Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: GlaxoSmithKline Trading Services Limited 6900 Cork Airport Business Park Kinsale Road Cork Ireland
Pharmacotherapeutic group: Antihemorrhagics
ATC code: B02BX05
TPO is the main cytokine involved in regulation of megakaryopoiesis and platelet production, and is the endogenous ligand for the TPO-R. Eltrombopag interacts with the transmembrane domain of the human TPO-R and initiates signaling cascades similar but not identical to that of endogenous thrombopoietin (TPO), inducing proliferation and differentiation of megakaryocytes from bone marrow progenitor cells.
Two Phase III, randomised, double-blind, placebo-controlled studies RAISE (TRA102537) and TRA100773B and two open-label studies REPEAT (TRA108057) and EXTEND (TRA105325) evaluated the safety and efficacy of eltrombopag in adult patients with previously treated chronic ITP. Overall, eltrombopag was administered to 277 ITP patients for at least 6 months and 202 patients for at least 1 year.
RAISE: 197 ITP patients were randomised 2:1, eltrombopag (n=135) to placebo (n=62), and randomisation was stratified based upon splenectomy status, use of ITP medication at baseline and baseline platelet count. The dose of eltrombopag was adjusted during the 6 month treatment period based on individual platelet counts. All subjects initiated treatment with eltrombopag 50 mg. From Day 29 to the end of treatment, 15 to 28 % of eltrombopag treated patients were maintained on ≤ 25 mg and 29 to 53 % received 75 mg.
In addition, patients could taper off concomitant ITP medicinal products and receive rescue treatments as dictated by local standard of care. More than half of all patients in each treatment group had ≥ 3 prior ITP therapies and 36 % had a prior splenectomy.
Median platelet counts at baseline were 16,000/μl for both treatment groups and in the eltrombopag group were maintained above 50,000/µl at all on-therapy visits starting at Day 15; in contrast, median platelet counts in the placebo group remained < 30,000/µl throughout the study.
Platelet count response between 50,000-400,000/μl in the absence of rescue medication was achieved by significantly more patients in the eltrombopag treated group during the 6 month treatment period, p < 0.001. Fifty-four percent of the eltrombopag-treated patients and 13 % of placebo-treated patients achieved this level of response after 6 weeks of treatment. A similar platelet response was maintained throughout the study, with 52 % and 16 % of patients responding at the end of the 6-month treatment period.
Table 2 – Secondary efficacy results from RAISE:
| Eltrombopag N = 135 | Placebo N = 62 | |
|---|---|---|
| Key secondary endpoints | ||
| Number of cumulative weeks with platelet counts ≥ 50,000-400,000/µl, Mean (SD) | 11.3 (9.46) | 2.4 (5.95) |
| Patients with ≥ 75 % of assessments in the target range (50,000 to 400,000/μl), n (%) | 51 (38) | 4 (7) |
| P value a | < 0.001 | |
| Patients with bleeding (WHO Grades 1-4) at any time during 6 months, n (%) | 106 (79) | 56 (93) |
| P value a | 0.012 | |
| Patients with bleeding (WHO Grades 2-4) at any time during 6 months, n (%) | 44 (33) | 32 (53) |
| P value a | 0.002 | |
| Requiring rescue therapy, n (%) | 24 (18) | 25 (40) |
| P value a | 0.001 | |
| Patients receiving ITP therapy at baseline (n) | 63 | 31 |
| Patients who attempted to reduce or discontinue baseline therapy, n (%) b | 37 (59) | 10 (32) |
| P value a | 0.016 | |
a Logistic regression model adjusted for randomisation stratification variables
b 21 out of 63 (33 %) patients treated with eltrombopag who were taking an ITP medication at baseline permanently discontinued all baseline ITP medications.
At baseline, more than 70 % of ITP patients in each treatment group reported any bleeding (WHO Grades 1-4) and more than 20 % reported clinically significant bleeding (WHO Grades 2-4), respectively. The proportion of eltrombopag-treated patients with any bleeding (Grades 1-4) and clinically significant bleeding (Grades 2-4) was reduced from baseline by approximately 50 % from Day 15 to the end of treatment throughout the 6 month treatment period.
TRA100773B: The primary efficacy endpoint was the proportion of responders, defined as ITP patients who had an increase in platelet counts to ≥ 50,000/μl at Day 43 from a baseline of < 30,000/μl; patients who withdrew prematurely due to a platelet count > 200,000/μl were considered responders, those that discontinued for any other reason were considered non-responders irrespective of platelet count. A total of 114 patients with previously treated chronic ITP were randomised 2:1 eltrombopag (n = 76) to placebo (n = 38).
