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Pharmacology: Pharmacodynamics: Mechanism of action: TPO is the main cytokine involved in regulation of megakaryopoiesis and platelet production, and is the endogenous ligand for the TPO-R. Elthropa 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.
Clinical efficacy and safety: Immune (primary) thrombocytopenia (ITP) studies: 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 Elthropa in adult patients with previously treated ITP. Overall, Elthropa was administered to 277 ITP patients for at least 6 months and 202 patients for at least 1 year. The single-arm phase II study TAPER (CETB115J2411) evaluated the safety and efficacy of eltrombopag and its ability to induce sustained response after treatment discontinuation in 105 adult ITP patients who relapsed or failed to respond to first-line corticosteroid treatment.
Double-blind placebo-controlled studies: RAISE:197 ITP patients were randomised 2:1, Elthropa (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 Elthropa was adjusted during the 6-month treatment period based on individual platelet counts. All patients initiated treatment with Elthropa 50 mg. From Day 29 to the end of treatment, 15 to 28% of Elthropa 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 Elthropa 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 Elthropa treated group during the 6-month treatment period, p<0.001. Fifty-four percent of the Elthropa-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. (See Table 1.)
Click on icon to see table/diagram/imageAt 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 Elthropa-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 Elthropa (n=76) to placebo (n=38). (See Table 2.)
Click on icon to see table/diagram/imageIn both RAISE and TRA100773B the response to Elthropa 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 Elthropa responded after 6 weeks of treatment. In addition, in the RAISE study, 42% of patients with baseline platelet count ≤15,000/μL treated with Elthropa responded at the end of the 6-month treatment period. Forty-two to 60% of the Elthropa-treated patients in the RAISE study were receiving 75 mg from Day 29 to the end of treatment.
Open-label non-controlled studies: REPEAT (TRA108057): This 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 Elthropa has demonstrated no loss of response.
EXTEND (TRA105325): Elthropa was administered to 302 ITP patients in this open-label extension study, 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/μLprior to Elthropa 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.
TAPER (CETB115J2411): This was a single-arm phase II study including ITP patients treated with eltrombopag after first-line corticosteroid failure irrespective of time since diagnosis. A total of 105 patients were enrolled on the study and started eltrombopag treatment on 50 mg once daily (25 mg once daily for patients of East-/Southeast-Asian ancestry). The dose of eltrombopag was adjusted during the treatment period based on individual platelet counts with the goal to achieve a platelet count ≥100,000/μL.
Of the 105 patients who were enrolled in the study and who received at least one dose of eltrombopag, 69 patients (65.7%) completed treatment and 36 patients (34.3%) discontinued treatment early.
Analysis of sustained response off treatment: The primary endpoint was the proportion of patients with sustained response off treatment until Month 12. Patients who reached a platelet count of ≥100,000/μL and maintained platelet counts around ≥100,000/μL for 2 months (no counts below 70,000/μL) were eligible for tapering off eltrombopag and treatment discontinuation. To be considered as having achieved a sustained response off treatment, a patient had to maintain platelet counts ≥30,000/μL, in the absence of bleeding events or the use of rescue therapy, both during the treatment tapering period and following discontinuation of treatment until Month 12.
The duration of tapering was individualised depending on the starting dose and the response of the patient. The tapering schedule recommended dose reductions of 25 mg every 2 weeks if the platelet counts were stable. After the daily dose was reduced to 25 mg for 2 weeks, the dose of 25 mg was then only administered on alternate days for 2 weeks until treatment discontinuation. The tapering was done in smaller decrements of 12.5 mg every second week for patients of East-/Southeast-Asian ancestry. If a relapse (defined as platelet count <30,000/μL) occurred, patients were offered a new course of eltrombopag at the appropriate starting dose.
Eighty-nine patients (84.8%) achieved a complete response (platelet count ≥100,000/μL) (Step 1, Table 3) and 65 patients (61.9%) maintained the complete response for at least 2 months with no platelet counts below 70,000/μL (Step 2, Table 3). Forty-four patients (41.9%) were able to be tapered off eltrombopag until treatment discontinuation while maintaining platelet counts ≥30,000/μL in the absence of bleeding events or the use of rescue therapy (Step 3, Table 3).
