Avatrombopag for the Treatment of Immune Thrombocytopenia and Periprocedural Thrombocytopenia Associated With Chronic Liver Disease

Abstract

Objective: To review the pharmacology, pharmacokinetics, clinical efficacy, safety, dosing and administration, and place in therapy of avatrombopag for the treatment of immune thrombocytopenia and chronic liver disease-associated thrombocytopenia. Summary: Avatrombopag is an orally administered thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenia and is the first oral thrombopoietin receptor agonist approved for the treatment of perioperative thrombocytopenia associated with chronic liver disease in adults. The efficacy and safety of avatrombopag has been demonstrated in a multicenter, randomized, double blind, placebo-controlled phase III study in the setting of immune thrombocytopenia and in 2 identically designed, multicenter, randomized, double blind, placebo-controlled phase III trials in the setting of thrombocytopenia associated with chronic liver disease. The most common adverse events reported in the clinical trials were headache, fatigue, and gastrointestinal toxicities. The incidence of bleeding events was comparable between the avatrombopag and placebo treatment groups in each study. Avatrombopag has not been shown to be associated with hepatoxicity and does not require food restriction like the other oral thrombopoietin receptor agonist for immune thrombocytopenia, eltrombopag. Also, unlike eltrombopag for immune thrombocytopenia, it can be dosed less frequently than once daily. Conclusion: Avatrombopag offers another safe and effective oral option for the treatment of immune thrombocytopenia without food restrictions and an alternative, transfusion-sparing option for thrombocytopenia associated with chronic liver disease patients undergoing surgery.

Keywords

chronic liver disease immune thrombocytopenia purpura TPO receptor agonist thrombocytopenia surgery

Background

The thrombopoietin receptor agonists (TPO-RAs) are a drug class that are indicated for the treatment of thrombocytopenia in several conditions including immune thrombocytopenia (ITP), antiviral treatment-related thrombocytopenia in hepatitis C, aplastic anemia, and periprocedural thrombocytopenia in chronic liver disease (CLD).¹ Further, this class has emerged as a favorable and often preferred set of agents for the management of thrombocytopenia in several settings as thrombocytopenia can lead to an increased risk of severe bleeding and can be preclusive to being able to undergo surgical procedures.^2,3

Romiplostim and eltrombopag were the first TPO-RAs approved by the United States Food and Drug Administration (FDA) in 2008 for the treatment of ITP in patients who have an insufficient response to prior therapies including corticosteroids.^4,5 Since then, they have become a mainstay in the treatment of ITP with response rates of ∼60-70%.^6-8 While efficacious medications, there are some drug-specific limitations to their use. Romiplostim is a subcutaneous injection that requires weekly clinic visits for administration per FDA approval.⁴ Eltrombopag, an oral agent, has the potential to be more convenient for patients to take at home, however there are food restrictions associated with ensuring proper administration and absorption.⁵ TPO agonism in ITP offers a high response rate and durable responses, however it is typically considered a maintenance therapy that patients may take indefinitely. Avatrombopag is a newer oral TPO-RA that has demonstrated efficacy in the treatment of chronic ITP. It offers the advantages of being orally administered without food or dietary restrictions and can be a reasonable alternative to romiplostim and eltrombopag.

Patients with CLD often develop thrombocytopenia that can increase in severity with a worsening degree of cirrhosis.⁹ Severe thrombocytopenia in patients with CLD has been associated with poor outcomes due to an increased risk of bleeding.³ Patients with CLD-associated thrombocytopenia have an increased risk of serious bleeding complications during surgical procedures. Platelet transfusion can be used to increase platelet count prior to surgery as well as during surgery. However, the effect is often transient and unpredictable, which can lead to an increased risk of bleeding in the post-operative setting. Moreover, platelet availability is limited to plasma donation, and are associated with transfusion reactions and infection transmission.^10,11 Patients who receive frequent platelet transfusions can become refractory to future and subsequent platelet transfusions.¹² Therapeutic alternatives to platelet transfusions are needed for patients with CLD and thrombocytopenia who are undergoing surgical procedures.

