Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Pharmacotherapeutic group: Antihemorrhagics, other systemic hemostatics
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 signalling cascades similar but not identical to that of endogenous thrombopoietin (TPO), inducing proliferation and differentiation 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 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 medicinal products at baseline and baseline platelet count. The dose of eltrombopag was adjusted during the 6-month treatment period based on individual platelet counts. All patients 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 treatment 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 4. 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-valuea | <0.001 | |
| Patients with bleeding (WHO Grades 1-4) at any time during 6 months, n (%) | 106 (79) | 56 (93) |
| p-valuea | 0.012 | |
| Patients with bleeding (WHO Grades 2-4) at any time during 6 months, n (%) | 44 (33) | 32 (53) |
| p-valuea | 0.002 | |
| Requiring rescue therapy, n (%) | 24 (18) | 25 (40) |
| p-valuea | 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-valuea | 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 medicinal product at baseline permanently discontinued all baseline ITP medicinal products.
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 ITP were randomised 2:1 eltrombopag (n=76) to placebo (n=38).
Table 5. 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-valuea | <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-valuea | 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 medicinal product 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 302 ITP patients in the open-label extension study EXTEND (TRA105325), 218 patients completed 1 year, 180 completed 2 years, 107 completed 3 years, 75 completed 4 years, 34 completed 5 years and 18 completed 6 years. The median baseline platelet count was 19,000/μl prior to eltrombopag administration. Median platelet counts at 1, 2, 3, 4, 5, 6 and 7 years on study were 85,000/μl, 85,000/μl, 105,000/μl, 64,000/μl, 75,000/μl, 119,000/μl and 76,000/μl, respectively.
Clinical studies comparing eltrombopag to other treatment options (e.g. splenectomy) have not been conducted. The long-term safety of eltrombopag should be considered prior to starting therapy.
The safety and efficacy of eltrombopag in paediatric patients have been investigated in two studies.
TRA115450 (PETIT2): The primary endpoint was a sustained response, defined as the proportion of patients receiving eltrombopag, compared to placebo, achieving platelet counts ≥50,000/μl for at least 6 out of 8 weeks (in the absence of rescue therapy), between weeks 5 to 12 during the double-blind randomised period. Patients were diagnosed with chronic ITP for at least 1 year and were refractory or relapsed to at least one prior ITP therapy or unable to continue other ITP treatments for a medical reason and had platelet count <30,000/μl. Ninety-two patients were randomised by three age cohort strata (2:1) to eltrombopag (n=63) or placebo (n=29). The dose of eltrombopag could be adjusted based on individual platelet counts.
Overall, a significantly greater proportion of eltrombopag patients (40%) compared with placebo patients (3%) achieved the primary endpoint (Odds Ratio: 18.0 [95% CI: 2.3, 140.9] p<0.001) which was similar across the three age cohorts (Table 6).
Table 6. Sustained platelet response rates by age cohort in paediatric patients with chronic ITP:
| Eltrombopag n/N (%) [95% CI] | Placebo n/N (%) [95% CI] | |
|---|---|---|
| Cohort 1 (12 to 17 years) | 9/23 (39%) [20%, 61%] | 1/10 (10%) [0%, 45%] |
| Cohort 2 (6 to 11 years) | 11/26 (42%) [23%, 63%] | 0/13 (0%) [N/A] |
| Cohort 3 (1 to 5 years) | 5/14 (36%) [13%, 65%] | 0/6 (0%) [N/A] |
Statistically fewer eltrombopag patients required rescue treatment during the randomised period compared to placebo patients (19% [12/63] vs. 24% [7/29], p=0.032).
At baseline, 71% of patients in the eltrombopag group and 69% in the placebo group reported any bleeding (WHO Grades 1-4). At Week 12, the proportion of eltrombopag patients reporting any bleeding was decreased to half of baseline (36%). In comparison, at Week 12, 55% of placebo patients reported any bleeding.
Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the study and 53% (8/15) of patients were able to reduce (n=1) or discontinue (n=7) baseline ITP therapy, mainly corticosteroids, without needing rescue therapy.
TRA108062 (PETIT): The primary endpoint was the proportion of patients achieving platelet counts ≥50,000/μl at least once between weeks 1 and 6 of the randomised period. Patients were diagnosed with ITP for at least 6 months and were refractory or relapsed to at least one prior ITP therapy with a platelet count <30,000/μl (n=67). During the randomised period of the study, patients were randomised by three age cohort strata (2:1) to eltrombopag (n=45) or placebo (n=22). The dose of eltrombopag could be adjusted based on individual platelet counts.
