Avatrombopag for Thrombocytopenia in Adults

Avatrombopag (Doptelet, Dova) received FDA approval in May for treatment of thrombocytopenia in adults with chronic liver disease who are scheduled to undergo medical or dental procedures. Avatrombopag is a small molecule thrombopoietin (TPO) receptor agonist that increases production of platelets by stimulating development of megakaryocytes from progenitor cells in bone marrow. Mega-karyocytes produce platelets. Avatrombopag noncom-petitively binds the TPO receptor resulting in an additive effect on platelet production. 

Efficacy

Avatrombopag was approved based on results from two multicenter trials, ADAPT-1 and ADAPT-2. The trials include 435 participants. In both trials, participants were assigned to a cohort based on their baseline plate-let count. Participants with a platelet count less than 40 x109/L were assigned to the low-baseline platelet count cohort. Participants with platelet counts between 40 and 50 x109/L were assigned to the high-baseline platelet count cohort. Within the cohorts, participants were randomized to receive avatrombopag or placebo for five days. Participants in the low-baseline cohort received 40 mg daily. Participants in the high-baseline cohort received 60 mg daily. Five to eight days after the last dose of treatment, participants could undergo their scheduled procedure.

The percent of patients undergoing procedures associated with low, moderate, and high bleeding risk are 60.8%, 17.2%, and 22.1%, respectively. Patients scheduled for a neurosurgical intervention, thoracotomy, organ resection, or laparotomy were excluded from studies. The primary efficacy endpoint of both studies is the proportion of responders; patients not requiring a platelet transfusion or rescue procedure as a result of bleeding within a week of the scheduled procedure.

In the low-baseline cohort, 66% and 69% of participants who received avatrombopag in the ADAPT-1 and ADAPT-2 trials were identified as responders, compared to 23% and 35% of those receiving placebo. In the high-base-line platelet count cohorts, 88% of those who received avatrombopag in both ADAPT trials responded, com-pared to 38% (ADAPT-1) and 33% (ADAPT-2) of those receiving placebo. The proportion of patients with a platelet count greater than 50 x109/L on the day of the procedure and the change in platelet count from base-line to the day of scheduled procedure represented secondary end-points in the studies. 

Safety

In both trials, more participants in both cohorts who received avatrombopag showed a greater mean change in platelet counts and achieved target platelet counts.

The most common adverse reactions reported in greater than 3% of total participants from both cohorts include fever (10%), abdominal pain (7%), nausea (7%), headache (6%), fatigue (4%), and peripheral edema (3%). Patients must be monitored for changes to platelet counts and thromboembolic events. TPO receptor agonists have been associated with thrombotic events in patients with chronic liver disease.  Avatrombopag should not be used for maintenance of increased platelet levels in patients with chronic liver disease. 

Dosage

Avatrombopag is approved for use starting 10 to 13 days before a scheduled procedure and daily for 5 consecutive days. It is available as 20-mg tab-lets. The recommended daily dose for use is related to the patient’s platelet count prior to the procedure: 60 mg (three tablets) daily for patients with less than 40x109/L and 40 mg (two tablets) daily for patients with platelet count between 40 and 50x109/L. 

References:

Doptelet [package insert]. Durham, North Carolina: AkaRx, Inc., May 2018