Avatrombopag and lusutrombopag are oral TPO-RAs approved in May 2018 and July 2018, respectively, by the FDA for the treatment of thrombocytopenia in adults with CLD scheduled to undergo a procedure.^13,14 Both agents have demonstrated efficacy in increasing platelet counts following 5 days and 7 days of oral administration, respectively, compared with placebo treatment.¹⁵ Lusutrombopag is available as a single dose of 3 mg orally for 7 days, regardless of platelet count, whereas avatrombopag can be tailored based on the baseline platelet count^13,14 In 2019, avatrombopag gained an additional approval for the treatment of chronic ITP in adults who have had an insufficient response to a prior therapy. Avatrombopag is the only TPO-RA approved for both indications. Herein, this review will summarize the pharmacology, pharmacokinetics, clinical efficacy, safety, dosing and administration, and place in therapy of avatrombopag for the management of thrombocytopenia in these indications.

Pharmacology

TPO is the primary regulator of platelet production and activation.¹⁶ This protein is produced in the liver and has an inverse relationship with platelet production. Dysregulation of TPO production, for example via chronic hepatic dysfunction, can lead to thrombocytopenia and therefore a risk of bleeding. Avatrombopag is an orally available non-peptide TPO-RA that binds to and activates the TPO receptor to stimulate production of megakaryocytes and platelets. Rather than activating platelets or competing with endogenous TPO, this agent works synergistically with endogenous TPO to elevate platelets by as much as 200% more than TPO alone.¹⁷ Avatrombopag has demonstrated dose and exposure dependent elevations in platelet counts in adults. The onset of platelet count increase is noted within 3-5 days, with peak between days 10-13.

Pharmacokinetics

Avatrombopag has poor aqueous solubility, leading to slow gut absorption and a peak plasma concentration (Cmax) that is reached 5-9 hours after administration.¹⁸ The solubility of avatrombopag does not affect its absorption in the tested range (20-60 mg), as Cmax and area under the curve (AUC) both increase proportionally with dose.^24,25 The terminal half-life is approximately 16-19 hrs. Volume of distribution does increase with body weight (measured in the range of 39-175 kg); this change was statistically significant but may not be clinically significant.^24,25

Clinical Efficacy

Chronic Immune Thrombocytopenia

Jurcsak et al conducted a multicenter, randomized, double blind, placebo-controlled phase III study with an open-label extension phase to assess the efficacy of avatrombopag vs placebo in adults with chronic ITP and platelet <30 × 10⁹/L.¹⁹ The primary end point of the core study was the cumulative number of weeks of platelet response, defined as a platelet count ≥50 × 10⁹/L, without rescue therapy over a 6-month period. The efficacy of long‐term avatrombopag therapy was assessed in the extension phase by measuring platelet response rate and the use of rescue therapy.

Patients were eligible if they were ≥18 years of age with ITP ≥12 months in duration, and an average of 2 platelet counts <30 × 10⁹/L. Patients were randomized to receive either avatrombopag at a starting dose of 20 mg once daily or placebo. The daily dose could be titrated up to a maximum dose of 40 mg or down to a minimum dose of 5 mg, according to pre‐specified protocol thresholds and individual response to treatment with the overall goal of maintaining platelet counts between ≥50 × 10⁹/L and ≤150 × 10⁹/L, and to reduce the need for concomitant ITP medications. The primary endpoint assessment was made during the maintenance period of the core study, as concomitant ITP medications were to be administered at a stable dose and downward titration of the study medication was not permitted during this period.

Patients who completed the maintenance period of the core study or discontinued from the core study early due to lack of treatment effects, and who had no significant safety or tolerability concerns, were eligible to continue into the extension phase. All patients started the extension phase with open‐label avatrombopag 20 mg once daily. During the 90‐week maintenance period of the extension phase, avatrombopag dose titration and downward titration of concomitant ITP medications were allowed. At the end of the extension phase, a 4‐week, dose‐tapering period was followed by a 30‐day follow‐up after the last dose of avatrombopag.

