An alternative intermittent eltrombopag dosing protocol for the treatment of chronic immune thrombocytopenia

Abstract

Eltrombopag, an oral thrombopoietin receptor agonist, is dosed daily to treat chronic immune thrombocytopenia (ITP). As it has a half‐life of 26–35 h in ITP patients and requires patents to abide by strict dietary restrictions that may impair quality of life and reduce compliance, we developed an alternative intermittent (AI) eltrombopag dosing protocol for ITP, with dosing less frequent than once daily. Ten patients were treated with AI dosing for a median of 94 (range: 29–156) weeks, with most patients treated with 2–4 weekly doses for extended durations. During AI dosing, 95%, 84% and 71% of all platelet counts were ≥20 × 10⁹ l^–1, ≥50 × 10⁹ l^–1 and ≥100 × 10⁹ l^–1, respectively. Five patients required rescue treatment for thrombocytopenia and World Health Organization grade 1 mucocutaneous bleeding, and there were no thromboembolic events. In summary, intermittently dosed eltrombopag was efficacious in treating chronic ITP in a small cohort, with rates of platelet response and rescue treatment comparable with rates in studies evaluating daily dosing.

What is Already Known about this Subject

• Eltrombopag is a thrombopoietin receptor agonist that is effective in raising the platelet count and reducing bleeding events in patients with chronic immune thrombocytopenia.

• Eltrombopag, normally dosed once daily, requires patients to abide by strict dietary restrictions to ensure adequate absorption. This may impair quality of life and compliance.

What this Study Adds

• An alternative eltrombopag dosing protocol was developed, utilizing intermittent dosing 1–5 times weekly, which is rational from a pharmacokinetic and pharmacodynamic perspective.

• The study showed that intermittent dosing was effective in achieving a platelet response with no major bleeding or thrombotic events, and a requirement for rescue treatment similar to what has been reported in studies examining daily dosing.

Introduction

Eltrombopag is an oral, small‐molecule, nonpeptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5063 receptor agonist approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of chronic immune thrombocytopenia (ITP) in adults and children, refractory severe aplastic anaemia and thrombocytopenia associated with hepatitis C infection (to facilitate the use of interferon‐based treatment regimens) 1. Although this agent is safe and effective in raising the platelet count, the current dosing algorithm, which calls for daily dosing, with dose adjustments made based on interval platelet count measurements, may not be the only effective means to dose the drug. Indeed, early pharmacokinetic studies incorporated alternate‐day dosing as part of the researched dosing algorithms, a rational approach, given the drug's 26–35‐h half‐life in ITP patients 1, 2. Moreover, the pharmacodynamics of http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1722 agonists, which reflect the normal kinetics of thrombopoiesis 3, suggest that less‐than‐daily dosing is reasonable from a biological perspective.

Eltrombopag requires strict dietary compliance, to facilitate absorption. It must be taken on an empty stomach, with at least a 4‐h interval before other medications or any calcium‐, iron‐, aluminium‐, magnesium‐, selenium‐ or zinc‐rich foods can be consumed, a considerable burden for patients with chronic ITP, who may use the medication daily for several years 4. Dietary fat also considerably reduces the oral bioavailability of eltrombopag, with a standard high‐fat breakfast reducing plasma eltrombopag AUC_0‐∞ (area under the plasma concentration–time curve from zero to infinity) by 59% and C _max (peak plasma concentration) by 65% in pharmacokinetic studies 5. Given the pharmacodynamic, pharmacokinetic and practical dietary considerations, we have developed a novel alternative intermittent (AI) dosing protocol for the treatment of chronic ITP with eltrombopag at our institution. The study was a retrospective analysis of the patients treated with this protocol, assessing the efficacy of the protocol on the platelet response and need for rescue treatment. There have been no other studies published assessing the efficacy or safety of intermittent eltrombopag dosing.

