Avatrombopag is an oral thrombopoietin (TPO) receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic liver disease scheduled to undergo a medical or dental procedure or with chronic immune thrombocytopenia (ITP) who have had an insufficient response to previous treatment. TPO agonists have been associated with thrombotic and thromboembolic complications. Avatrombopag should not be administered to patients with either condition in an attempt to normalize platelet counts.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Take with food.
-In the event of a missed dose, take the next dose as soon as possible. Do not take 2 doses at same time to make up for a missed dose. Take the next dose at the usual scheduled time.
Thrombotic and thromboembolic complications have been reported in patients with chronic liver disease or chronic immune thrombocytopenia receiving thrombopoietin receptor agonists. Portal vein thrombosis was reported in 0.2% (1/430) of patients with chronic liver disease during avatrombopag clinical trials. Arterial or venous thromboembolism occurred in 7% (9/128) of patients with chronic immune thrombocytopenia receiving avatrombopag during clinical trials.
Abdominal pain and nausea were each reported in 7% of avatrombopag-treated patients vs. 6% and 7% for placebo, respectively, during clinical trials in patients with chronic liver disease.
Headache (31% vs. 14%), fatigue (28% vs. 9%), and arthralgia (13% vs. 0%) were reported more frequently in avatrombopag-treated patients compared to placebo, respectively, during chronic immune thrombocytopenia trials. Headache was considered serious, resulting in drug discontinuation, in 2 of 128 patients. Headache (6% vs. 6%), fatigue (4% vs. 3%), and fever (10% vs. 9%) were reported as or more frequently in avatrombopag-treated patients compared to placebo, respectively, during chronic liver disease trials. Anemia, fever, and myalgia each resulted in discontinuation of avatrombopag therapy in a single patient with chronic liver disease in the 60 mg treatment group.
Peripheral edema was reported in 3% of avatrombopag-patients (vs. 2% placebo) during chronic liver disease trials.
Hyponatremia (0.7%) was the most serious adverse reaction reported with avatrombopag during chronic liver disease trials.
Contusion (26% vs. 18%), epistaxis (19% vs. 18%), gingival bleeding (14% vs. 0%), and petechiae (11% vs. 9%) were reported more frequently in avatrombopag-treated patients compared to placebo, respectively, during chronic immune thrombocytopenia trials.
Upper respiratory tract infection (15% vs. 5%) and naso-pharyngitis (10% vs. 0%) were reported more frequently in avatrombopag-treated patients compared to placebo, respectively, during chronic immune thrombocytopenia trials.
Hypersensitivity reactions, including pruritus, rash, choking sensation, erythema, pharyngeal edema, macular rash, facial swelling, and swollen tongue (glossitis), have been reported with postmarketing use of avatrombopag.
Thrombopoietin (TPO) receptor agonists, such as avatrombopag, have been associated with thrombotic and thromboembolic complications. Consider the potential increased thrombotic risk when administering avatrombopag to patients with known risk factors for thromboembolism, including patients with chronic hepatic disease or genetic prothrombotic conditions (e.g., Factor V Leiden, prothrombin 20210A, antithrombin deficiency, protein C deficiency, protein S deficiency). Do not administer avatrombopag to patients with chronic liver disease or chronic immune thrombocytopenia in an attempt to normalize platelet counts. Follow dosing guidelines to achieve target platelet counts. Monitor patients receiving avatrombopag for signs and symptoms of thromboembolism and institute prompt treatment if such events occur.
Advise pregnant women of the potential risk to the fetus if avatrombopag is administered during pregnancy. The available data on the use of avatrombopag in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. However, based on data from animal reproduction studies, avatrombopag may cause fetal harm when administered to a pregnant woman. When rats and rabbits were administered avatrombopag doses resulting in exposures substantially higher than the AUC observed in humans at the recommended dose, spontaneous abortions, total litter losses, decreased body weight in pups, and increased pup mortality were observed.