Table 3 – Efficacy results from TRA100773B:
| Eltrombopag N = 74 | Placebo N = 38 | |
|---|---|---|
| Key primary endpoints | ||
| Eligible for efficacy analysis, n | 73 | 37 |
| Patients with platelet count ≥ 50,000/μl after up to 42 days of dosing (compared to a baseline count of < 30,000/μl), n (%) | 43 (59) | 6 (16) |
| P value a | < 0.001 | |
| Key secondary endpoints | ||
| Patients with a Day 43 bleeding assessment, n | 51 | 30 |
| Bleeding (WHO Grades 1-4) n (%) | 20 (39) | 18 (60) |
| P value a | 0.029 | |
a Logistic regression model adjusted for randomisation stratification variables
In both RAISE and TRA100773B the response to eltrombopag relative to placebo was similar irrespective of ITP medication use, splenectomy status and baseline platelet count (≤ 15,000/µl, > 15,000/µl) at randomisation.
In RAISE and TRA100773B studies, in the subgroup of ITP patients with baseline platelet count ≤ 15,000/μl the median platelet counts did not reach the target level (> 50,000/μl), although in both studies 43 % of these patients treated with eltrombopag responded after 6 weeks of treatment. In addition, in the RAISE study, 42 % of patients with baseline platelet count ≤ 15,000/μl treated with eltrombopag responded at the end of the 6 month treatment period. Forty-two to 60 % of the eltrombopag-treated patients in the RAISE study were receiving 75 mg from Day 29 to the end of treatment.
An open label, repeat dose study (3 cycles of 6 weeks of treatment, followed by 4 weeks off treatment) showed that episodic use with multiple courses of eltrombopag has demonstrated no loss of response.
Eltrombopag was administered to 299 ITP patients in an open-label extension study, 126 patients completed 1 year, 48 completed 18 months and 17 completed 2 years. The median baseline platelet count was 19,500/μl prior to eltrombopag administration. Median platelet counts at 12, 18 and 24 months on study were 68,000/μl, 75,000/μl and 119,000/μl, respectively.
The European Medicines Agency has deferred the obligation to submit the results of studies with Revolade in one or more subsets of the paediatric population in chronic idiopathic thrombocytopenic purpura (ITP) (see section 4.2 for information on paediatric use).
The plasma eltrombopag concentration-time data collected in 88 subjects with ITP in Studies TRA100773A and TRA100773B were combined with data from 111 healthy adult subjects in a population PK analysis. Plasma eltrombopag AUC and Cmax estimates for ITP subjects are presented (Table 4).
Table 4 – Geometric mean (95 % confidence intervals) of steady-state plasma eltrombopag pharmacokinetic parameters in adults with ITP:
| Eltrombopag dose, once daily | N | AUC (0- τ) a , μg.h/ml | C max a , μg/ml |
|---|---|---|---|
| 30 mg | 28 | 47 (39, 58) | 3.78 (3.18, 4.49) |
| 50 mg | 34 | 108 (88, 134) | 8.01 (6.73, 9.53) |
| 75 mg | 26 | 168 (143, 198) | 12.7 (11.0, 14.5) |
| a – AUC (0- τ) and C max based on population PK post-hoc estimates. | |||
Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Administration of eltrombopag concomitantly with antacids and other products containing polyvalent cations such as dairy products and mineral supplements significantly reduces eltrombopag exposure (see section 4.2). The absolute oral bioavailability of eltrombopag after administration to humans has not been established. Based on urinary excretion and metabolites eliminated in faeces, the oral absorption of drug-related material following administration of a single 75 mg eltrombopag solution dose was estimated to be at least 52 %.
Eltrombopag is highly bound to human plasma proteins (> 99.9 %), predominantly to albumin. Eltrombopag is a substrate for BCRP, but is not a substrate for P-glycoprotein or OATP1B1.
Eltrombopag is primarily metabolized through cleavage, oxidation and conjugation with glucuronic acid, glutathione, or cysteine. In a human radiolabel study, eltrombopag accounted for approximately 64 % of plasma radiocarbon AUC0-∞. Minor metabolites due to glucuronidation and oxidation were also detected. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for oxidative metabolism of eltrombopag. Uridine diphosphoglucuronyl transferase UGT1A1 and UGT1A3 are responsible for glucuronidation, and bacteria in the lower gastrointestinal tract may be responsible for the cleavage pathway.
