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Mechanism of Action
Eltrombopag is an orally bioavailable, small-molecule TPO-receptor agonist that interacts with the transmembrane domain of the human TPO-receptor and initiates signaling cascades that induce proliferation and differentiation of megakaryocytes from bone marrow progenitor cells.
Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. Based on urinary excretion and biotransformation products eliminated in feces, the oral absorption of drug-related material following administration of a single 75 mg solution dose was estimated to be at least 52%.
An open-label, randomized, crossover trial was conducted to assess the effect of food on the bioavailability of eltrombopag. A standard high-fat breakfast significantly decreased plasma eltrombopag AUC0-∞ by approximately 59% and Cmax by 65% and delayed tmax by 1 hour. The calcium content of this meal may have also contributed to this decrease in exposure.
The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins ( > 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1.
Absorbed eltrombopag is extensively metabolized, predominantly through pathways including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag.
The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine. The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy subjects and 26 to 35 hours in ITP patients.
Polyvalent Cation-containing Antacids: In a clinical trial, coadministration of 75 mg of PROMACTA with a polyvalent cation-containing antacid (1,524 mg aluminum hydroxide, 1,425 mg magnesium carbonate, and sodium alginate) to 26 healthy adult subjects decreased plasma eltrombopag AUC0-∞, and Cmax by approximately 70%. The contribution of sodium alginate to this interaction is not known.
Cytochrome P450 Enzymes (CYPs): In a clinical trial, PROMACTA 75 mg once daily was administered for 7 days to 24 healthy male subjects did not show inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) in humans. Probe substrates for CYP2C8 were not evaluated in this trial.
Rosuvastatin: In a clinical trial, co-administration of 75 mg of PROMACTA once daily for 5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate, rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin AUC0-∞, by 55% and Cmax by 103%.
Lopinavir/Ritonavir: In a clinical trial, co-administration of repeat dose lopinavir 400 mg /ritonavir 100 mg twice daily with a single dose of PROMACTA 100 mg to 40 healthy adult subjects decreased plasma eltrombopag AUC0-∞, by 17%.
Pegylated Interferon alfa-2a + Ribavirin and Pegylated Interferon alfa-2b + Ribavirin: The pharmacokinetics of eltrombopag in both the presence and absence of pegylated interferon alfa 2a and 2b therapy were evaluated using a population pharmacokinetic analysis in 635 patients with chronic hepatitis C. The population PK model estimates of clearance indicate no significant difference in eltrombopag clearance in the presence of pegylated interferon alfa plus ribavirin therapy.
In vitro Studies: Eltrombopag is an inhibitor of CYP2C8 and CYP2C9 in vitro. Eltrombopag is an inhibitor of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 in vitro. Eltrombopag is an inhibitor of the organic anion transporting polypeptide OATP1B1 and BCRP in vitro.
Ethnicity: Based on two population PK analyses of eltrombopag concentrations in ITP and chronic hepatitis C patients, East Asian (i.e., Japanese, Chinese, Taiwanese, and Korean) subjects exhibited 50 to 55% higher eltrombopag plasma concentrations compared to non-East Asian subjects [see DOSAGE AND ADMINISTRATION]. An approximately 40% higher systemic eltrombopag exposure in healthy African-American subjects was noted in at least one clinical pharmacology trial. The effect of African-American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established.
Hepatic Impairment: In a pharmacokinetic trial, the disposition of a single 50 mg dose of PROMACTA in patients with mild, moderate, and severe hepatic impairment was compared to subjects with normal hepatic function. The degree of hepatic impairment was based on Child-Pugh score. Plasma eltrombopag AUC0-∞ was 41% higher in patients with mild hepatic impairment (Child-Pugh Class A) compared to subjects with normal hepatic function. Plasma eltrombopag AUC0-∞ was approximately 2-fold higher in patients with moderate (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh Class C). The half-life of eltrombopag was prolonged 2-fold in these patients. This clinical trial did not evaluate protein binding effects.
