Promacta (eltrombopag olamine)

Eltrombopag is a small-molecule thrombopoietin receptor agonist (TPO-RA).

Eltrombopag is a small-molecule, nonpeptide, thrombopoietin-receptor agonist (TPO-RA). The drug interacts with the transmembrane domain of the TPO receptor, initiating a cascade of intracellular signaling events leading to proliferation and differentiation of bone marrow progenitor cells within the megakaryocytic lineage and subsequently increasing the production of platelets. In clinical trials, treatment with eltrombopag resulted in dose-dependent increases in platelet counts, which reached a maximum approximately 2 weeks after initiation, and returned to baseline within approximately 2 weeks after the last dose.

Eltrombopag (up to 150 mg daily for 5 days) did not demonstrate clinically relevant effects on QT or QT corrected for rate (QTc)-interval.

The pharmacokinetics of eltrombopag are dose proportional over the dosage range of 50 to 150 mg daily. Steady-state concentrations are achieved after approximately 1 week of once-daily treatment.

Peak plasma eltrombopag (Promacta(R)) concentrations are achieved within 2-6 hours after oral administration, and steady-state concentrations are achieved approximately 1 week following once-daily administration. Systemic exposure following administration of the oral suspension is approximately 22% higher than the tablet formulation. Following administration of a high-fat breakfast with a high calcium content (427 mg), systemic exposure of eltrombopag (Promacta(R)) was significantly decreased by approximately 59%, peak plasma concentrations were significantly decreased by 65%, and time to peak plasma concentrations was significantly delayed by 1 hour.

A low-calcium meal (<=50 mg calcium) did not significantly impact plasma eltrombopag (Promacta(R)) exposure, regardless of calorie and fat content. The effect of administration of a single 25-mg dose of eltrombopag (as the oral suspension) with a high-calcium, moderate-fat, moderate-calorie meal was evaluated at different time points of eltrombopag (Promacta(R)) administration (concurrently, 2 hours before, or 2 hours after the meal); plasma concentrations of eltrombopag were reduced by approximately 75-79% when administered concurrently with the meal, by approximately 47-48% when administered 2 hours after the meal, and by approximately 14-20% when administered 2 hours before the meal.

Peak eltrombopag (Alvaiz(R)) concentrations are achieved 1.5-5.5 hours after oral administration under fasting conditions, and 1-8 hours under fed (high-fat, high-calorie) conditions. A low-calcium meal (<=50 mg calcium) did not significantly impact plasma eltrombopag (Alvaiz(R)) exposure, regardless of calorie and fat content. Following administration of a high-fat, high-calorie meal, systemic exposure of eltrombopag (Alvaiz(R)) was decreased by approximately 36%, peak plasma concentrations were decreased by 39%, and time to peak plasma concentrations was delayed by 30 minutes as compared to fasted conditions.

The concentration of eltrombopag in blood cells is approximately 50-79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (>99%). The plasma elimination half-life of eltrombopag is approximately 26-35 hours in patients with immune thrombocytopenia (ITP).

Eltrombopag is extensively metabolized. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag and UGT1A1 and UGT1A3 are responsible for glucuronidation of the drug. Eltrombopag is predominantly excreted via feces (59%); 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. Compared with non-Asian subjects, eltrombopag concentrations in East-/Southeast-Asian patients with ITP or chronic hepatitis C were 50-55% higher. Compared with white subjects, eltrombopag exposure in healthy African-American subjects was approximately 40% higher in a clinical pharmacology trial, but similar in 3 other trials.

The effects of African-American ethnicity on exposure and related safety and efficacy of eltrombopag have not been established. Systemic exposure of eltrombopag is approximately 41% higher in patients with mild hepatic impairment (Child-Pugh Class A), and approximately 2-fold higher in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment; the half-life of eltrombopag was prolonged by 2-fold in these patients. Clinical trials have demonstrated that patients with chronic liver disease or chronic hepatitis C and hepatic impairment have increased plasma concentrations and prolonged half-life of eltrombopag.

Systemic exposure of eltrombopag is approximately 32-36% lower in patients with mild (creatinine clearance 50-80 mL/minute) or moderate (creatinine clearance 30-49 mL/minute) renal impairment, and approximately 60% lower in patients with severe (creatinine clearance <30 mL/minute) renal impairment. The effect of renal impairment on unbound (active) eltrombopag exposure has not been assessed. In pharmacokinetic evaluations of eltrombopag in pediatric patients >=1 year of age with ITP, apparent clearance of the drug increased with increasing body weight.

East-/Southeast-Asian pediatric patients with ITP had approximately 43% higher plasma concentrations of eltrombopag compared with non-Asian patients. Systemic exposure and peak plasma concentrations of eltrombopag in pediatric patients 12-17 years of age were similar to the values observed in adults.

Eltrombopag is available as two different brands of the same medication: eltrombopag olamine (Promacta(R)) and eltrombopag choline (Alvaiz(R)). The efficacy and safety of eltrombopag choline (Alvaiz(R)) are based on results from studies of eltrombopag olamine (Promacta(R)) in adults and pediatric patients >=6 years of age with persistent or chronic immune thrombocytopenia (ITP), adults with chronic hepatitis C-associated thrombocytopenia, and adults with refractory severe aplastic anemia.

Generic name: eltrombopag olamine
Pronunciation: (el-TROM-boe-pag)

The following indications are listed for Promacta:

• Aplastic Anemia
• Severe Thrombocytopenia In Refractory Chronic Immune Thrombocytopenia Purpura
• Thrombocytopenia Associated With Chronic Hepatitis C

Also known as: Anemia Gravis, Ehrlich's Anemia, Severe Thrombocytopenia In Refractory Chronic Idiopathic Thrombocytopenia Purpura.

No ICD codes are available for this drug.