Overall, a significantly greater proportion of eltrombopag patients (62%) compared with placebo patients (32%) met the primary endpoint (Odds Ratio: 4.3 [95% CI: 1.4, 13.3] p=0.011).
Sustained response was seen in 50% of the initial responders during 20 out of 24 weeks in the PETIT 2 study and 15 out of 24 weeks in the PETIT study.
The efficacy and safety of eltrombopag for the treatment of thrombocytopenia in patients with HCV infection were evaluated in two randomised, double-blind, placebo-controlled studies. ENABLE 1 utilised peginterferon alfa-2a plus ribavirin for antiviral treatment and ENABLE 2 utilised peginterferon alfa-2b plus ribavirin. Patients did not receive direct acting antiviral agents. In both studies, patients with a platelet count of <75,000/μl were enrolled and stratified by platelet count (<50,000/μl and ≥50,000/μl to <75,000/μl), screening HCV RNA (<800,000 IU/ml and ≥800,000 IU/ml), and HCV genotype (genotype 2/3, and genotype 1/4/6).
Baseline disease characteristics were similar in both studies and were consistent with compensated cirrhotic HCV patient population. The majority of patients were HCV genotype 1 (64%) and had bridging fibrosis/cirrhosis. Thirty-one percent of patients had been treated with prior HCV therapies, primarily pegylated interferon plus ribavirin. The median baseline platelet count was 59,500/μl in both treatment groups: 0.8%, 28% and 72% of the patients recruited had platelet counts <20,000/μl, <50.000/μl and ≥50,000/μl respectively.
The studies consisted of two phases – a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label eltrombopag to increase the platelet count to ≥90,000/μl for ENABLE 1 and ≥100,000/μl for ENABLE 2. The median time to achieve the target platelet count ≥90,000/μl (ENABLE 1) or ≥100,000/μl (ENABLE 2) was 2 weeks.
The primary efficacy endpoint for both studies was sustained virologic response (SVR), defined as the percentage of patients with no detectable HCV-RNA at 24 weeks after completion of the planned treatment period.
In both HCV studies, a significantly greater proportion of patients treated with eltrombopag (n=201, 21%) achieved SVR compared to those treated with placebo (n=65, 13%) (see Table 7). The improvement in the proportion of patients who achieved SVR was consistent across all subgroups in the randomisation strata (baseline platelet counts (<50,000 vs. >50,000), viral load (<800,000 IU/ml vs. ≥800,000 IU/ml) and genotype (⅔ vs. 1/4/6)).
Table 7. Virologic response in HCV patients in ENABLE 1 and ENABLE 2:
| Pooled data | ENABLE 1a | ENABLE 2b | ||||
|---|---|---|---|---|---|---|
| Patients achieving target platelet counts and initiating antiviral therapyc | 1,439/1,520 (95%) | 680/715 (95%) | 759/805 (94%) | |||
| Eltrombopag | Placebo | Eltrombopag | Placebo | Eltrombopag | Placebo | |
| Total number of patients entering antiviral treatment phase | n=956 | n=485 | n=450 | n=232 | n=506 | n=253 |
| % patients achieving virologic response | ||||||
| Overall SVRd | 21 | 13 | 23 | 14 | 19 | 13 |
| HCV RNA Genotype | ||||||
| Genotype ⅔ | 35 | 25 | 35 | 24 | 34 | 25 |
| Genotype 1/4/6e | 15 | 8 | 18 | 10 | 13 | 7 |
| Albumin levelsf | ||||||
| ≤35g/l | 11 | 8 | ||||
| >35g/l | 25 | 16 | ||||
| MELD scoref | ||||||
| ≥10 | 18 | 10 | ||||
| <10 | 23 | 17 | ||||
a Eltrombopag given in combination with peginterferon alfa-2a (180 μg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype ⅔) plus ribavirin (800 to 1200 mg daily in 2 divided doses orally)
b Eltrombopag given in combination with peginterferon alfa-2b (1.5 μg/kg once weekly for 48 weeks for genotype 1/4/6; 24 weeks for genotype ⅔) plus ribavirin (800 to 1400 mg orally in 2 divided doses)
c Target platelet count was ≥90,000/μl for ENABLE 1 and ≥100,000/μl for ENABLE 2. For ENABLE 1, 682 patients were randomised to the antiviral treatment phase; however 2 patients then withdrew consent prior to receiving antiviral therapy
d p-value <0.05 for eltrombopag versus placebo
e 64% patients participating in ENABLE 1 and ENABLE 2 were genotype 1
f Post-hoc analyses
Other secondary findings of the studies included the following: significantly fewer patients treated with eltrombopag prematurely discontinued antiviral therapy compared to placebo (45% vs. 60%, p=<0.0001). A greater proportion of patients on eltrombopag did not require any antiviral dose reduction as compared to placebo (45% vs. 27%). Eltrombopag treatment delayed and reduced the number of peginterferon dose reductions.
