Avatrombopag

649.67

649.65

1312995-182-4

3H8GSZ4SQL

DTXSID30205667

C150559

B02BX|B - Blood and blood forming organs

158

6.82

1.4±0.1 g/cm3

1.671

H2O: Insoluble

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.

In clinical trials in patients with ITP, ALT elevations occurred in 10% to 11% of eltrombopag vs 3% to 7% of placebo treated subjects, but the elevations were usually mild and transient, resolving once eltrombopag was discontinued and sometimes even with continued use. Instances in which there was recurrence of serum enzyme elevations with restarting eltrombopag have been reported and several patients were said to have developed serious liver disease on treatment, perhaps as a result of portal vein thrombosis. Because of such reports, eltrombopag has a boxed warning about hepatotoxicity and the possibility of hepatic decompensation when treating patients with chronic hepatitis C, in which situation monitoring of liver tests is recommended. Despite this, there have been no published reports of idiosyncratic clinically apparent liver injury attributable to eltrombopag therapy in the medical literature and the clinical characteristics, timing on onset, pattern of enzyme elevations and response to withdrawal of therapy of the liver injury attributed to the drug have not been described. Furthermore, with the development of more potent antiviral agents for hepatitis C, interferon is now rarely used and the indication for concurrent use of eltrombopag for thrombocytopenia during interferon therapy is rarely encountered.

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

Indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure.|FDA Label|Doptelet is indicated for the treatment of severe thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo an invasive procedure.Doptelet is indicated for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory to other treatments (e.g. corticosteroids, immunoglobulins).|Treatment of chemotherapy-induced thrombocytopenia

The thrombopoietin receptor agonists mimic the action of thrombopoietin on its receptor and stimulate the activation, proliferation and maturation of megakaryocytes, resulting in an increase in circulating platelet counts. Thrombopoietin itself acts in this manner, but when recombinant thrombopoietins were used clinically, they were found to cause rebound thrombocytopenia, probably due to induction of anti-thrombopoietin antibodies. For this reason, direct administration of thrombopoietin was abandoned as an approach to treating thrombocytopenia and other approaches to activating the thrombopoietin receptor were sought.

Hematologic Growth Factors

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.

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.|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.|Avatrombopag has an estimated mean volume of distribution (%CV) of 180 L (25%).|The mean (%CV) of the clearance of avatrombopag is estimated to be 6.9 L/hr (29%).

Avatrombopag is primarily metabolized by cytochrome P450 (CYP) 2C9 and CYP3A4.

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

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.

1-(3-chloro-5-((4-(4-chloro-2-thienyl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl)carbamoyl)-2-pyridyl)piperidine-4-carboxylic acid

Human drugs -> Doptelet -> EMA Drug Category|Antihemorrhagics -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients