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Effects: Revolade differs from TPO with respect to the effects on platelet aggregation. Unlike TPO, Revolade treatment of normal human platelets does not enhance adenosine diphosphate (ADP)-induced aggregation or induce P-selectin expression. Revolade does not antagonize platelet aggregation induced by ADP or collagen.
Pharmacokinetics: The pharmacokinetic parameters of eltrombopag after administration of Revolade to patients with idiopathic thrombocytopenic purpura (ITP) are shown in table 1.
Click on icon to see table/diagram/imageAbsorption and Bioavailability: Eltrombopag is absorbed with a peak concentration occurring 2-6 hrs after oral administration. Administration of Revolade concomitantly with antacids and other products containing polyvalent cations eg, dairy products and mineral supplements significantly reduces eltrombopag exposure (see Dosage & Administration and Interactions). The absolute oral bioavailability of eltrombopag after administration to humans has not been established. Based on urinary excretion and metabolites eliminated in feces, the oral absorption of drug-related material following administration of a single dose of eltrombopag 75 mg solution was estimated to be at least 52%.
Distribution: Eltrombopag is highly bound to human plasma proteins (>99.9%). Eltrombopag is a substrate for breast cancer resistance protein (BCRP), but is not a substrate for P-glycoprotein or organic anion transporter polypeptide (OATP1B1).
Metabolism: Eltrombopag is primarily metabolized through cleavage, oxidation and conjugation with glucuronic acid, glutathione or cysteine. In a human radiolabel study, eltrombopag accounted for approximately 64% of plasma radiocarbon AUC0-∞. Minor metabolites, each accounting for <10% of the plasma radioactivity, arising from glucuronidation and oxidation were also detected. Based on a human study with radiolabel eltrombopag, it is estimated that approximately 20% of a dose is metabolized by oxidation. In vitro studies identified CYP1A2 and CYP2C8 as the isoenzymes responsible for oxidative metabolism, uridine diphosphoglucuronyl transferase UGT1A1 and UGT1A3 as the isozymes responsible for glucuronidation, and that bacteria in the lower gastrointestinal tract may be responsible for the cleavage pathways.
Elimination: Absorbed eltrombopag is extensively metabolized. The predominant route of eltrombopag excretion is via feces (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 feces accounts for approximately 20% of the dose. The plasma elimination t½ of eltrombopag is approximately 21-32 hrs.
Interactions: 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 and potential co-medications.
Based on a human study with radiolabelled 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. In studies utilizing human liver microsomes, eltrombopag (up to 100 microM) showed no in vitro inhibition of the CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 3A4/5 and 4A9/11 and was an inhibitor of CYP2C8 and CYP2C9 as measured using paclitaxel and diclofenac as the probe substrates, with IC50 values of 24.8 microM (11 mcg/mL) and 20.2 microM (8.9 mcg/mL), respectively. Administration of Revolade 75 mg once daily for 7 days to 24 healthy male subjects did not inhibit or induce the metabolism of probe substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 (flurbiprofen) or 3A4 (midazolam) in humans. No clinically significant interactions are expected when Revolade and CYP450 substrates, inducers or inhibitors are co-administered.
In vitro studies demonstrate that eltrombopag is an inhibitor of the OATP1B1 transporter, with an IC50 value of 2.7 microM (1.2 mcg/mL) and an inhibitor of the BCRP transporter, with an IC50 value of 2.7 microM (1.2 mcg/mL). Administration of Revolade 75 mg 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 rosuvastastin Cmax 103% (90% CI: 82%, 126%) and AUC0-∞ 55% (90% CI: 42%, 69%) (see Interactions).
Administration of a single dose of Revolade 75 mg with a polyvalent cation-containing antacid (aluminium hydroxide 1524 mg and magnesium carbonate 1425 mg) decreased plasma eltrombopag AUC0-∞ by 70% (90% CI: 64%, 76%) and Cmax by 70% (90% CI: 62 %, 76%) (see Dosage & Administration and Interactions).
Administration of a single 50-mg dose of Revolade with a standard high-calorie, high-fat breakfast that included dairy products reduced plasma eltrombopag AUC(0-∞) by 59% (90% CI: 54%, 64%) and Cmax by 65% (90% CI: 59%, 70%). Whereas, low-calcium food (<50 mg calcium) did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content (see Dosage & Administration and Interactions).