Eltrombopag was studied in a single-arm, single-centre open-label study in 43 patients with severe aplastic anaemia with refractory thrombocytopenia following at least one prior immunosuppressive therapy (IST) and who had a platelet count ≤30,000/μl.
The majority of patients, 33 (77%), were considered to have ‘primary refractory disease’, defined as having no prior adequate response to IST in any lineage. The remaining 10 patients had insufficient platelet response to prior therapies. All 10 had received at least 2 prior IST regimens and 50% had received at least 3 prior IST regimens. Patients with diagnosis of Fanconi anaemia, infection not responding to appropriate therapy, PNH clone size in neutrophils of ≥50%, where excluded from participation.
At baseline the median platelet count was 20,000/μl, haemoglobin was 8.4 g/dl, ANC was 0.58 × 109/l and absolute reticulocyte count was 24.3 × 109/l. Eighty-six percent of patients were RBC transfusion dependent, and 91% were platelet transfusion dependent. The majority of patients (84%) had received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline.
The primary endpoint was haematological response assessed after 12 weeks of eltrombopag treatment. Haematological response was defined as meeting one or more of the following criteria: 1) platelet count increases to 20,000/μl above baseline or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) haemoglobin increase by >1.5g/dl, or a reduction in ≥4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) absolute neutrophil count (ANC) increase of 100% or an ANC increase >0.5 × 109/l.
The haematological response rate was 40% (17/43 patients; 95% CI 25, 56), the majority were unilineage responses (13/17, 76%) whilst there were 3 bilineage and 1 trilineage responses at week 12. Eltrombopag was discontinued after 16 weeks if no haematological response or transfusion independence was observed. Patients who responded continued therapy in an extension phase of the study. A total of 14 patients entered the extension phase of the trial. Nine of these patients achieved a multi-lineage response, 4 of the 9 remain on treatment and 5 tapered off treatment with eltrombopag and maintained the response (median follow up: 20.6 months, range: 5.7 to 22.5 months). The remaining 5 patients discontinued treatment, three due to relapse at the month 3 extension visit.
During treatment with eltrombopag 59% (23/39) became platelet transfusion independent (28 days without platelet transfusion) and 27% (10/37) became RBC transfusion independent (56 days without RBC transfusion). The longest platelet transfusion-free period for non-responders was 27 days (median). The longest platelet transfusion-free period for responders was 287 days (median). The longest RBC transfusion-free period for non-responders was 29 days (median). The longest RBC transfusion-free period for responders was 266 days (median).
Over 50% of responders who were transfusion-dependent at baseline, had >80% reduction in both platelet and RBC transfusion requirements compared to baseline.
Preliminary results from a supportive study (Study ELT116826), an ongoing non-randomised, phase II, single-arm, open-label study in refractory SAA patients, showed consistent results. Data are limited to 21 out of the planned 60 patients with haematological responses reported by 52% of patients at 6 months. Multilineage responses were reported by 45% of patients.
The plasma eltrombopag concentration-time data collected in 88 patients with ITP in studies TRA100773A and TRA100773B were combined with data from 111 healthy adult subjects in a population PK analysis. Plasma eltrombopag AUC(0-τ) and Cmax estimates for ITP patients are presented (Table 8).
Table 8. 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 | Cmaxa, 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 Cmax based on population PK post-hoc estimates.
Plasma eltrombopag concentration-time data collected in 590 patients with HCV enrolled in phase III studies TPL103922/ENABLE 1 and TPL108390/ENABLE 2 were combined with data from patients with HCV enrolled in the phase II study TPL102357 and healthy adult patients in a population PK analysis. Plasma eltrombopag Cmax and AUC(0-τ) estimates for patients with HCV enrolled in the phase III studies are presented for each dose studied in Table 9.