Absorbed eltrombopag is extensively metabolised. The predominant route of eltrombopag excretion is via faeces (59 %) with 31 % of the dose found in the urine as metabolites. Unchanged parent compound (eltrombopag) is not detected in urine. Unchanged eltrombopag excreted in faeces accounts for approximately 20 % of the dose. The plasma elimination half-life of eltrombopag is approximately 21-32 hours.
Based on a human study with radiolabelled eltrombopag, glucuronidation plays a minor role in the metabolism of eltrombopag. Human liver microsome studies identified UGT1A1 and UGT1A3 as the enzymes responsible for eltrombopag glucuronidation. Eltrombopag was an inhibitor of a number of UGT enzymes in vitro. Clinically significant drug interactions involving glucuronidation are not anticipated due to limited contribution of individual UGT enzymes in the glucuronidation of eltrombopag.
Approximately 21 % of an eltrombopag dose could undergo oxidative metabolism. Human liver microsome studies identified CYP1A2 and CYP2C8 as the enzymes responsible for eltrombopag oxidation. Eltrombopag does not inhibit or induce CYP enzymes based on in vitro and in vivo data (see section 4.5).
In vitro studies demonstrate that eltrombopag is an inhibitor of the OATP1B1 transporter and an inhibitor of the BCRP transporter and eltrombopag increased exposure of the OATP1B1 and BCRP substrate rosuvastatin in a clinical drug interaction study (see section 4.5). In clinical studies with eltrombopag, a dose reduction of statins by 50 % was recommended.
Eltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium and zinc (see sections 4.2 and 4.5).
Administration of a single 50 mg dose of eltrombopag with a standard high-calorie, high-fat breakfast that included dairy products reduced plasma eltrombopag AUC~(0-∞ )~ and Cmax. Whereas, low-calcium food [< 50 mg calcium] did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content (see sections 4.2 and 4.5).
The pharmacokinetics of eltrombopag has been studied after administration of eltrombopag to adult subjects with renal impairment. Following administration of a single 50 mg-dose, the AUC0-∞ of eltrombopag was 32 % to 36 % lower in subjects with mild to moderate renal impairment, and 60 % lower in subjects with severe renal impairment compared with healthy volunteers. There was substantial variability and significant overlap in exposures between patients with renal impairment and healthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein bound medicinal product were not measured. Patients with impaired renal function should use eltrombopag with caution and close monitoring, for example by testing serum creatinine and/or urine analysis (see section 4.2).
The pharmacokinetics of eltrombopag has been studied after administration of eltrombopag to adult subjects with hepatic impairment. Following the administration of a single 50 mg dose, the AUC0-∞ of eltrombopag was 41 % higher in subjects with mild hepatic impairment and 80 % to 93 % higher in subjects with moderate to severe hepatic impairment compared with healthy volunteers. There was substantial variability and significant overlap in exposures between patients with hepatic impairment and healthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein bound medicinal product were not measured. The influence of hepatic impairment on the pharmacokinetics of eltrombopag following repeat administration was evaluated using a population pharmacokinetic analysis in 28 healthy adults and 79 patients with chronic liver disease (37 mild hepatic impairment, 40 with moderate hepatic impairment, and 2 with severe hepatic impairment). Based on estimates from the population pharmacokinetic analysis, patients with hepatic impairment had higher plasma eltrombopag AUC(0-τ) values as compared to healthy volunteers, and AUC(0-τ) increased with increasing Child-Pugh score. Compared to healthy volunteers, patients with mild hepatic impairment had approximately 87 % to 110 % higher plasma eltrombopag AUC(0-τ) values and patients with moderate hepatic impairment had approximately 141 % to 240 % higher plasma eltrombopag AUC(0-τ) values. Therefore, eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥ 5) unless the expected benefit outweighs the identified risk of portal venous thrombosis (see sections 4.2 and 4.4).
The influence of East Asian ethnicity on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (31 East Asians) and 88 patients with ITP (18 East Asians). Based on estimates from the population pharmacokinetic analysis, East Asian (i.e. Japanese, Chinese, Taiwanese and Korean) ITP patients had approximately 87 % higher plasma eltrombopag AUC(0-τ) values as compared to non-East Asian patients who were predominantly Caucasian, without adjustment for body weight differences (see section 4.2).