Chronic Liver Disease: A population PK analysis in thrombocytopenic patients with chronic liver disease following repeat doses of eltrombopag demonstrated that mild hepatic impairment resulted in an 87% to 110% higher plasma eltrombopag AUC(0-t) and patients with moderate hepatic impairment had approximately 141% to 240% higher plasma eltrombopag AUC(0-t) values compared to patients with normal hepatic function. The half-life of eltrombopag was prolonged 3-fold in patients with mild hepatic impairment and 4-fold in patients with moderate hepatic impairment. This clinical trial did not evaluate protein binding effects.
Chronic Hepatitis C: A population PK in 28 healthy adults and 635 patients with chronic hepatitis C demonstrated that patients with chronic hepatitis C treated with PROMACTA had higher plasma AUC(0-t) values as compared to healthy subjects, and AUC(0-t) increased with increasing Child-Pugh score. Patients with chronic hepatitis C and mild hepatic impairment had approximately 100% to 144% higher plasma AUC(0-t) compared with healthy subjects. This clinical trial did not evaluate protein binding effects.
Renal Impairment: The disposition of a single 50 mg dose of PROMACTA in patients with mild (creatinine clearance (CrCl) of 50 to 80 mL/min), moderate (CrCl of 30 to 49 mL/min), and severe (CrCl less than 30 mL/min) renal impairment was compared to subjects with normal renal function. Average total plasma eltrombopag AUC0-∞ 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 subjects. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed.
Assessment of Risk of QT/QTc Prolongation
There is no indication of a QT/QTc prolonging effect of PROMACTA at doses up to 150 mg daily for 5 days. The effects of PROMACTA at doses up to 150 mg daily for 5 days (supratherapeutic doses) on the QT/QTc interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg, single oral dose) crossover trial in healthy adult subjects. Assay sensitivity was confirmed by significant QTc prolongation by moxifloxacin.
Eltrombopag is phototoxic in vitro. There was no evidence of in vivo cutaneous or ocular phototoxicity in rodents.
Treatment-related cataracts were detected in rodents in a dose- and time-dependent manner. At ≥ 6 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 3 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day, cataracts were observed in mice after 6 weeks and in rats after 28 weeks of dosing. At ≥ 4 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 2 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing [see WARNINGS AND PRECAUTIONS].
Renal tubular toxicity was observed in studies up to 14 days in 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. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC in ITP patients at 75 mg/day and 0.6 times the human clinical exposure based on AUC in chronic hepatitis C patients at 100 mg/day. No similar effects were observed in mice after 13 weeks at exposures greater than those associated with renal changes in the 2-year study, suggesting that this effect is both dose- and time-dependent.
The efficacy and safety of PROMACTA in adult patients with chronic ITP were evaluated in 3 randomized, double-blind, placebo-controlled trials and in an open-label extension trial.
Trials 1 and 2
In trials 1 and 2, patients who had completed at least one prior ITP therapy and who had a platelet count < 30 x 109/L were randomized to receive either PROMACTA or placebo daily for up to 6 weeks, followed by 6 weeks off therapy. During the trials, PROMACTA or placebo was discontinued if the platelet count exceeded 200 x 109/L. The primary efficacy endpoint was response rate, defined as a shift from a baseline platelet count of < 30 x 109/L to ≥ 50 x 109/L at any time during the treatment period.
The median age of the patients was 50 years and 60% were female. Approximately 70% of the patients had received at least 2 prior ITP therapies (predominantly corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine) and 40% of the patients had undergone splenectomy. The median baseline platelet counts (approximately 18 x 109/L) were similar among all treatment groups.
Trial 1 randomized 114 patients (2:1) to PROMACTA 50 mg or placebo. Trial 2 randomized 117 patients (1:1:1:1) among placebo or 1 of 3 dose regimens of PROMACTA, 30 mg, 50 mg, or 75 mg each administered daily.