Table 9. Geometric mean (95% CI) steady-state plasma eltrombopag pharmacokinetic parameters in patients with chronic HCV:
| Eltrombopag dose (once daily) | N | AUC(0-τ) (μg.h/ml) | Cmax (μg/ml) |
|---|---|---|---|
| 25 mg | 330 | 118 (109, 128) | 6.40 (5.97, 6.86) |
| 50 mg | 119 | 166 (143, 192) | 9.08 (7.96, 10.35) |
| 75 mg | 45 | 301 (250, 363) | 16.71 (14.26, 19.58) |
| 100 mg | 96 | 354 (304, 411) | 19.19 (16.81, 21.91) |
Data presented as geometric mean (95% CI).
AUC(0-τ) and Cmax based on population PK post-hoc estimates at the highest dose in the data for each patient.
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). In a relative bioavailability study in adults, the eltrombopag powder for oral suspension delivered 22% higher plasma AUC(0-∞) than the film-coated tablet formulation. 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 metabolised 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).
In vitro studies demonstrated that eltrombopag is not a substrate for the organic anion transporter polypeptide, OATP1B1, but is an inhibitor of this transporter (IC50 value of 2.7 μM (1.2 μg/ml). In vitro studies also demonstrated that eltrombopag is a breast cancer resistance protein (BCRP) substrate and inhibitor (IC50 value of 2.7 μM (1.2 μg/ml).
The pharmacokinetics of eltrombopag have been studied after administration of eltrombopag to adult patients with renal impairment. Following administration of a single 50 mg dose, the AUC0-∞ of eltrombopag was 32% to 36% lower in patients with mild to moderate renal impairment, and 60% lower in patients 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 efficacy and safety of eltrombopag have not been established in patients with both moderate to severe renal impairment and hepatic impairment.
The pharmacokinetics of eltrombopag have been studied after administration of eltrombopag to adult patients with hepatic impairment. Following the administration of a single 50 mg dose, the AUC0-∞ of eltrombopag was 41% higher in patients with mild hepatic impairment and 80% to 93% higher in patients 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 714 patients with hepatic impairment (673 patients with HCV and 41 patients with chronic liver disease of other aetiology). Of the 714 patients, 642 were with mild hepatic impairment, 67 with moderate hepatic impairment, and 2 with severe hepatic impairment. Compared to healthy volunteers, patients with mild hepatic impairment had approximately 111% (95% CI: 45% to 283%) higher plasma eltrombopag AUC(0-τ) values and patients with moderate hepatic impairment had approximately 183% (95% CI: 90% to 459%) 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). For patients with HCV initiate eltrombopag at a dose of 25 mg once daily (see section 4.2).
The influence of Asian ethnicity (such as Japanese, Chinese, Taiwanese and Korean) on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (31 Asians) and 88 patients with ITP (18 Asians). Based on estimates from the population pharmacokinetic analysis, Asian ITP patients had approximately 49% higher plasma eltrombopag AUC(0-τ) values as compared to non-Asian patients who were predominantly Caucasian (see section 4.2).
The influence of Asian ethnicity (such as Chinese, Japanese, Taiwanese, Korean, and Thai) on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 635 patients with HCV (145 Asians and 69 South Asians). Based on estimates from the population pharmacokinetic analysis, Asian patients had approximately 55% higher plasma eltrombopag AUC(0-τ) values as compared to patients of other races who were predominantly Caucasian (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 23% higher plasma eltrombopag AUC(0-τ) as compared to male patients, without adjustment for body weight differences.
The influence of gender on eltrombopag pharmacokinetics was evaluated using population pharmacokinetics analysis in 635 patients with HCV (260 females). Based on model estimate, female HCV patient had approximately 41% higher plasma eltrombopag AUC(0-τ) as compared to male patients.
The influence of age on eltrombopag pharmacokinetics was evaluated using population pharmacokinetics analysis in 28 healthy subjects, 673 patients with HCV, and 41 patients with chronic liver disease of other aetiology ranging from 19 to 74 years old. There are no PK data on the use of eltrombopag in patients ≥75 years. Based on model estimate, elderly (≥65 years) patients had approximately 41% higher plasma eltrombopag AUC(0-τ) as compared to younger patients (see section 4.2).