Study met the primary objective by demonstrating that eltrombopag was able to induce sustained response off treatment, in the absence of bleeding events or the use of rescue therapy, by Month 12 in 32 of the 105 enrolled patients (30.5%; p<0.0001; 95% CI: 21.9, 40.2) (Step 4, Table 3). By Month 24, 20 of the 105 enrolled patients (19.0%; 95% CI: 12.0, 27.9) maintained sustained response off treatment in the absence of bleeding events or the use of rescue therapy (Step 5, Table 3).
The median duration of sustained response after treatment discontinuation to Month 12 was 33.3 weeks (min-max: 4-51), and the median duration of sustained response after treatment discontinuation to Month 24 was 88.6 weeks (min-max: 57-107).
After tapering off and discontinuation of eltrombopag treatment, 12 patients had a loss of response, 8 of them re-started eltrombopag and 7 had a recovery response.
During the 2-year follow-up, 6 out of 105 patients (5.7%) experienced thromboembolic events, of which 3 patients (2.9%) experienced deep vein thrombosis, 1 patient (1.0%) experienced superficial vein thrombosis, 1 patient (1.0%) experienced cavernous sinus thrombosis, 1 patient (1.0%) experienced cerebrovascular accident and 1 patient (1.0%) experienced pulmonary embolism. Of the 6 patients, 4 patients experienced thromboembolic events that were reported at or greater than Grade 3, and 4 patients experienced thromboembolic event that were reported as serious. No fatal cases were reported.
Twenty out of 105 patients (19.0%) experienced mild to severe haemorrhage events on treatment before tapering started. Five out of 65 patients (7.7%) who started tapering experienced mild to moderate haemorrhage events during tapering. No severe haemorrhage event occurred during tapering. Two out of 44 patients (4.5%) who tapered off and discontinued eltrombopag treatment experienced mild to moderate haemorrhage events after treatment discontinuation until Month 12. No severe haemorrhage event occurred during this period. None of the patients who discontinued eltrombopag and entered the second year follow-up experienced haemorrhage event during the second year. Two fatal intracranial haemorrhage events were reported during the 2-year follow-up. Both events occurred on treatment, not in the context of tapering. The events were not considered to be related to study treatment.
The overall safety analysis is consistent with previously reported data and the risk-benefit assessment remained unchanged for the use of eltrombopag in patients with ITP. (See Table 3.)
Click on icon to see table/diagram/imageResults of response on treatment analysis by time since ITP diagnosis: An ad-hoc analysis was conducted on the n=105 patients by time since ITP diagnosis to assess the response to eltrombopag across four different ITP categories by time since diagnosis (newly diagnosed ITP <3 months, persistent ITP 3 to <6 months, persistent ITP 6 to ≤12 months, and chronic ITP >12 months). 49% of patients (n=51) had an ITP diagnosis of <3 months, 20% (n=21) of 3 to <6 months, 17% (n=18) of 6 to ≤12 months and 14% (n=15) of >12 months.
Until the cut-off date (22-Oct-2021), patients were exposed to eltrombopag for a median (Q1-Q3) duration of 6.2 months (2.3-12.0 months). The median (Q1-Q3) platelet count at baseline was 16 000/μl (7,800-28,000/µL).
Platelet count response, defined as a platelet count ≥50,000/µL at least once by Week 9 without rescue therapy, was achieved in 84% (95% CI: 71% to 93%) of newly diagnosed ITP patients, 91% (95% CI: 70% to 99%) and 94% (95% CI: 73% to 100%) of persistent ITP patients (i.e. with ITP diagnosis 3 to <6 months and 6 to ≤12 months, respectively), and in 87% (95% CI: 60% to 98%) of chronic ITP patients.
Rate of complete response, defined as platelet count ≥100,000/µL at least once by Week 9 without rescue therapy, was 75% (95% CI: 60% to 86%) in newly diagnosed ITP patients, 76% (95% CI: 53% to 92%) and 72% (95% CI: 47% to 90%) in persistent ITP patients (ITP diagnosis 3 to <6 months and 6 to ≤12 months, respectively), and 87% (95% CI: 60% to 98%) in chronic ITP patients.