Of the 49 patients included in the study, 32 were randomized to the treatment group and 17 to the placebo group. Twenty‐two patients (68.8%) in the avatrombopag treatment group and 1 (5.9%) in the placebo treatment group completed the core study. The most frequent reason for discontinuation from the core study was lack of treatment effect (avatrombopag, 21.9%; placebo, 88.2%). Thirty‐nine patients who entered the extension phase were included in the modified full analysis set with 29 patients (74.4%) completing the extension phase and 9 (23.1%) discontinuing; 1 patient was lost to follow‐up. Baseline demographics and characteristics were generally balanced across the avatrombopag and placebo treatment groups. Most patients had severe thrombocytopenia at baseline (≤15 × 10⁹/L; 57.1%), not splenectomized (67.3%) and were not using concomitant ITP medication (55.1%). Approximately 30% of patients had previously received 5 or more ITP medications.

Avatrombopag was found to be superior to placebo in the cumulative number of weeks of platelet response with a significantly longer duration of a platelet count ≥50 × 10⁹/L in the absence of rescue therapy compared with placebo (median: 12.4 vs 0 weeks; P < ·0001). More patients in the avatrombopag treatment group (65.6%) had a platelet response at day 8 than in the placebo‐treated group (.0%; P < .0001). Further, 5 out of 15 patients on concomitant ITP therapy (33.3%) in the avatrombopag treatment group reduced their use of concomitant ITP medication from baseline compared with none of the placebo‐treated patients (95% confidence interval, 9.48-57.19), although this treatment difference did not reach statistical significance (P = 0·1348), likely due to the small number of patients using ITP medications at baseline.

The authors concluded that avatrombopag was shown to be well tolerated with a safety profile that was similar to placebo when adjusted for the duration of treatment exposure. There was a low incidence of adverse events reported with avatrombopag with only 1 avatrombopag-treated patient reporting a bleeding event grade 3 or higher or recurrence of thrombocytopenia. Three patients developed had a thromboembolic event with avatrombopag in the core study (1 deep vein thrombosis, 1 pulmonary embolism and 1 cerebrovascular accident); no patient experienced a recurrent thromboembolic event.

Chronic Liver Disease-Associated Perioperative Thrombocytopenia

The ADAPT-1 and ADAPT-2 studies were identically designed, international, multicenter, randomized, double blind, placebo-controlled phase III trials conducted to assess the efficacy of avatrombopag in adults with CLD and thrombocytopenia undergoing a scheduled procedure.¹⁸ The primary end point of both studies was the proportion of patients not requiring platelet transfusions or rescue procedure for bleeding up to 7 days after a scheduled procedure. Secondary efficacy endpoints were the proportion of patients achieving the target platelet count of at least 50 × 10⁹/L on procedure day and the change in platelet count from baseline to procedure day.

Eligible patients were ≥18 years of age with CLD (Model for End-Stage Liver Disease [MELD] score ≤24) and thrombocytopenia with a mean baseline platelet count of <50 × 10⁹/L, who were scheduled to under a procedure with an associated risk of bleeding that would require a platelet transfusion, unless there was a clinically significant increase in platelet count from baseline. Permitted procedures were classified by the associated bleeding risk based on the published literature and investigator input into 3 categories: low, moderate, and high risk. Patients were randomized into 1 of 2 cohorts accordingly to baseline platelet count: patients with low baseline platelets (<40 × 10⁹/L) received 60 mg or placebo; patients with high baseline platelets (40 to <50 ×10⁹/L) received 40 mg or placebo once daily with a meal for 5 consecutive days, 5-8 days prior to planned procedure.