The pharmacokinetics of eltrombopag have been evaluated in 168 paediatric ITP patients dosed once daily in two studies, TRA108062/PETIT and TRA115450/PETIT-2. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. The effects of race and sex on plasma eltrombopag CL/F estimates were consistent between paediatric and adult patients. Asian paediatric ITP patients had approximately 43% higher plasma eltrombopag AUC(0-τ) values as compared to non-Asian patients. Female paediatric ITP patients had approximately 25% higher plasma eltrombopag AUC(0-τ) values as compared to male patients.
The pharmacokinetic parameters of eltrombopag in paediatric patients with ITP are shown in Table 10.
Table 10. Geometric mean (95% CI) steady-state plasma eltrombopag pharmacokinetic parameters in paediatric patients with ITP (50 mg once daily dosing regimen):
| Age | Cmax (µg/ml) | AUC(0-τ) (µg.hr/ml) |
|---|---|---|
| 12 to 17 years (n=62) | 6.80 (6.17, 7.50) | 103 (91.1, 116) |
| 6 to 11 years (n=68) | 10.3 (9.42, 11.2) | 153 (137, 170) |
| 1 to 5 years (n=38) | 11.6 (10.4, 12.9) | 162 (139, 187) |
Data presented as geometric mean (95%CI).
AUC(0-τ) and Cmax based on population PK post-hoc estimates.
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 in adult ITP patients at 75 mg/day and 3 times the human clinical exposure in adult HCV patients at 100 mg/day, 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 in ITP patients at 75 mg/day and 2 times the human exposure in HCV patients at 100 mg/day, based on AUC, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing. At non-tolerated doses in pre-weaning juvenile rats dosed from Days 4-32 (approximately equating to a 2-year-old human at the end of the dosing period), ocular opacities were observed (histology not performed) at 9 times the maximum human clinical exposure in paediatric ITP patients at 75 mg/day, based on AUC. However, cataracts were not observed in juvenile rats given tolerated doses at 5 times the human clinical exposure in paediatric ITP patients, based on AUC. Cataracts have not been observed in adult dogs after 52 weeks of dosing at 2 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC).
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 characterised by a spectrum of regenerative changes. The exposure at the lowest dose was 1.2 or 0.8 times the human clinical exposure based on AUC in adult or paediatric ITP patients at 75 mg/day and 0.6 times the human clinical exposure in HCV patients at 100 mg/day, 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 the human clinical exposure in adult ITP patients and 3 and 2 times the human clinical exposure in paediatric ITP patients at 75 mg/day and 2 times and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC.
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) and in dogs (52 weeks) at 4 or 2 times the human clinical exposure in adult ITP patients and 3 or 2 times the human clinical exposure in paediatric ITP patients at 75 mg/day and 2 times or equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on AUC.
At poorly tolerated doses in rats and dogs (>10 or 7 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and>4 times the human clinical exposure in HCV patients at 100 mg/day, 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 human clinical exposure in adult or paediatric ITP patients at 75 mg/day and ≤2 times the human clinical exposure in HCV patients at 100 mg/day, 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 or 4 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). There were no bone changes observed in mice or rats after lifetime exposure (2 years) at 4 times or 2 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, 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 or 2 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, 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 or 8 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 7 times the human clinical exposure in HCV patients at 100 mg/day, 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 in adult or adolescent (12-17 years old) ITP patients at 75 mg/day and equivalent to the human clinical exposure in HCV patients at 100 mg/day, 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 (0.3 to 0.5 times the human clinical exposure in ITP patients at 75 mg/day and HCV patients at 100 mg/day, based on AUC). However, at a maternally toxic dose of 60 mg/kg/day (6 times the human clinical exposure in ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, 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 should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus (see section 4.6). 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 in ITP patients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, 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, neurobehavioural 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 or 7 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 5 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC) or ocular phototoxicity (4 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, 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.
At non-tolerated doses in pre-weaning rats, ocular opacities were observed. At tolerated doses, no ocular opacities were observed (see above subsection ‘Safety pharmacology and repeat-dose toxicity’). In conclusion, taking into account the exposure margins based on AUC, a risk of eltrombopag-related cataracts in paediatric patients cannot be excluded. There are no findings in juvenile rats to suggest a greater risk of toxicity with eltrombopag treatment in paediatric vs. adult ITP patients.
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