Special Patient Populations: Renal Impairment: The pharmacokinetics of eltrombopag has been studied after administration of Revolade to adult patients with renal impairment. Following administration of a single 50 mg-dose, the AUC0-∞ of eltrombopag was decreased by 32% (90% CI: 63% decrease, 26% increase) in patients with mild renal impairment, 36% (90% CI: 66% decrease, 19% increase) in patients with moderate renal impairment, and 60% (90% CI: 18% decrease, 80% decrease) in patients with severe renal impairment compared with healthy volunteers. There was a trend for reduced plasma eltrombopag exposure in patients with renal impairment, but there was a substantial variability and significant overlap in exposures between patients with renal impairment and healthy volunteers. Patients with impaired renal function should use Revolade with caution and close monitoring (see Precautions). For patients with moderate and severe hepatic impairment, initiate Revolade at a reduced dose of 25 mg once daily (see Dosage & Administration).
Hepatic Impairment: The pharmacokinetics of eltrombopag has been studied after administration of Revolade to adult patients with hepatic impairment. Following the administration of a single 50-mg dose, the AUC0-∞ of eltrombopag was increased by 41% (90% CI: 13% decreased, 128% increased) in patients with mild hepatic impairment, 93% (90% CI: 19%, 213%) in patients with moderate hepatic impairment and 80% (90% CI: 11%, 192%) in patients with severe hepatic impairment compared with healthy volunteers. There was substantial variability and significant overlap in exposures between patients with hepatic impairment and healthy volunteers.
Revolade should be used with caution and close monitoring to patients with hepatic impairment.
Race: The influence of East Asian ethnicity on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (31 East Asians) and 88 patients with ITP (18 East Asians). Based on estimates from the population pharmacokinetic analysis, East Asian (ie, Japanese, Chinese, Taiwanese and Korean) ITP patients had approximately 87% higher plasma eltrombopag AUC0-τ values as compared to non-East Asian patients who were predominantly Caucasian, without adjustment for body weight differences (see Dosage & Administration).
Gender: The influence of gender on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (14 females) and 88 patients with ITP (57 females). Based on estimates from the population pharmacokinetic analysis, female ITP patients had approximately 50% higher plasma eltrombopag AUC0-τ as compared to male patients, without adjustment for body weight differences.
Clinical Studies: The safety and efficacy of Revolade has been demonstrated in 2, randomized, double-blind, placebo-controlled studies (RAlSE TRA102537 and TRA100773B) and 2 open-label studies (REPEAT TRA108057 and EXTEND TRA105325) in adult patients with previously treated chronic ITP.
Double-Blind Placebo-Controlled Studies: TRA102537: In RAISE, the primary efficacy endpoint was the odds of achieving a platelet count ≥50,000/microliter and ≤400,000/microliter, during the 6-month treatment period for subjects receiving Revolade relative to placebo. One hundred and ninety seven (197) subjects were randomized 2:1, Revolade (n=135) to placebo (n=62), and were stratified based upon splenectomy status, use of ITP medication at baseline and baseline platelet count. Subjects received study medication for up to 6 months, during which time the dose of Revolade could be adjusted based on individual platelet counts. In addition, subjects could have tapered off concomitant ITP medications and received rescue treatments as dictated by local standard of care. The odds of achieving a platelet count between 50,000/microliter and 400,000/microliter during the 6-month treatment period were 8 times higher for Revolade-treated subjects than for placebo-treated subjects [Odds Ratio: 8.2 (99% CI:3.59, 18.73) p=<0.001]. Median platelet counts were maintained above 50,000/microliter at all on-therapy visits starting at day 15 in the Revolade group; in contrast, median platelet counts in the placebo group remained below 30,000/microliter throughout the study.
At baseline, 77% of subjects in the placebo group and 73% of subjects in the Revolade group reported any bleeding (WHO grades 1-4); clinically significant bleeding (WHO grades 2-4) at baseline was reported in 28% and 22% of subjects in the placebo and Revolade groups, respectively. The proportion of subjects with any bleeding (grades 1-4) and clinically significant bleeding (grades 2-4) was reduced from baseline by approximately 50% throughout the 6-month treatment period in Revolade-treated subjects. When compared to the placebo group, the odds of any bleeding (grades 1-4) and the odds of clinically significant bleeding (grades 2-4) were 76% and 65% lower in the Revolade-treated subjects compared to the placebo-treated subjects (p<0.001).