Due to the potential for serious adverse reactions in the breast-fed child, breast-feeding is not recommended during avatrombopag treatment and for at least 2 weeks after the last dose. Advise a breast-feeding woman to interrupt breast-feeding and pump and discard breastmilk during treatment and for 2 weeks after the last avatrombopag dose to minimize exposure to the breast-fed child. There are no data regarding the presence of avatrombopag in human milk, the effects on the breast-fed child, or the effects on milk production. However, avatrombopag was present in the milk of lactating rats.
For the treatment of chronic liver disease-associated thrombocytopenia in patients who are scheduled to undergo a procedure:
Oral dosage:
Adults: 60 mg PO once daily for 5 days if the platelet count is less than 40,000/mm3 or 40 mg PO once daily for 5 days if the platelet count is 40,000 to 49,999/mm3 beginning 10 to 13 days before the scheduled procedure. Schedule the procedure 5 to 8 days after the last dose.
For the treatment of chronic immune thrombocytopenic purpura (ITP) in patients who have had an insufficient response to previous treatment:
Oral dosage:
Adults: 20 mg PO once daily initially. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Assess platelet counts weekly until a stable platelet count of 50,000/mm3 or more is achieved. For platelets less than 50,000/mm3 after at least 2 weeks of treatment, increase the dose by 1 dose level; do not exceed 40 mg/day PO. For platelets 200,000 to 400,000/mm3, decrease the dose by 1 dose level. Wait 2 weeks to assess the effects of any dosage adjustments. For platelets more than 400,000/mm3, stop therapy; increase frequency of platelet monitoring to twice weekly. Once the platelet count is less than 150,000/mm3, reinitiate therapy at a dose reduced by 1 dose level. Dose levels are as follows: Dose Level 1 = 20 mg PO once weekly; Dose Level 2 = 20 mg PO twice weekly or 40 mg PO once weekly; Dose Level 3 = 20 mg PO 3 times weekly; Dose Level 4 (Initial Dose) = 20 mg PO once daily; Dose Level 5 = 40 mg PO 3 times weekly and 20 mg PO on the remaining 4 days per week; Dose Level 6 = 40 mg PO once daily. If platelets do not increase to 50,000/mm3 or more after 4 weeks of the maximum dose or if the platelet count is more than 400,000/mm3 after 2 weeks of the lowest dose, discontinue avatrombopag. Use the lowest possible dose to maintain platelet counts of 50,000/mm3 or more.
Therapeutic Drug Monitoring:
-In patients with chronic liver disease, obtain a platelet count before administration of avatrombopag and on the day of the procedure to ensure an adequate increase in platelet count has occurred.
-In patients with chronic immune thrombocytopenia (ITP), assess platelet counts weekly until a stable platelet count of 50,000/mm3 or more has been achieved. Obtain platelet counts monthly thereafter. After avatrombopag discontinuation, obtain platelet counts weekly for at least 4 weeks.
Maximum Dosage Limits:
-Adults
60 mg/day PO in chronic liver disease and 40 mg/day PO in chronic immune thrombocytopenia.
-Geriatric
60 mg/day PO in chronic liver disease and 40 mg/day PO in chronic immune thrombocytopenia.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Amobarbital: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with barbiturates. In patients starting barbiturates while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as barbiturates decrease avatrombopag exposure, which may reduce efficacy.
Aspirin, ASA; Butalbital; Caffeine: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with barbiturates. In patients starting barbiturates while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as barbiturates decrease avatrombopag exposure, which may reduce efficacy.
Barbiturates: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with barbiturates. In patients starting barbiturates while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as barbiturates decrease avatrombopag exposure, which may reduce efficacy.
Bosentan: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with bosentan. In patients starting bosentan while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as bosentan decrease avatrombopag exposure, which may reduce efficacy.
Butalbital; Acetaminophen: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with barbiturates. In patients starting barbiturates while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as barbiturates decrease avatrombopag exposure, which may reduce efficacy.
Butalbital; Acetaminophen; Caffeine: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with barbiturates. In patients starting barbiturates while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as barbiturates decrease avatrombopag exposure, which may reduce efficacy.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with barbiturates. In patients starting barbiturates while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as barbiturates decrease avatrombopag exposure, which may reduce efficacy.