Methods

The study was approved by the institutional review board (approval 2015P000152/PHS) of the Massachusetts General Hospital. Between 1 January 1 2008 and 7 March 2018, all patients with chronic ITP, aged ≥18 years, who received eltrombopag were identified via the Research Patient Data Registry at the Massachusetts General Hospital, and those receiving eltrombopag less frequently than once daily (ʻintermittentʼ dosing) as the sole treatment for chronic ITP were selected for further analysis. Patients could receive glucocorticoids or intravenous immunoglobulin (IVIG) as rescue treatments during eltrombopag therapy. Patient data collected included: age, gender, aetiology of ITP, date of ITP diagnosis, prior ITP therapies, platelet counts, dates and doses of eltrombopag, rescue treatments given, red blood cell (RBC) transfusions given, and bleeding and thrombotic events during eltrombopag treatment. Analysis was performed using Microsoft Excel 2016 (Microsoft Corp., Redmond, WA, USA).

Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 6, and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 7.

Results

Of 12 patients treated with intermittent eltrombopag dosing, 10 were selected for further analysis. One patient was excluded owing to incomplete data in the medical record, and another for receiving rituximab during eltrombopag treatment. Patient characteristics (demographics, aetiology and duration of ITP, prior ITP therapies), standard daily dosing data prior to transition to AI dosing (dosing information, duration) and AI dosing data (duration, dosing information, and number and type of rescue treatments) are shown in Table 1. The median age was 38 (range: 21–90) years and five patients were male. The median number of prior ITP treatments was three (range: 1–5) and two patients had previously undergone splenectomy. No patient had significant pre‐existing hepatic or renal impairment.

Table 1.

Baseline characteristics and the results of alternative intermittent dosing of the patient cohort

Age	Gender	ITP aetiology (duration, years)	Prior ITP therapies	Standard dose (duration, weeks) prior to AI dosing	Total AI dosing (duration, weeks)	AI dose given for longest duration (weeks)	Rescue treatments, number (type)
32	M	Primary (1)	Glucocorticoids, IVIG	50 mg daily (11)	95	50 mg twice weekly (70)	2 (glucocorticoids)
57	F	Primary (4)	Glucocorticoids, IVIG, lusutrombopag, romiplostim, eltrombopag	75 mg daily (59)	156	75 mg every other day (69)	0
90	M	Primary (2)	Glucocorticoids, rituximab, romiplostim	25 mg daily (2)	104	25 mg twice weekly (100)	0
21	F	Primary (2)	Glucocorticoids, IVIG, eltrombopag	25 mg daily (2)	29	25 mg 4 times weekly (17)	1 (glucocorticoids)
28	M	Secondary, common variable immunodeficiency (8)	Glucocorticoids, romiplostim	75 mg daily (17)	50	75 mg once weekly (35)	1 (glucocorticoids)
32	F	Primary (3)	Glucocorticoids, IVIG, rituximab, eltrombopag	75 mg daily (2)	83	75 mg 3 times weekly (79)	0
60	M	Primary (58)	Glucocorticoids, splenectomy, IVIG, danazol	75 mg daily (181)	137	75 mg 5 times weekly (80)	1 (Glucocorticoids)
72	F	Secondary, Sjögren syndrome (6)	Glucocorticoids	75 mg daily (2)	106	75 mg 4 times weekly (97)	0
26	M	Primary (7)	Glucocorticoids, romiplostim, eltrombopag, IVIG, splenectomy	75 mg daily (6)	75	75 mg every other day (43)	2 (glucocorticoids, IVIG)
44	F	Primary (18)	Glucocorticoids, rituximab, romiplostim	50 mg daily (6)	92	50 mg 3 times weekly (61)	0

AI, alternative intermittent; F, female; ITP, immune thrombocytopenia; IVIG, intravenous immunoglobulin; M, male

Patients were treated with standard daily eltrombopag dosing for at least 2 weeks prior to transitioning to the AI dosing protocol (Figure 1). Patients were then transitioned to AI dosing using the same daily eltrombopag dose (25, 50 or 75 mg) but this was now administered on fewer than 7 days per week. Patients were transitioned to AI dosing for the following reasons: platelet count too high (≥200 × 10⁹ l^–1), dietary concerns or patient preference. The median duration of AI dosing was 94 (range: 29–156) weeks; using this protocol, most patients were treated with 2–4 weekly doses of eltrombopag for extended durations.