Table 6 shows for each trial the primary efficacy outcomes for the placebo groups and the patient groups who received the 50 mg daily regimen of PROMACTA.
Table 6: Trials 1 and 2 Platelet Count Response
( ≥ 50 x 109/L) Rates in Adults With Chronic Immune (Idiopathic)
|Trial||PROMACTA 50 mg Daily||Placebo|
|1||43/73 (59%)a||6/37 (16%)|
|2||19/27 (70%)a||3/27 (11%)|
|a P value < 0.001 for PROMACTA versus placebo.|
The platelet count response to PROMACTA was similar among patients who had or had not undergone splenectomy. In general, increases in platelet counts were detected 1 week following initiation of PROMACTA and the maximum response was observed after 2 weeks of therapy. In the placebo and 50 mg dose groups of PROMACTA, the trial drug was discontinued due to an increase in platelet counts to > 200 x 109/L in 3% and 27% of the patients, respectively.
The median duration of treatment with the 50 mg dose of PROMACTA was 42 days in Trial 1 and 43 days in Trial 2.
Of 7 patients who underwent hemostatic challenges, additional ITP medications were required in 3 of 3 placebo group patients and 0 of 4 patients treated with PROMACTA. Surgical procedures accounted for most of the hemostatic challenges. Hemorrhage requiring transfusion occurred in one placebo group patient and no patients treated with PROMACTA.
In this trial, 197 patients were randomized (2:1) to receive either PROMACTA 50 mg once daily (n = 135) or placebo (n = 62) for 6 months, during which time the dose of PROMACTA could be adjusted based on individual platelet counts. Patients were allowed to taper or discontinue concomitant ITP medications after being treated with PROMACTA for 6 weeks. Patients were permitted to receive rescue treatments at any time during the trial as clinically indicated. The primary endpoint was the odds of achieving a platelet count ≥ 50 x 109/L and ≤ 400 x 109/L for patients receiving PROMACTA relative to placebo and was based on patient response profiles throughout the 6-month treatment period.
The median age of the patients treated with PROMACTA and placebo was 47 years and 52.5 years, respectively. Approximately half of the patients treated with PROMACTA and placebo (47% and 50%, respectively) were receiving concomitant ITP medication (predominantly corticosteroids) at randomization and had baseline platelet counts ≤ 15 x 109/L (50% and 48%, respectively). A similar percentage of patients treated with PROMACTA and placebo (37% and 34%, respectively) had a prior splenectomy.
In 134 patients who completed 26 weeks of treatment, a sustained platelet response (platelet count ≥ 50 x 109/L and ≤ 400 x 109/L for 6 out of the last 8 weeks of the 26-week treatment period in the absence of rescue medication at any time) was achieved by 60% of patients treated with PROMACTA, compared to 10% of patients treated with placebo (splenectomized patients: PROMACTA 51%, placebo 8%; non-splenectomized patients: PROMACTA 66%, placebo 11%). The proportion of responders in the PROMACTA treatment group was between 37% and 56% compared to 7% and 19% in the placebo treatment group for all on-therapy visits. Patients treated with PROMACTA were significantly more likely to achieve a platelet count between 50 x 109/L and 400 x 109/L during the entire 6-month treatment period compared to those patients treated with placebo.
Outcomes of treatment are presented in Table 7 for all patients enrolled in the trial.
Table 7: Outcomes of Treatment from Trial 3 in Adults
With Chronic Immune (Idiopathic) Thrombocytopenia
N = 135
N = 62
|Mean number of weeks with platelet counts &g;50 x 109/L||11.3||2.4|
|Requiring rescue therapy, n (%)||24 (18)||25 (40)|
Among 94 patients receiving other ITP therapy at baseline, 37 (59%) of 63 patients in the PROMACTA group and 10 (32%) of 31 patients in the placebo group discontinued concomitant therapy at some time during the trial.