The influence of gender on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (14 females) and 88 patients with ITP (57 females). Based on estimates from the population pharmacokinetic analysis, female ITP patients had approximately 50 % higher plasma eltrombopag AUC(0-τ) as compared to male patients, without adjustment for body weight differences.
Eltrombopag does not stimulate platelet production in mice, rats or dogs because of unique TPO receptor specificity. Therefore, data from these animals do not fully model potential adverse effects related to the pharmacology of eltrombopag in humans, including the reproduction and carcinogenicity studies.
Treatment-related cataracts were detected in rodents and were dose and time-dependent. At ≥ 6 times the human clinical exposure based on AUC, cataracts were observed in mice after 6 weeks and rats after 28 weeks of dosing. At ≥ 4 times the human clinical exposure based on AUC, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing. Cataracts have not been observed in dogs after 52 weeks of dosing (2 times the human clinical exposure based on AUC). The clinical relevance of these findings is unknown (see section 4.4).
Renal tubular toxicity was observed in studies of up to 14 days duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2 year oral carcinogenicity study in mice at doses of 25, 75 and 150 mg/kg/day. Effects were less severe at lower doses and were characterized by a spectrum of regenerative changes. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC. Renal effects were not observed in rats after 28 weeks or in dogs after 52 weeks at exposures 4 and 2 times respectively, the human clinical exposure based on AUC. The clinical relevance of these findings is unknown.
Hepatocyte degeneration and/or necrosis, often accompanied by increased serum liver enzymes, was observed in mice, rats and dogs at doses that were associated with morbidity and mortality or were poorly tolerated. No hepatic effects were observed after chronic dosing in rats (28 weeks) or dogs (52 weeks) at exposures up to 4 or 2 times, respectively, the human clinical exposure based on AUC.
At poorly tolerated doses in rats and dogs (> 10 times maximum human clinical exposure based on AUC), decreased reticulocyte counts and regenerative bone marrow erythroid hyperplasia (rats only) were observed in short term studies. There were no effects of note on red cell mass or reticulocyte counts after dosing for up to 28 weeks in rats, 52 weeks in dogs and 2 years in mice or rats at maximally tolerated doses which were 2 to 4 times maximum human clinical exposure based on AUC.
Endosteal hyperostosis was observed in a 28 week toxicity study in rats at a non-tolerated dose of 60 mg/kg/day (6 times maximum human clinical exposure based on AUC). There were no bone changes observed in mice or rats after lifetime exposure (2 years) at 4 times maximum human clinical exposure based on AUC.
Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day (exposures up to 4 times the human clinical exposure based on AUC). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on Cmax). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (< 3-fold increase in mutation frequency). These in vitro and in vivo findings suggest that eltrombopag does not pose a genotoxic risk to humans.
Eltrombopag did not affect female fertility, early embryonic development or embryofoetal development in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC). Also there was no effect on embryofoetal development in rabbits at doses up to 150 mg/kg/day, the highest dose tested (0.5 times the human clinical exposure based on AUC). However, at a maternally toxic dose of 60 mg/kg/day (6 times the human clinical exposure based on AUC) in rats, eltrombopag treatment was associated with embryo lethality (increased pre- and post-implantation loss), reduced foetal body weight and gravid uterine weight in the female fertility study and a low incidence of cervical ribs and reduced foetal body weight in the embryofoetal development study. Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC). In the pre- and post-natal development study in rats, there were no undesirable effects on pregnancy, parturition or lactation of F0 female rats at maternally non-toxic doses (10 and 20 mg/kg/day) and no effects on the growth, development, neurobehavioral or reproductive function of the offspring (F1). Eltrombopag was detected in the plasma of all F1 rat pups for the entire 22 hour sampling period following administration of medicinal product to the F0 dams, suggesting that rat pup exposure to eltrombopag was likely via lactation.
In vitro studies with eltrombopag suggest a potential phototoxicity risk; however, in rodents there was no evidence of cutaneous phototoxicity (10 times the human clinical exposure based on AUC) or ocular phototoxicity (≥ 5 times the human clinical exposure based on AUC). Furthermore, a clinical pharmacology study in 36 subjects showed no evidence that photosensitivity was increased following administration of eltrombopag 75 mg. This was measured by delayed phototoxic index. Nevertheless, a potential risk of photoallergy cannot be ruled out since no specific preclinical study could be performed.
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