Of the 231 patients included in ADAPT-1, 149 were randomized to receive avatrombopag and 82 to received placebo. In ADAPT-2, 204 patients were included, 128 were randomized to the treatment group and 76 to receive placebo. Patient demographics and disease characteristics were balanced between treatment groups in both ADAPT-1 and ADAPT-2, with 94% of patients completing each study. The categories of procedure bleeding risk for the scheduled procedures were also balanced between study groups with most patients (60.8%) undergoing a procedure with a low bleeding risk.

Both studies found avatrombopag to be superior to placebo in the proportion of patients who did not require a platelet transfusion or rescue procedure for bleeding. In the ADAPT-1 study, 65.6% of patients who received 60 mg avatrombopag and 88.1% of patients who received 40 mg avatrombopag met the primary endpoint compared with 22.9% and 38.2% of patients receiving placebo, respectively (P < .0001 for both). In the ADAPT-2 study, 68.6% of patients who received 60 mg avatrombopag and 87.9% of patients who received 40 mg avatrombopag met the primary endpoint compared with 34.9% and 33.3% of patients who received placebo, respectively (P < .001 for both). Avatrombopag led to a measured increase in platelet counts and increased the proportion of patients who achieved the target platelet count ≥50 × 10⁹/L on procedure day vs placebo. The incidence and severity of adverse events were similar for the avatrombopag and placebo groups and were consistent with those expected in the CLD population. The trials were identically designed but conducted in different countries, demonstrating the reproducibility of the data.

Safety and Adverse Events

The most common adverse events in Jurczak et al, which evaluated avatrombopag in the setting of ITP, were headache (37.5% avatrombopag vs 11.8% placebo) and contusion (31.3% avatrombopag vs 23.5% placebo).¹⁷ There was no statistically significant difference in bleeding events between patients randomized to avatrombopag and the placebo group (43.8% vs 52.9%; P = .5934). The overall occurrence of treatment emergent adverse events was higher in the avatrombopag treatment group compared to placebo (96.9% vs 58.8%). However, when adjusted for exposure, there was no clinically significant difference in the incidence rates of adverse events.

For those patients with CLD-associated thrombocytopenia enrolled in ADAPT-1 and ADAPT-2 trials, most adverse events were mild to moderate in severity and similar between the avatrombopag and placebo groups.²⁰ The most common adverse events (>5% incidence in treatment group) included pyrexia, abdominal pain, nausea, headache, fatigue, and peripheral edema. The incidence of bleeding events was comparable between the avatrombopag and placebo treatment groups in both studies.

TPO-RAs, including avatrombopag, have been associated with an increased risk for the development of thromboembolic complications. In the phase III trial in ITP, 3 patients (9.4%) experienced a thromboembolic event, which included a deep vein thrombosis, an asymptomatic pulmonary embolism, and a cerebrovascular event.¹⁹ In ADAPT-1 no thromboembolic treatment emergent adverse events were reported. In ADAPT-2, 1 avatrombopag-treated patient developed a thromboembolic treatment emergent adverse event (partial portal vein thrombosis) and 2 placebo treated patients developed thromboembolic treatment emergent adverse events (disseminated intravascular coagulation, acute myocardial infarction).²⁰ Patients with prothrombotic conditions such as Factor V Leiden, Protein C or S deficiencies, or Antithrombin deficiency may be at a potentially increased risk of thrombotic complications with the use of a TPO-RA such as avatrombopag. Platelet counts should be monitored closely as to assess response with avatrombopag; however, the goal is not to normalize platelet counts, but rather to achieve a target platelet count as needed to reduce the risk of bleeding, which is often between 50-200 × 10⁹/L in the setting of chronic ITP.

Dosing and Administration

Avatrombopag is available in 20 mg oral tablets.¹³ Dosing is based on the indication for use. The recommended initial dosage of avatrombopag for the treatment of chronic ITP is 20 mg once daily taken orally with food. The maximum dose for the treatment of ITP is 40 mg daily. The lowest dose needed to achieve and maintain a platelet count ≥50 × 10⁹/L should be used. Dose adjustments are based on platelet count response with dose and frequency increased or decreased according to package insert labeling. Avatrombopag therapy should be discontinued if platelet counts do not increase to ≥ 50 × 10⁹/L after 4 weeks of therapy at the maximum dose of 40 mg once daily or if the platelet count is >400 × 10⁹/L after 2 weeks of therapy at 20 mg once weekly.