The rate of durable response, defined as a platelet count ≥50,000/µL for at least 6 out of 8 consecutive assessments without rescue therapy during the first 6 months on study, was 71% (95% CI: 56% to 83%) in newly diagnosed ITP patients, 81% (95% CI: 58% to 95%) and 72% (95% CI: 47% to 90.3%) in persistent ITP patients (ITP diagnosis 3 to <6 months and 6 to ≤12 months, respectively), and 80% (95% CI: 52% to 96%) in chronic ITP patients.
When assessed with the WHO Bleeding Scale, the proportion of newly diagnosed and persistent ITP patients without bleeding at Week 4 ranged from 88% to 95% compared to 37% to 57% at baseline. For chronic ITP patients it was 93% compared to 73% at baseline.
The safety of eltrombopag was consistent across all ITP categories and in line with its known safety profile.
Clinical studies comparing Elthropa to other treatment options (e.g. splenectomy) have not been conducted. The long-term safety of Elthropa should be considered prior to starting therapy.
Paediatric population (aged 1 to 17 years): The safety and efficacy of Elthropa 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 Elthropa, 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 Elthropa (n=63) or placebo (n=29). The dose of Elthropa could be adjusted based on individual platelet counts.
Overall, a significantly greater proportion of Elthropa 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 (See Table 4).
Click on icon to see table/diagram/imageStatistically fewer Elthropa 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 Elthropa group and 69% in the placebo group reported any bleeding (WHO Grades 1-4). At Week 12, the proportion of Elthropa 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 Elthropa (n=45) or placebo (n=22). The dose of Elthropa could be adjusted based on individual platelet counts.
Overall, a significantly greater proportion of Elthropa 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.
Chronic hepatitis C associated thrombocytopenia studies: The efficacy and safety of Elthropa 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 Elthropa 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 Elthropa (n=201, 21%) achieved SVR compared to those treated with placebo (n=65, 13%) (see Table 5). 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 (2/3 vs. 1/4/6)). (See Table 5.)
Click on icon to see table/diagram/imageOther secondary findings of the studies included the following: significantly fewer patients treated with Elthropa prematurely discontinued antiviral therapy compared to placebo (45% vs. 60%, p=<0.0001). A greater proportion of patients on Elthropa did not require any antiviral dose reduction as compared to placebo (45% vs. 27%). Elthropa treatment delayed and reduced the number of peginterferon dose reductions.
Definitive immunosuppresive therapy-naïve severe aplastic anemia study: Elthropa in combination with horse antithymocyte globulin (h-ATG) and cyclosporine was investigated in a single-arm, single-center, open-label sequential cohort trial in patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy (i.e., ATG therapy, alemtuzumab, or high dose cyclophosphamide). The multiple cohorts differed by treatment start day and duration of Elthropa and the initiation of low dose of cyclosporine (maintenance dose) for patients who achieved a hematologic response at 6 months. A total of 153 patients received Elthropa in sequential cohorts: Elthropa on Day 14 to Month 6 (D14-M6) plus h-ATG and cyclosporine (the trial's Cohort 1 regimen, n=30).
Elthropa on Day 14 to Month 3 (D14-M3) plus h-ATG and cyclosporine (the trial's Cohort 2 regimen, n=31), with half of the patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a hematologic response at 6 months.
Elthropa on Day 1 to Month 6 (D1-M6) plus h-ATG and cyclosporine (the trial's Cohort 3 regimen, n=92), with all patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a hematologic response at 6 months.
The starting dose of Elthropa for adults and adolescent patients aged 12 to 17 years was 150 mg once daily (a reduced dose of 75 mg was administered for East and Southeast Asians), 75 mg once daily for patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered for East and Southeast Asians), and 2.5 mg/kg once daily for patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered for East and Southeast Asians). The dose of Elthropa was reduced if the platelet count exceeded 200,000/microL and interrupted and reduced if it exceeded 400,000/microL.
All patients received h-ATG 40 mg/kg/day on Days 1 to 4 of the 6-month treatment period and a total daily dose of 6 mg/kg/day of cyclosporine for 6 months in patients aged 12 years and older or a total daily dose of 12 mg/kg/day for 6 months in patients aged 2 to 11 years. A 2 mg/kg/day maintenance dose of cyclosporine was administered for an additional 18 months to 15 patients who achieved a hematologic response at 6 months in the Elthropa D14-M3 cohort and all patients who achieved a hematologic response at 6 months in the Elthropa D1-M6 cohort.