Revolade therapy allowed significantly more subjects to reduce or discontinue baseline ITP therapies compared to placebo (59% vs. 32%; p<0.016).
Significantly fewer Revolade-treated subjects required rescue treatment compared to placebo-treated subjects (19% vs. 40%; p=0.001).
Four placebo and 14 Revolade subjects had at least 1 hemostatic challenge (defined as an invasive diagnostic or surgical procedure) during the study. Fewer Revolade-treated subjects (29%) required rescue treatment to manage their hemostatic challenge compared to placebo-treated subjects (50%).
In terms of improvements in health-related quality of life, statistically significant improvements from baseline were observed in the Revolade group in fatigue, including severity and impact on thrombocytopenia-impacted daily activities and concerns [as measured by the vitality subscale of the Short Form(36) (SF36), the motivation and energy inventory and the 6-item extract from the thrombocytopenia subscale of the Functional Assessment of Chronic Illness Therapy with Thrombocytopenia (FACIT-Th)].
Comparing the Revolade group to the placebo group, statistically significant improvements were observed with thrombocytopenia impacted activities and concerns specifically regarding motivation, energy and fatigue, as well as physical and emotional role and overall mental health. The odds of meaningful improvement in health-related quality of life while on therapy was significantly greater among patients treated with Revolade than placebo.
TRA100773B: In TRA100773B, the primary efficacy endpoint was the proportion of responders, defined as patients who had an increase in platelet counts to ≥50,000/microliter at day 43 from a baseline <30,000/microliter; patients who withdrew prematurely due to a platelet count >200,000/microliter were considered responders, those discontinued for any other reason were considered nonresponders irrespective of platelet count. A total of 114 subjects with previously treated chronic ITP were randomized 2:1 into the study, with 76 randomized to Revolade and 38 randomized to placebo.
Fifty-nine percent of subjects on Revolade responded, compared to 16% of subjects on placebo. The odds of responding were 9 times higher for Revolade-treated subjects compared to placebo [Odds Ratio: 9.6 (95% CI: 3.31, 27.86) p<0.001]. At baseline, 61% of subjects in the Revolade group and 66% of subjects in the placebo group reported any bleeding (grade 1-4). At day 43, 39% of subjects in the Revolade treatment group had bleeding compared with 60% in the placebo group. Analysis over the treatment period using a repeated measures model for binary data confirmed that a lower proportion of Revolade subjects had bleeding (grade 1-4) at any point in time over the course of their treatment (day 8 up to day 43) compared to subjects in the placebo group [OR=0.49, 95% Cl=(0.26, 0.89), p=0.021]. Two placebo and 1 Revolade subject had at least 1 hemostatic challenge during the study.
In both RAISE and TRA100773B, the response to Revolade relative to placebo was similar irrespective of ITP medication use, splenectomy status and baseline platelet count (≤15,000/microliter, >15,000/microliter) at randomization.
Open Label Studies: TRA108057: REPEAT was an open-label, repeat-dose, study which evaluated the efficacy, safety and consistency of response following repeated, intermittent, short-term dosing of Revolade over 3 cycles of therapy in adults with previously treated chronic ITP. A cycle was defined as an up to 6-week on-therapy period followed by an up to 4-week off-therapy period. The primary endpoint in REPEAT was the proportion of subjects who achieved a platelet count of ≥50,000/microliter and at least 2x baseline in Cycle 2 or 3, given this response in Cycle 1.
Click on icon to see table/diagram/imageOf the 52 subjects who responded in Cycle 1, 33 (63%) achieved a platelet count of ≥50,000/microliter and at least 2x baseline on day 8 in Cycle 1; on day 15, 37 (79%) of 47 evaluable subjects achieved this level of response. A reduction in any bleeding (WHO grade 1-4) and clinically significant bleeding (WHO grade 2-4) during the treatment phases was demonstrated in each cycle. At the baseline visit of Cycle 1, 50% and 19% of subjects reported any bleeding and clinically significant bleeding, respectively. At the day 43 visit of Cycle 1, the proportion of subjects bleeding was reduced; 12% and 0% of subjects reported any bleeding and clinically significant bleeding, respectively. Similar results were found during the subsequent treatment cycles.
Eight subjects successfully managed 10 hemostatic challenges without need for additional therapy to elevate platelet counts and without unexpected bleeding.