Patients who completed any prior clinical trial with PROMACTA were enrolled in an open-label, single-arm trial in which attempts were made to decrease the dose or eliminate the need for any concomitant ITP medications. PROMACTA was administered to 299 patients; 249 completed 6 months, 210 patients completed 12 months, and 138 patients completed 24 months of therapy. The median baseline platelet count was 19 x 109/L prior to administration of PROMACTA.
Chronic Hepatitis C-Asso ciated Thrombocytopenia
The efficacy and safety of PROMACTA for the treatment of thrombocytopenia in adult patients with chronic hepatitis C were evaluated in 2 randomized, double-blind, placebocontrolled trials. Trial 1 utilized peginterferon alfa-2a (PEGASYS®) plus ribavirin for antiviral treatment and Trial 2 utilized peginterferon alfa-2b (PEGINTRON®) plus ribavirin. In both trials, patients with a platelet count of < 75 x 109/L were enrolled and stratified by platelet count, screening HCV RNA, and HCV genotype. Patients were excluded if they had evidence of decompensated liver disease with Child-Pugh score > 6 (class B and C), history of ascites, or hepatic encephalopathy. The median age of the patients in both trials was 52 years, 63% were male, and 74% were Caucasian. Sixty-nine percent of patients had HCV genotypes 1, 4, 6 with the remainder genotypes 2 and 3. Approximately 30% of patients had been previously treated with interferon and ribavirin. The majority of patients (90%) had bridging fibrosis and cirrhosis, as indicated by noninvasive testing. A similar proportion (95%) of patients in both treatment groups had Child-Pugh level A (score 5-6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) > 1.7. Median baseline platelet counts (approximately 60 x 109/L) were similar in both treatment groups. The trials consisted of two phases - a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label PROMACTA to increase the platelet count to a threshold of ≥ 90 x 109/L for Trial 1 and ≥ 100 x 109/L for Trial 2. PROMACTA was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25 mg increments over 2 to 3 week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximal time patients could receive open-label PROMACTA was 9 weeks. If threshold platelet counts were achieved, patients were randomized (2:1) to the same dose of PROMACTA at the end of the pre-treatment phase or to placebo. PROMACTA was administered in combination with pegylated interferon and ribavirin per their respective prescribing information for up to 48 weeks.
The primary efficacy endpoint for both trials was sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment. The median time to achieve the target platelet count ≥ 90 x 109/L was approximately 2 weeks. Ninety-five percent of patients were able to initiate antiviral therapy.
In both trials, a significantly greater proportion of patients treated with PROMACTA achieved SVR (see Table 8). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count ( < 50 x 109/L versus ≥ 50 x 109/L). In patients with high baseline viral loads ( ≥ 800,000), the SVR rate was 18% (82/452) for PROMACTA versus 8% (20/239) for placebo.
Table 8: Trials 1 and 2 Sustained Virologic Response
in Adults With Chronic Hepatitis C
|Pre-antiviral Treatment Phase||Trial 1a
N = 715
N = 805
|% Patients who achieved target platelet counts and initiated antiviral therapyc||95%||94%|
|Antiviral Treatment Phase||PROMACTA
N = 450 %
N = 232 %
N = 506 %
N = 253 %
|HCV Genotype 2,3||35||24||34||25|
|HCV Genotype 1,4,6||18||10||13||7|
|aPROMACTA given in combination with
peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24
weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses
bPROMACTA given in peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally). Target platelet count was > 90 x 109/L for Trial 1 and > 100 x 109/L for Trial 2.
cP value < 0.05 for PROMACTA versus placebo.
The majority of patients treated with PROMACTA (76%) maintained a platelet count > 50 x 109/L compared to 19% for placebo. A greater proportion of patients on PROMACTA did not require any antiviral dose reduction as compared to placebo (45% versus 27%).
Last reviewed on RxList: 12/5/2012
This monograph has been modified to include the generic and brand name in many instances.
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