For those patients receiving avatrombopag for CLD associated thrombocytopenia, therapy should be initiated 10 to 13 days prior to the scheduled procedure. Dosing is based on platelet count with a platelet count of 40 000 to <50 × 10⁹/L requiring 40 mg once daily with food for 5 consecutive days and a platelet count of <40 × 10⁹/L requiring 60 mg once daily with food for 5 consecutive days. The procedure should be completed within 5 to 8 days after the last dose of avatrombopag and a platelet count should be obtained the day of the procedure to ensure adequate response. There are no dosage adjustments for those patients on concomitant moderate or dual cytochrome P450 (CYP) 2C9 and CYP3A4 inhibitors.

Avatrombopag should be taken with food. If a dose is missed, patients can resume taking the medication at the next scheduled administration time. Renal and hepatic impairment had no clinically meaningful effects on avatrombopag pharmacokinetics and dose adjustments are therefore not necessary for chronic ITP patients with pre-existing renal or liver dysfunction. However, due to primary metabolism through CYP enzymatic pathways, avatrombopag is prone to drug-drug interactions and dose adjustments may be warranted. If a patient is receiving a concomitant moderate or strong dual CYP2C9 and CYP3A4 inhibitor, such as fluconazole, the initial avatrombopag dose should be reduce to 20 mg 3 times weekly. The initial dose should be increased to 40 mg daily if patient is on a concomitant moderate or strong dual CYP2C9 and CYP3A4 inducer, such as rifampin.

In the event of an overdose, thrombotic complications may present with excessive increases in platelet counts. There is no antidote for avatrombopag overdose and hemodialysis is not expected to enhance elimination. Patients should be closely monitored, and thrombotic complications should be treated in accordance with standard of care.

Place in Therapy

Avatrombopag is FDA approved for the treatment of adult patients with chronic ITP who have had an insufficient response to a previous treatment and thrombocytopenia in adult patients with CLD who are scheduled to undergo a procedure.¹³ Treatment guidelines for ITP do not include avatrombopag in their recommendations, however, these guidelines were likely still in development at the time when avatrombopag was being reviewed and subsequently approved by the FDA.^8,19,21 Avatrombopag was the first TPO-RA to receive approval for the indication of CLD-associated thrombocytopenia in the periprocedural setting in May 2018.¹³

Avatrombopag is TPO-RA that binds to and activates the TPO receptor to stimulate production of megakaryocytes and platelets similar to romiplostim and eltrombopag, which have been pillars of therapy in chronic ITP for several years. Avatrombopag differs from both romiplostim and eltrombopag in its administration. Romiplostim requires weekly clinic appointments in the health care setting per US FDA approval, and eltrombopag requires administration on an empty stomach or specifically with a low calcium meal.^4,5 Avatrombopag requires administration with a meal (no qualifications like eltrombopag) but allows the ease of at home administration compared to subcutaneous administration with romiplostim by a provider. What may be considered an advantage of avatrombopag is the 6 FDA approved dose levels in chronic ITP allowing for dose titration and tapering to maximize both efficacy and safety in an oral therapy, providing more dose flexibility than eltrombopag, but similar flexibility to romiplostim but potentially without the need for administration in a health care setting.¹³ The dosing and administration benefits of avatrombopag allows chronic ITP patients with an additional viable therapy option in this difficult to treat population.