TRA105325: EXTEND is an open-label extension study which has evaluated the safety and efficacy of Revolade in subjects with chronic ITP who were previously enrolled in an Revolade trial. In this study, subjects were permitted to modify their dose of study medication as well as decrease or eliminate concomitant ITP medications.
Revolade was administered to 207 patients; 104 completed 3 months of treatment, 74 completed 6 months and 27 patients completed 1 year of therapy. The median baseline platelet count was 18,000/microliter prior to Revolade administration. Median platelet counts at 3, 6 and 9 months on study were 86,000, 67,000 and 92,500/microliter, respectively. The median daily dose of Revolade following 6 months of therapy was 50 mg (n=74).
At baseline, 59% of subjects had any bleeding (WHO bleeding grades 1-4) and 18% had clinically significant bleeding. The proportion of subjects with any bleeding and clinically significant bleeding decreased from baseline by approximately 50% for the majority of assessments up to 1 year.
Seventy percent of subjects who reduced a baseline medication permanently discontinued or had a sustained reduction of their baseline ITP medication and did not require any subsequent rescue treatment. Sixty-five percent of these subjects maintained this discontinuation or reduction for at least 24 weeks. Sixty-one percent of subjects completely discontinued at least 1 baseline ITP medication and 55% of subjects permanently discontinued all baseline ITP medications, without subsequent rescue treatment.
Twenty-four subjects experienced at least 1 hemostatic challenge during the study. No subject experienced unexpected bleeding complications related to the procedure while on study.
Toxicology: Preclinical Safety Data: 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 and 5 times the human clinical exposure based on AUC, respectively). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in 2 in vivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times the human clinical exposure based on Cmax). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (<3-fold increase in mutation frequency). These in vitro and in vivo findings suggest that Revolade does not pose a genotoxic risk to humans.
Eltrombopag was not teratogenic in rats or rabbits. Eltrombopag did not affect female fertility, early embryonic development or embryofetal development in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure based on AUC). Also, there was no effect on embryofetal development in rabbits at doses up to 150 mg/kg/day, the highest dose tested (0.5 times the human clinical exposure based on AUC). However, at a maternally toxic dose of 60 mg/kg/day (6 times the human clinical exposure based on AUC) in rats, eltrombopag treatment was associated with embryo lethality (increased pre- and post-implantation loss) in the female fertility study, a low incidence of cervical ribs (a nonteratogenic fetal variation) in the embryofetal development study and reduced fetal body weight in both studies. Eltrombopag did not affect male fertility in rats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure based on AUC).
Eltrombopag is phototoxic and photoclastogenic in vitro. However, in vitro photoclastogenic effects were observed only at drug concentrations that were cytotoxic (≥15 mcg/mL) in the presence of high UV light exposure intensity [30 minimal erythematous dose (MED)]. There was no evidence of in vivo cutaneous phototoxicity in mice at exposures up to 10 times the human clinical exposure based on AUC or photo-ocular toxicity in mice or rats at exposures up to 11 and 6 times the human clinical exposure based on AUC, respectively. Furthermore, a clinical pharmacology study in 36 subjects showed no evidence that photosensitivity was increased following administration of Revolade 75 mg once daily for 6 days. This was measured by delayed phototoxic index.
Treatment-related cataracts were detected in rodents and were dose and time-dependent. At ≥6 times the human clinical exposure based on AUC, cataracts were observed in mice after 6 weeks and rats after 28 weeks of dosing. At ≥4 times the human clinical exposure based on AUC, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing. Cataracts have not been observed in dogs after 52 weeks of dosing 2 times the human clinical exposure based on AUC. The clinical relevance of these findings is unknown (see Precautions).
Renal tubular toxicity was observed in studies of up to 14 days duration in mice and rats at exposures that were generally associated with morbidity and mortality. Tubular toxicity was also observed in a 2-year oral carcinogenicity study in mice at doses of 25, 75 and 150 mg/kg/day. Effects were less severe at lower doses and were characterized by a spectrum of regenerative changes. The exposure at the lowest dose was 1.2 times the human clinical exposure based on AUC. Renal effects were not observed in rats after 28 weeks or in dogs after 52 weeks at exposures 4 and 2 times respectively, the human clinical exposure based on AUC. The clinical relevance of these findings is unknown.
