peak platelet counts overlapped among the body weight groups, suggesting no clinically significant effect on body weight.. The modelling and simulation support lusutrombopag 3 mg once daily for 7 days without platelet monitoring.

Topics: Adult; Aged; Aged, 80 and over; Blood Platelets; Chronic Disease; Cinnamates; Female; Humans; Liver Diseases; Male; Middle Aged; Models, Biological; Platelet Count; Receptors, Thrombopoietin; Thiazoles; Thrombocytopenia; Young Adult

Topics: Adolescent; Biopsy; Cinnamates; Humans; Liver; Liver Transplantation; Living Donors; Male; Platelet Count; Preoperative Care; Receptors, Thrombopoietin; Thiazoles; Thrombocytopenia

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

Topics: Carcinoma, Hepatocellular; Cinnamates; Hepatitis C; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Thiazoles; Thrombocytopenia

The efficacy of repeated lusutrombopag administration for thrombocytopenia in patients with chronic liver disease who undergo two or more planned invasive procedures is unknown. We herein report our findings regarding the effects of repeated lusutrombopag administration given to avoid platelet transfusion in a patient with chronic liver disease and thrombocytopenia. The platelet count showed a positive response to lusutrombopag treatment prior to the initial invasive procedure to treat a hepatoma, so platelet transfusion was not necessary. In conclusion, lusutrombopag may be a useful drug for patients with thrombocytopenia to avoid platelet transfusion in those undergoing two or more planned invasive procedures.

Topics: Carcinoma, Hepatocellular; Chronic Disease; Cinnamates; Female; Humans; Liver Diseases; Liver Neoplasms; Middle Aged; Platelet Count; Thiazoles; Thrombocytopenia

Lusutrombopag (Mulpleta®) is an orally bioavailable, small molecule thrombopoietin (TPO) receptor agonist being developed by Shionogi for chronic liver disease (CLD) patients with thrombocytopenia prior to elective invasive surgery. Lusutrombopag acts selectively on the human TPO receptor and activates signal transduction pathways that promote the proliferation and differentiation of bone marrow cells into megakaryocytes, thereby increasing platelet levels. In September 2015, lusutrombopag received its first global approval in Japan for the improvement of CLD-associated thrombocytopenia in patients scheduled to undergo elective invasive procedures. This article summarizes the milestones in the development of lusutrombopag leading to this first approval.

Topics: Cinnamates; Drug Approval; Humans; Japan; Liver Diseases; Receptors, Thrombopoietin; Thiazoles; Thrombocytopenia