Data from the recommended schedule of Elthropa on Day 1 to Month 6 in combination with h-ATG and cyclosporine (the trial's Cohort 3 regimen) are presented as follows. This cohort had the highest complete response rates.
In the Elthropa D1-M6 cohort, the median age was 28 years (range 5 to 82 years) with 16.3% and 28.3% of patients ≥65 years of age and <18 years of age, respectively. 45.7% of patients were male and the majority of patients were White (62.0%).
The efficacy of Elthropa in combination with h-ATG and cyclosporine was established on the basis of complete hematological response at 6 months. A complete response was defined as hematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) >1,000/microL, platelet count >100,000/microL and hemoglobin >10 g/dL. A partial response was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in severe aplastic anemia equivalent to 2 of the following values on 2 consecutive serial blood count measurements at least one week apart: ANC >500/microL, platelet count >20,000/microL, or reticulocyte count >60,000/microL. (See Table 6.)
Click on icon to see table/diagram/imageThe overall and complete hematological response rates at Year 1 (N=78) are 56.4% and 38.5% and at Year 2 (N=62) are 38.7% and 30.6% respectively.
Paediatric patients: Thirty seven patients aged 2 to 17 years were enrolled in the single-arm, sequential-cohort trial. Of the 36 patients who reached the 6-month assessment point or withdrew earlier, the complete response rate at 6 months was 30.6% (0/2 in patients aged 2 to 5 years, 1/12 in patients aged 6 to 11 years, and 10/22 in patients aged 12 to 17 years) and the overall response rate at 6 months was 72.2% (2/2 in patients aged 2 to 5 years, 7/12 in patients aged 6 to 11 years, and 17/22 in patients aged 12 to 17 years). Out of 25 evaluable patients in the Elthropa D1-M6 cohort, the complete response rate at 6 months was 28% (7/12) and the overall response rate at 6 months was 68%.
Refractory severe aplastic anaemia: Elthropa 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 0.58x109/L and absolute reticulocyte count was 24.3x109/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 Elthropa 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 >1.5 g/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 >0.5x109/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. Elthropa 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 Elthropa 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 Elthropa 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.
Pharmacokinetics: The plasma Elthropa 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 Elthropa AUC(0-τ) and Cmax estimates for ITP patients are presented (see Table 7).
Click on icon to see table/diagram/imagePlasma Elthropa 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 Elthropa Cmax and AUC(0-τ) estimates for patients with HCV enrolled in the phase III studies are presented for each dose studied in Table 8. (See Table 8.)
Click on icon to see table/diagram/imageThe pharmacokinetic parameters of Elthropa after administration of Elthropa 150 mg to 45 patients with definitive immunosuppressive therapy-naïve severe aplastic anemia are shown in Table 9. (See Table 9.)
Click on icon to see table/diagram/imageAbsorption and bioavailability: Elthropa is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Administration of Elthropa concomitantly with antacids and other products containing polyvalent cations such as dairy products and mineral supplements significantly reduces Elthropa exposure (see Dosage & Administration). The absolute oral bioavailability of Elthropa 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 Elthropa solution dose was estimated to be at least 52%.
Distribution: Elthropa is highly bound to human plasma proteins (>99.9%), predominantly to albumin. Elthropa is a substrate for BCRP, but is not a substrate for P-glycoprotein or OATP1B1.
Biotransformation: Elthropa is primarily metabolised through cleavage, oxidation and conjugation with glucuronic acid, glutathione, or cysteine. In a human radiolabel study, Elthropa 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 Elthropa. Uridine diphosphoglucuronyl transferase UGT1A1 and UGT1A3 are responsible for glucuronidation, and bacteria in the lower gastrointestinal tract may be responsible for the cleavage pathway.
Elimination: Absorbed Elthropa is extensively metabolised. The predominant route of Elthropa excretion is via faeces (59%) with 31% of the dose found in the urine as metabolites. Unchanged parent compound (Elthropa) is not detected in urine. Unchanged Elthropa excreted in faeces accounts for approximately 20% of the dose. The plasma elimination half-life of Elthropa is approximately 21-32 hours.
Pharmacokinetic interactions: Based on a human study with radiolabelled Elthropa, glucuronidation plays a minor role in the metabolism of Elthropa. Human liver microsome studies identified UGT1A1 and UGT1A3 as the enzymes responsible for Elthropa glucuronidation. Elthropa 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 Elthropa.