Butalbital; Aspirin; Caffeine; Codeine: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with barbiturates. In patients starting barbiturates while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as barbiturates decrease avatrombopag exposure, which may reduce efficacy.
Enzalutamide: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with enzalutamide. In patients starting enzalutamide while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as enzalutamide decrease avatrombopag exposure, which may reduce efficacy.
Fluconazole: (Major) In patients with chronic immune thrombocytopenia (ITP), reduce the starting dose of avatrombopag to 20 mg PO 3 times weekly when used concomitantly with fluconazole. In patients starting fluconazole while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inhibitors such as fluconazole increase avatrombopag exposure, increasing the risk of avatrombopag toxicity.
Fosphenytoin: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with fosphenytoin. In patients starting fosphenytoin while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as fosphenytoin decrease avatrombopag exposure, which may reduce efficacy.
Grapefruit juice: (Major) Avoid consumption of grapefruit during avatrombopag therapy. Avatrombopag is a CYP2C9 and CYP3A4 substrate, dual moderate or strong inhibitors such as grapefruit juice increase avatrombopag exposure, increasing the risk of avatrombopag toxicity.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with rifampin. In patients starting rifampin while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as rifampin decrease avatrombopag exposure, which may reduce efficacy.
Isoniazid, INH; Rifampin: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with rifampin. In patients starting rifampin while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as rifampin decrease avatrombopag exposure, which may reduce efficacy.
Lopinavir; Ritonavir: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with ritonavir. In patients starting ritonavir while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as ritonavir decrease avatrombopag exposure, which may reduce efficacy.
Mavacamten: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with mavacamten. In patients starting mavacamten while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A substrate, and dual moderate or strong inducers such as mavacamten decrease avatrombopag exposure, which may reduce efficacy.
Meropenem: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with meropenem. In patients starting meropenem while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A substrate, and dual moderate or strong inducers such as meropenem decrease avatrombopag exposure, which may reduce efficacy.
Meropenem; Vaborbactam: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with meropenem. In patients starting meropenem while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A substrate, and dual moderate or strong inducers such as meropenem decrease avatrombopag exposure, which may reduce efficacy.
Methohexital: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with barbiturates. In patients starting barbiturates while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as barbiturates decrease avatrombopag exposure, which may reduce efficacy.
Mifepristone: (Major) In patients with chronic immune thrombocytopenia (ITP), reduce the starting dose of avatrombopag to 20 mg PO 3 times weekly when used concomitantly with mifepristone. In patients starting mifepristone while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inhibitors such as mifepristone increase avatrombopag exposure, increasing the risk of avatrombopag toxicity.
Mitapivat: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with mitapivat. In patients starting mitapivat while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A substrate, and dual moderate or strong inducers such as mitapivat decrease avatrombopag exposure, which may reduce efficacy.
Nirmatrelvir; Ritonavir: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with ritonavir. In patients starting ritonavir while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as ritonavir decrease avatrombopag exposure, which may reduce efficacy.
Pentobarbital: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with barbiturates. In patients starting barbiturates while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as barbiturates decrease avatrombopag exposure, which may reduce efficacy.
Phenobarbital: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with barbiturates. In patients starting barbiturates while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as barbiturates decrease avatrombopag exposure, which may reduce efficacy.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with barbiturates. In patients starting barbiturates while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as barbiturates decrease avatrombopag exposure, which may reduce efficacy.
Phenytoin: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with phenytoin. In patients starting phenytoin while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as phenytoin decrease avatrombopag exposure, which may reduce efficacy.
Primidone: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with barbiturates. In patients starting barbiturates while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as barbiturates decrease avatrombopag exposure, which may reduce efficacy.
Rifampin: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with rifampin. In patients starting rifampin while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as rifampin decrease avatrombopag exposure, which may reduce efficacy.
Rifapentine: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with rifapentine. In patients starting rifapentine while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as rifapentine decrease avatrombopag exposure, which may reduce efficacy.