Figure 1.

Alternative intermittent dosing protocol. Plt, platelet count; QOD, every other day

Median platelet counts (with interquartile ranges shown) for the entire cohort are shown in Figure 2. During AI dosing, 95% of all recorded platelet counts were at or above the goal of 20 × 10⁹ l^–1; 84% and 71% were ≥50 ×10⁹ l^–1 and ≥100 × 10⁹ l^–1, respectively; and 6.4% of all recorded platelet counts were ≥400 ×10⁹ l^–1.

Figure 2.

Median (± interquartile ranges) platelet counts over time for entire cohort over the first 6 months of treatment using the alternative intermittent (AI) dosing protocol. Time 0 indicates the initiation of AI dosing. As a result of the pharmacodynamics of thrombopoietin receptor agonists, platelet counts over the first 10–14 days are reflective of the standard daily dosing prior to AI dosing protocol initiation. Overall dosing intensity is indicated at regular intervals. PPW, pills per week

Half of patients required rescue treatment with glucocorticoids or IVIG (Table 1) while receiving AI dosing; in all cases, bleeding was limited to World Health Organization (WHO) grade 1 mucocutaneous bleeding (skin purpura or oral haemorrhagic blisters) and no patient required RBC transfusion. Need for rescue was precipitated by infection in five cases, inflammatory bowel disease flare in one case and receipt of influenza vaccination in one case. No patient suffered venous thromboembolism. At the time of the analysis, three patients were successfully weaned from eltrombopag treatment and seven continue to receive AI‐dosed eltrombopag according to protocol.

Discussion

Long‐term use of TPO receptor agonists to treat chronic ITP is common. Although evidence has emerged demonstrating remissions in a minority of patients treated in this fashion 8, 9, most patients require continuing maintenance therapy. The plasma elimination half‐life of eltrombopag is 21–32 h in healthy subjects and 26–35 h in subjects with ITP 1, making dosing less frequently than once daily practical. This half‐life, plus consideration of the dietary restrictions imposed by eltrombopag and associated noncompliance and/or reduced efficacy concerns, led to the development of our AI dosing protocol. When dose reduction on standard daily eltrombopag was indicated owing to a platelet count ≥200 ×10⁹ l^–1, patients were transitioned to eltrombopag 5 days per week at the same daily eltrombopag dose, rather than reducing the daily dose, as is instructed by the prescribing information. Interval platelet count reassessment no sooner than 2 weeks after a reduction in dose frequency then allows for a further reduction in dose frequency until the platelet count stabilizes in the 20–100 × 10⁹ l^–1 range, or higher, according to patient or provider preference. The protocol gives patients more flexibility in dietary planning, especially if patients achieve goal platelet counts on once‐ or twice‐weekly dosing.

The eltrombopag prescribing information recommends initiation of 50 mg (or 25 mg in patients of East Asian ethnicity) once daily and instructs modification of daily dosage based on platelet response, to achieve a goal platelet count of 50–200 × 10⁹ l^–1 1. By contrast, our AI dosing protocol advises initiation of eltrombopag 50–75 mg daily (25 mg daily if East Asian), with gradual reductions in doses per week, to achieve a goal platelet count ≥20 × 10⁹ l^–1 (Figure 1). Despite this modest goal, chosen for its greater clinical relevance 10 and achieved 95% of the time according to our protocol, 84% of platelet counts in patients receiving intermittent dosing were ≥50 × 10⁹ l^–1, the platelet count goal recommended in the prescribing information. The rate of platelet count ≥50 × 10⁹ l^–1 in our study was comparable with that reported in the phase III trials of both eltrombopag and romiplostim in chronic ITP 11, 12. This efficacy was demonstrated with a median duration of AI dosing of nearly 2 years, during which time no patient experienced worse than WHO grade 1 mucocutaneous bleeding. Rescue treatments were required a total of seven times for the entire cohort over the study duration (17.8 patient‐years), equivalent to a rate of 0.39 rescue events per patient‐year of AI dosing. There were no apparent adverse effects of eltrombopag in our study, consistent with other studies that have suggested that it is generally well tolerated 12. No thrombotic events were observed.

