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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.

Pharmacokinetics

A population pharmacokinetic model analysis suggests that the pharmacokinetic profile for eltrombopag following oral administration is best described by a 2-compartment model. Based on this model, the estimated exposures of eltrombopag after administration to patients with ITP are shown in Table 4.

Table 4: Geometric Mean (95% Confidence Intervals) of Steady-State Plasma Eltrombopag Pharmacokinetic Parameters in Adults With Chronic Immune (Idiopathic) Thrombocytopenia

Absorption

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 study 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.

Distribution

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.

Metabolism

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.

Elimination

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.

Race

The influence of East Asian ethnicity (i.e., Japanese, Chinese, Taiwanese, and Korean) on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic approach in 111 healthy adults (31 East Asians) and 88 patients with ITP (18 East Asians). After adjusting for body weight differences, East Asians had approximately 50% higher plasma eltrombopag AUC(0-τ) values as compared to non-East Asian patients who were predominantly Caucasian. In a separate population PK analysis of PROMACTA in 28 healthy adults (non-East Asians) and 79 patients with chronic liver disease (45 East Asians), East Asian patients had approximately 110% higher plasma eltrombopag AUC(0-τ) values as compared to non-East Asian patients, after adjusting for body weight differences. A reduction in the initial dose of PROMACTA is recommended for patients of East Asian ancestry and East Asian patients with hepatic impairment (Child-Pugh Class A, B, C) [see DOSAGE AND ADMINISTRATION].

An approximately 40% higher systemic eltrombopag exposure in healthy African American subjects was noted in at least one clinical pharmacology study. The effect of African American ethnicity on exposure and related safety and efficacy of eltrombopag has not been established.

Gender

The influence of gender on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic approach in 111 healthy adults (14 females) and 88 patientswith ITP (57 females). After adjustment for body weight differences, females had approximately 23% higher plasma eltrombopag AUC(0-τ) values than males.

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.

Animal Pharmacology/Toxicology

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, 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, cataracts were observed in mice after 13 weeks and in rats after 39 weeks of dosing. The clinical relevance of these findings is unknown [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. 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.

Clinical Studies

The efficacy and safety of PROMACTA in adult patients with chronic ITP were evaluated in 3 randomized, double-blind, placebo-controlled studies and in an open-label extension study.

Studies 1 and 2

In studies 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 studies, 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.

Study 1 randomized 114 patients (2:1) to PROMACTA 50 mg or placebo. Study 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 5 shows for each study the primary efficacy outcomes for the placebo groups and the patient groups who received the 50 mg daily regimen of PROMACTA.

Table 5: Studies 1 and 2 Platelet Count Response ( ≥ 50 x 10⁹/L) Rates

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 study 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 Study 1 and 43 days in Study 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.

Study 3

In this study, 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 study 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 6 for all patients enrolled in the study.

Table 6: Outcomes of Treatment from the Study 3

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 study.

Extension Study

Patients who completed any prior clinical study with PROMACTA were enrolled in an open-label, single-arm study 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.

Last reviewed on RxList: 12/28/2011
This monograph has been modified to include the generic and brand name in many instances.