Description
Avatrombopag maleate is a thrombopoietin receptor (TPO) agonist developed by AkaRx Inc and approved by the US FDA in May 2018 as Doptelet (20mg). For the treatment of low platelet count (thrombocytopenia CIT) in adult patients with chronic liver disease (CLD) who are scheduled to undergo medical or dental surgery.
Chemical Properties
Avatrombopag maleate drug substance is a white to off-white, non-hygroscopic, powder that is practically insoluble in water and in 0.1 M HCl. The aqueous solubility of avatrombopag maleate at various pH levels indicates that the drug substance is practically insoluble at pH 1 to 11. Avatrombopag maleate drug substance is an achiral molecule.
Uses
Avatrombopag Maleate is the maleate salt form of avatrombopag, an orally available platelet thrombopoietin receptor (TPOR; MPL) agonist, with potential megakaryopoiesis stimulating activity.
Definition
Avatrombopag maleate is an active ingredient in Doptelet. Doptelet is provided as an immediate-release tablet. Each DOPTELET tablet contains 20 mg avatrombopag (equivalent to 23.6 mg avatrombopag maleate). Other components of Doptelet include lactose monohydrate, colloidal silicon dioxide, crospovidone, and so on.
Indications
Avatrombopag maleate (Doptelet?) is an oral, second-generation TPO-RA approved in the US and EU for the treatment of adult patients with primary chronic ITP who have failed to respond (EU) or have had an inadequate response (US) to other treatments. It is also approved in the US for the treatment of thrombocytopenia in adult patients with CLD who are scheduled for surgery and in the EU for the treatment of severe thrombocytopenia in adult patients with CLD who are scheduled for invasive surgery[1].
Mechanism of action
Upon administration, Avatrombopag maleate binds to and stimulates TPOR, which may lead to the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. This increases the production of platelets and may prevent chemotherapy-induced thrombocytopenia (CIT). TPOR is a cytokine receptor and member of the hematopoietin receptor superfamily.
Side effects
Avatrombopag maleate is generally well tolerated in patients with ITP. Common adverse reactions include headache, fatigue, contusion, epistaxis, upper respiratory tract infection, arthralgia, gingival bleeding, petechiae, and nasopharyngitis. Serious adverse reactions are: severe headache (which may require discontinuation of the drug for relief), thromboembolism, and cerebrovascular. These events often occur when the platelet count is below the upper limit of normal (450 × 109/L), and there is no obvious relationship between the duration of drug exposure and the occurrence of thromboembolic events[1].
Synthesis
The synthesis of Avatrombopag maleate is as follows:
A mixture containing 80.1 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid, 580 mL of DMSO, 580 mL of acetone, 17.2 g of maleic acid, and 290 mL of water was stirred at 69 °C. The insoluble matter was filtered out, washed with a mixture of 32 mL of DMSO, 32 mL of acetone, and 16 mL of water, and then the filtrate was cooled and the precipitate was collected by filtering. Washing was successively performed using 150 mL of water, 80 mL of acetone, 650 mL of water, and 80 mL of acetone, followed by drying, to obtain 70.66 g of Avatrombopag maleate.
References
[1] MARKHAM A. Avatrombopag: A Review in Thrombocytopenia.[J]. ACS Chemical Neuroscience, 2021: 1905-1913. DOI:10.1007/s40265-021-01613-y.