Although AI eltrombopag dosing may be a more ideal long‐term treatment approach for many patients, achieving an optimal balance between disease management and quality of life issues, some patients are better candidates than others. Preferential candidates for AI dosing have a robust response to eltrombopag shortly after its initiation (with platelet counts commonly ≥200 × 10⁹ l^–1), a good overall track record of medication compliance (as missing one dose on twice‐weekly dosing may be more consequential than missing one dose on daily dosing) and an overall history of treatment‐responsive ITP. Conversely, those patients with treatment‐resistant disease, modest responses to high‐dose daily eltrombopag administration (with platelet counts usually <50–100 × 10⁹ l^–1) and difficulties in remembering to take medications dosed less regularly are likely to be poor candidates for AI dosing.

Although no pharmacoeconomic analysis was performed as part of the present study, it is conceivable that this alternative dosing protocol could result in cost savings. Intermittent dosing using a higher pill strength would be likely to cost less compared with daily dosing in certain patients. Although such comparisons were not possible in the present study, this could be examined as part of a prospective controlled study.

The limitations of the present retrospective observational study included the lack of randomization or blinding, and so the presence and magnitude of any difference between AI dosing and standard dosing could not be measured. In addition, although a median treatment duration of nearly 2 years is long for a study of chronic ITP management, the number of subjects included was small. Finally, as is the case with any study of TPO receptor agonist therapy for chronic ITP, it is possible that some patients entered remission while receiving eltrombopag and did not require any treatment. Our AI protocol (Figure 1) did address this consideration, and three of 10 patients were eventually weaned from eltrombopag completely. Additionally, median platelet counts decreased with decreasing dose intensity (Figure 2), confirming the necessity of treatment in our cohort.

There are currently no other published studies describing the intermittent dosing of eltrombopag for the treatment of chronic ITP. The current daily dosing algorithm for eltrombopag in ITP may not be optimal for all patients and may lead to reduced compliance owing to patient inconvenience. In patients with chronic ITP for whom TPO receptor agonist therapy is indicated, our study suggested that an AI eltrombopag dosing protocol is efficacious at maintaining an adequate platelet count. However, only a prospective study comparing such a protocol with the standard daily eltrombopag dosing protocol could confirm the utility and cost‐effectiveness of our approach.

Competing Interests

H.A. has been a consultant for Agios Pharmaceuticals. D.J.K. has received research funding from Protalex, Bristol‐Myers Squibb, Rigel, Bioverativ, Agios Pharmaceuticals, Syntimmune, Principia and Alnylam Pharmaceuticals; been a consultant for ONO, Pfizer, 3SBios, Eisai, GlaxoSmithKline, Genzyme, Shire, Amgen, Shionogi, Rigel, Syntimmune, MedImmune, Novartis, Bioverativ, Argenx and Zafgen; and been paid by Amgen and CRICO for expert testimony.

There were no sources of support (financial, equipment, or drugs) for this study.

Contributors

H.A. designed the study, collected data, analysed data, created the figures and tables, and wrote and revised the manuscript. D.K. designed the study and critically revised the manuscript.

Al‐Samkari, H. , and Kuter, D. J. (2018) An alternative intermittent eltrombopag dosing protocol for the treatment of chronic immune thrombocytopenia. Br J Clin Pharmacol, 84: 2673–2677. 10.1111/bcp.13717.