Approximately 21% of an Elthropa dose could undergo oxidative metabolism. Human liver microsome studies identified CYP1A2 and CYP2C8 as the enzymes responsible for Elthropa oxidation. Elthropa does not inhibit or induce CYP enzymes based on in vitro and in vivo data (see Interactions).
In vitro studies demonstrate that Elthropa is an inhibitor of the OATP1B1 transporter and an inhibitor of the BCRP transporter and Elthropa increased exposure of the OATP1B1 and BCRP substrate rosuvastatin in a clinical drug interaction study (see Interactions). In clinical studies with Elthropa, a dose reduction of statins by 50% was recommended.
Elthropa chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium and zinc (see Dosage & Administration and Interactions).
In vitro studies demonstrated that Elthropa 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 Elthropa is a breast cancer resistance protein (BCRP) substrate and inhibitor (IC50 value of 2.7 µM (1.2 µg/mL).
Special patient populations: Renal impairment: The pharmacokinetics of Elthropa have been studied after administration of Elthropa to adult patients with renal impairment. Following administration of a single 50 mg dose, the AUC0-∞ of Elthropa 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 Elthropa (active) concentrations for this highly protein-bound medicinal product were not measured.
Patients with impaired renal function should use Elthropa with caution and close monitoring, for example by testing serum creatinine and/or urine analysis (see Dosage & Administration). The efficacy and safety of Elthropa have not been established in patients with both moderate to severe renal impairment and hepatic impairment.
Hepatic impairment: The pharmacokinetics of Elthropa have been studied after administration of Elthropa to adult patients with hepatic impairment. Following the administration of a single 50 mg dose, the AUC0-∞ of Elthropa 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 Elthropa (active) concentrations for this highly protein-bound medicinal product were not measured.
The influence of hepatic impairment on the pharmacokinetics of Elthropa 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 Elthropa AUC(0-τ) values and patients with moderate hepatic impairment had approximately 183% (95% CI: 90% to 459%) higher plasma Elthropa AUC(0-τ) values.
Therefore, Elthropa 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 Dosage & Administration and Precautions). For patients with HCV initiate Elthropa at a dose of 25 mg once daily (see Dosage & Administration).
Race: The influence of East-Asian ethnicity on the pharmacokinetics of Elthropa 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 ITP patients had approximately 49% higher plasma Elthropa AUC(0-τ) values as compared to non-East-Asian patients who were predominantly Caucasian (see Dosage & Administration).
The influence of East-/Southeast-Asian ethnicity on the pharmacokinetics of Elthropa was evaluated using a population pharmacokinetic analysis in 635 patients with HCV (145 East-Asians and 69 Southeast-Asians). Based on estimates from the population pharmacokinetic analysis, East-/Southeast-Asian patients had approximately 55% higher plasma Elthropa AUC(0-τ) values as compared to patients of other races who were predominantly Caucasian (see Dosage & Administration).
Gender: The influence of gender on the pharmacokinetics of Elthropa 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 Elthropa AUC(0-τ) as compared to male patients, without adjustment for body weight differences.
The influence of gender on Elthropa 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 Elthropa AUC(0-τ) as compared to male patients.
Age: The influence of age on Elthropa 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 Elthropa in patients ≥75 years. Based on model estimate, elderly (≥65 years) patients had approximately 41% higher plasma Elthropa AUC(0-τ) as compared to younger patients (see Dosage & Administration).
Paediatric population (aged 1 to 17 years): The pharmacokinetics of Elthropa have been evaluated in 168 paediatric ITP patients dosed once daily in two studies, TRA108062/PETIT and TRA115450/PETIT-2. Plasma Elthropa apparent clearance following oral administration (CL/F) increased with increasing body weight. The effects of race and sex on plasma Elthropa CL/F estimates were consistent between paediatric and adult patients. East-/Southeast-Asian paediatric ITP patients had approximately 43% higher plasma Elthropa AUC(0-τ) values as compared to non-Asian patients. Female paediatric ITP patients had approximately 25% higher plasma Elthropa AUC(0-τ) values as compared to male patients.
The pharmacokinetic parameters of Elthropa in paediatric patients with ITP are shown in Table 10. (See Table 10.)
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