Considering the differences in the mechanisms of action between romiplostim and eltrombopag in how they interact with the TPO receptor, there is data supporting the use of switching from one TPO-RA to another in sequence in the treatment of chronic ITP either due to intolerance or inadequate response.^22,23 Avatrombopag, much like eltrombopag, agonizes the transmembrane domain of the TPO receptor, while romiplostim works on the extracellular domain; it is possible that avatrombopag could be used after romiplostim failure or intolerance, similar to eltrombopag, however data is lacking in this area. Further, there is no data to suggest alternative dosing strategies when switching from high doses of romiplostim to either oral TPO-RA. With both avatrombopag and eltrombopag having similar interactions with the receptor, it is unlikely that switching between them for refractoriness to 1 will illicit response with the other. However, given the differences in their administration with respect to food and dietary restrictions for proper absorption, patients could potentially be transitioned from eltrombopag to avatrombopag. If there is demonstrated inadequate response to eltrombopag in which there are issues or concerns of a patient not following the dietary counseling points associated with eltrombopag, then avatrombopag would be a reasonable alternative.

Avatrombopag also potentially offers a faster onset of action compared to the other TPO-RAs. Avatrombopag has shown to increase platelet count as early as 3-5 days after therapy initiation, compared to within 1-2 weeks, and 4-9 days for eltrombopag and romiplostim, respectively.^4,5,13 The rapid onset of action makes avatrombopag an appealing therapy choice in chronic ITP for patients needing a rapid platelet response but also is useful for its other FDA approved indication of thrombocytopenia in adult patients with CLD who are scheduled to undergo a procedure.

Another important consideration with the use of avatrombopag is the lack of reported hepatotoxicity. Eltrombopag carries a black box warning for hepatotoxicity and liver function tests need to be monitored periodically. This can be a limiting factor in treating patients with ITP with hepatic comorbidities. With its indication for use in CLD and lack of hepatic adverse events, avatrombopag could be considered the oral TPO-RA of choice in patients with various degrees of liver dysfunction. Data on ITP management with avatrombopag in patients with liver dysfunction is limited, however.

Lusutrombopag, another TPO-RA, subsequently received the same FDA approved indication of thrombocytopenia in CLD patients undergoing a procedure in July 2018.¹⁴ Avatrombopag and lusutrombopag have not been evaluated head-to-head for this indication, and slight differences between their dosing and administration should be considered. Avatrombopag should begin 10-13 days prior to surgery and this surgery should occur 5 to 8 days after the last avatrombopag dose. With lusutrombopag, treatment should begin 8-14 days prior to surgery and patients should undergo the procedure within 2 to 8 days after the last lusutrombopag dose. While there seems to be more flexibility in the time to being able to begin surgery respective to the last dose of lusutrombopag compared to avatrombopag, the recommended duration of surgical pretreatment with lusutrombopag is slight longer (3 mg once daily for 7 days) compared to avatrombopag (40 or 60 mg once daily for 5 days) in this setting. Additionally, lusutrombopag does not have any known, clinically significant drug-drug interactions, while avatrombopag dose needs to be adjusted in the setting of strong dual CYP2C9 and CYP3A4 inhibitors and inducers; therefore, this can be another consideration on choosing between these agents in the setting of thrombocytopenia in CLD prior to a scheduled procedure.

Conclusion

Avatrombopag is a safe and effective treatment option for adults with chronic ITP and with periprocedural CLD-associated thrombocytopenia. The comparative efficacy to standard therapies, rapid onset of action, ease of outpatient administration, and tolerable safety profile of avatrombopag has led to FDA approval in settings beyond that of other TPO-RAs. The approval of avatrombopag has added to the evolving therapeutic landscape for thrombocytopenia, specifically in chronic ITP and beyond. As the class of TPO-RAs evolves and expands, avatrombopag also provides an example of a familiar therapeutic option that is distinct. Clinicians who utilize TPO-RAs should review similarities and differences between these agents to best tailor treatment to the needs of their patients.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Thuy Tran

References

Merli

Strocchio

Vinti

Palumbo

Locatelli

. Eltrombopag for treatment of thrombocytopenia-associated disorders. Expet Opin Pharmacother. 2015;16(14):2243-2256.

Neunert

Noroozi

Norman

, et al. Severe bleeding events in adults and children with primary immune thrombocytopenia: A systematic review. J Thromb Haemost. 2015;13:457-464.

