Avatrombopag

Avatrombopag (Doptelet), is an orally administered, small-molecule thrombopoietin receptor (c-Mpl) agonist which increases platelet number, but not platelet activation , . This decreases the need for blood transfusions .

Patients with thrombocytopenia and chronic liver disease (leading to thrombocytopenia) often require platelet transfusions before surgical procedures to decrease the risk of bleeding . Thrombocytopenia (or decreased numbers of platelets) is a common complication in patients suffering from chronic liver disease, either as an immediate result of liver disease or a consequence of interferon-based antiviral therapy .

Avatrombopag was approved by the FDA on May 21, 2018 for thrombocytopenia (low platelets) in adults with chronic liver disease who are scheduled to undergo a procedure . It is administered orally as avatrombopag maleate, its salt form .

Doptelet (Avatrombopag) is the first orally administered treatment option for patients with chronic liver disease, allowing a large population of patients to avoid a platelet transfusion before a procedure by increasing platelet counts to the optimal level of greater or equal to 50,000 per microliter .

Avatrombopag is a thrombopoietin receptor agonist used to treat thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure.

Indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure .

• Thrombocytopenia

In a study of efficacy, avatrombopag resulted in dose and exposure-dependent elevations in platelet counts in adults . The onset of the platelet count increase was noted within 3 to 5 days of the start of a 5-day treatment course, with the highest level of effect measured after 10 to 13 days. Following this, platelet counts decreased gradually, returning to near baseline values at the 35-day point .

Increased platelet activation leads to increased blood clotting, which may lead to various complications . Avatrombopag does not lead to increased platelet activation .

Avatrombopag is an orally bioavailable, small molecule thrombopoietin (TPO) receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells resulting in an increased production of platelets. Avatrombopag is not competitive with thrombopoietin for binding to the TPO receptor and has an additive pharmacological effect with TPO on platelet production .

Avatrombopag is a thrombopoietin receptor (TPOR; MPL) agonist, with possible megakaryopoiesis stimulating activity. After administration, avatrombopag binds to and stimulates the platelet thrombopoeitin receptor (TPOR), which can lead to the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. This process increases the production of platelets and may serve to prevent chemotherapy-induced thrombocytopenia (CIT). TPOR is classified as a cytokine receptor and as a member of the hematopoietin receptor superfamily .

Following single dosing under fasted and fed conditions, mean peak concentrations occurred at 5-8 hours and declined with a half-life of 16-18 hours in Japanese and white subjects. Administration with food did not have an effect on the rate or extent of avatrombopag absorption, however, significantly reduced pharmacokinetic variability relative to the fasting state .

Avatrombopag showed dose-proportional pharmacokinetics after single doses from 10 mg (0.25-times the lowest approved dosage) to 80 mg (1.3-times the highest recommended dosage). Healthy subjects administered 40 mg of avatrombopag showed a geometric mean (%CV) maximal concentration (Cmax) of 166 (84%) ng/mL and area under the time-concentration curve, extrapolated to infinity (AUC0-inf) of 4198 (83%) ng.hr/mL. The pharmacokinetics of avatrombopag are similar in both healthy subjects and the chronic liver disease population .

Avatrombopag has an estimated mean volume of distribution (%CV) of 180 L (25%) .

Avatrombopag is greater than 96% bound to human plasma proteins .

Fecal excretion accounted for 88% of the administered dose, with 34% of the dose excreted as unchanged avatrombopag. Only 6% of the administered dose was found in urine .

The mean plasma elimination half-life (%CV) of avatrombopag is approximately 19 hours (19%) .

The mean (%CV) of the clearance of avatrombopag is estimated to be 6.9 L/hr (29%) .

The most common adverse reactions reported in at least 3% of patients were pyrexia, abdominal pain, nausea, headache, fatigue, and peripheral edema , . Hyponatremia was also a rare serious adverse effect of this drug, seen in only 2 patients in the treatment group . Adverse reactions resulting in discontinuation of this drug have been anemia, pyrexia, and myalgia .

Atrombopag is a thrombopoietin (TPO) receptor agonist, and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease. Portal venous thrombosis occurrence has been reported in patients with chronic liver disease who are treated with TPO receptor agonists . Patients should be monitored carefully .

• Take with food.

• Platelet count less than 40X10⁹/L: 60 mg (3 tablets) for 5 days
• Platelet count 40 to less than 50X10⁹/L: 40 mg (2 tablets) for 5 days