Ritonavir: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with ritonavir. In patients starting ritonavir while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as ritonavir decrease avatrombopag exposure, which may reduce efficacy.
Secobarbital: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with barbiturates. In patients starting barbiturates while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as barbiturates decrease avatrombopag exposure, which may reduce efficacy.
St. John's Wort, Hypericum perforatum: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with St. John's Wort. In patients starting St. John's Wort while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as St. John's Wort decrease avatrombopag exposure, which may reduce efficacy.
Voriconazole: (Major) In patients with chronic immune thrombocytopenia (ITP), reduce the starting dose of avatrombopag to 20 mg PO 3 times weekly when used concomitantly with voriconazole. In patients starting voriconazole while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inhibitors such as voriconazole increase avatrombopag exposure, increasing the risk of avatrombopag toxicity.
Avatrombopag is a thrombopoietin (TPO) receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells resulting in an increased production of platelets. Avatrombopag does not compete with TPO for binding to the TPO receptor and has an additive effect with TPO on platelet production.
Avatrombopag is administered orally. It is more than 96% bound to human plasma proteins. Estimated mean Vd is 180 L. Mean plasma elimination half-life is approximately 19 hours, with an estimated clearance of 6.9 L/hour. Avatrombopag is primarily metabolized by CYP2C9 and CYP3A4. The majority of the dose (88%) is excreted in feces, with 34% excreted as unchanged avatrombopag. Only 6% of the administered dose was recovered in urine.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C8, CYP2C9, OAT3, BCRP
Avatrombopag is primarily metabolized by CYP2C9 and CYP3A4 and is a substrate for P-glycoprotein (P-gp). Avatrombopag is a weak inducer of CYP2C8 and CYP2C9 and inhibits the organic anion transporting peptide (OAT) 3 and breast cancer resistance protein (BCRP). In a pharmacogenomic analysis, CYP2C9 intermediate and poor metabolizers had approximately 1.4-fold and 2-fold higher avatrombopag exposure, respectively, compared to normal metabolizers.
-Route-Specific Pharmacokinetics
Oral Route
Avatrombopag produces dose- and exposure-dependent increases in platelet counts. The onset of platelet count increase occurs within 3 to 5 days of the start of treatment, with a peak effect seen after 10 to 13 days. Post-treatment, platelet counts gradually decrease and return to near baseline values. Tmax is 5 to 6 hours post-dose. The variability of avatrombopag exposure is reduced by 40% to 60% when administered with food. Tmax is delayed by up to 2 hours when avatrombopag is administered with a low- or high-fat meal (median Tmax range: 5 to 8 hours) compared to the fasted state. Exposure (AUC and Cmax) are not affected by food.
-Special Populations
Hepatic Impairment
Hepatic impairment (Child-Turcotte-Pugh grade A, B, and C, or Model for End-Stage Liver Disease score 4 to 23) did not have any clinically significant effects on the pharmacokinetics of avatrombopag. Pharmacokinetics were similar in healthy subjects and those with chronic liver disease.
Renal Impairment
Mild to moderate renal impairment (CrCl 30 mL/minute or more) did not have any clinically significant effects on the pharmacokinetics of avatrombopag. The effect of severe renal impairment (CrCl less than 30 mL/minute), including patients requiring hemodialysis, on the pharmacokinetics of avatrombopag is unknown.
Geriatric
Age (18 to 86 years) did not have any clinically significant effects on the pharmacokinetics of avatrombopag.
Gender Differences
Gender did not have any clinically significant effects on the pharmacokinetics of avatrombopag.
Ethnic Differences
Ethnicity (i.e., Whites, African Americans, East Asians) did not have any clinically significant effects on the pharmacokinetics of avatrombopag.
Obesity
Body weight (39 to 175 kg) did not have any clinically significant effects on the pharmacokinetics of avatrombopag.
Other
CYP2C9 Intermediate and Poor Metabolizers
In a pharmacogenomic analysis, CYP2C9 intermediate and poor metabolizers had approximately 1.4-fold and 2-fold higher avatrombopag exposure, respectively, compared to normal metabolizers.