Giannini

Greco

Marenco

, et al. Incidence of bleeding following invasive procedures in patients with thrombocytopenia and advanced liver disease. Clin Gastroenterol Hepatol. 2010;8:899-902.

Nplate (Romiplostim) [prescribing Information]. Thousand Oaks, CA: Amgen Inc; February 2021.

Promacta (Eltrombopag) [prescribing Information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; January 2021.

Bussel

Cheng

Saleh

, et al. Eltrombopag for the treatment of chronic idiopathic -thrombocytopenic pupura. N Engl J Med. 2007;357:2237-2247.

Kuter

Bussel

Lyons

, et al. Efficacy of romiplostim with chronic immune thrombocytopenic purpura: A double-blind randomised controlled trial. Lancet. 2008;371:395-403.

Provan

Arnold

Bussel

, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780-3817.

Wang

Liu

, et al. Thrombocytopenia as a surrogate for cirrhosis and a marker for the identification of patients at high-risk for hepatocellular carcinoma. Cancer. 2006;107:2212-2222.

10.

Slichter

Kaufman

Assmann

, et al. Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med. 2010;362:600-613.

11.

Demetri

. Targeted approaches for the treatment of thrombocytopenia. Oncol. 2001;6(suppl 5):15-23.

12.

Kerkhoffs

Eikenboom

van de Watering

, et al. The clinical impact of platelet refractoriness: Correlation with bleeding and survival. Transfusion. 2008;48:1959-1965.

13.

Doptelet (Avatrombopag) [prescribing Information]. Durham, NC: Dova Pharmaceuticals; August 2020.

14.

Mulpleta (Lusutrombopag) [prescribing Information]. Florham Park, NJ: Shionogi Inc; April 2020.

15.

Nagrebetsky

Al-Samkari

Davis

, et al. Perioperative thrombocytopenia: Evidence, evaluation, and emerging therapies. Br J Anesthesia. 2019;122(1):19-31.

16.

Kuter

. The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol. 2013;98(1):10-23.

17.

Fukushima-Shintani

Suzuki

Iwatsuki

, et al. AKR-501 (YM477) in combination with thrombopoietin enhances human megakaryocytopoiesis. Exp Hematol. 2008;36(10):1337-1342.

18.

Cheloff

Al-Samkari

. Avatrombopag for the treatment of immune thrombocytopenia and thrombocytopenia of chronic liver disease. J Blood Med. 2019;10:313-321.

19.

Jurczak

Chojnowski

Mayer

, et al. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol. 2018;183(3):479-490.

20.

Terrault

Chen

Izumi

, et al. Avatrombopag before procedures reduces need for platelet transfusion in patients with chronic liver disease and thrombocytopenia. Gastroenterology. 2018;155:705-718.

21.

Neunert

Terrell

Arnold

, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829-3866.

22.

Kuter

Macahilig

Grotzinger

, et al. Treatment patterns and clinical outcomes in patients with chronic immune thrombocytopenia (ITP) switched to eltrombopag or romiplostim. Int J Hematol. 2015;101(3):255-263.

23.

González-Porras

Godeau

Carpenedo

. Switching thrombopoietin receptor agonist treatments in patients with primary immune thrombocytopenia. Ther Adv Hematol. 2019;10:2040620719837906.

24.

Nomoto

Pastino

Aluri

Han

. Pharmacokinetics, pharmacodynamics, pharmacogenomics, safety, and tolerability of avatrombopag in healthy Japanese and white subjects. Clin Pharm Drug Dev 2018;7(2):188-195. doi:10.1002/cpdd.349

25.

Nomoto

Ferry

Hussein

. Population pharmacokinetic/pharmacodynamic analyses of avatrombopag in patients with chronic liver disease and optimal dose adjustment guide with concomitantly administered CYP3A and CYP2C9 inhibitors. J Clin Pharmacol 2018;58:1629-1638. doi:10.1002/jcph.v58.12