Pharmacokinetic/pharmacodynamic drug–drug interactions of avatrombopag when coadministered with dual or selective CYP2C9 and CYP3A interacting drugs

Abstract

The results from coadministration of fluconazole or itraconazole suggest that CYP2C9 plays a more predominant role in metabolic clearance of avatrombopag than CYP3A. To achieve comparable platelet count increases when avatrombopag is coadministered with CYP3A and CYP2C9 inhibitors, an adjustment in the dose or duration of treatment is recommended, while coadministration with strong inducers is not currently recommended.

Population Pharmacokinetic/Pharmacodynamic Analyses of Avatrombopag in Patients With Chronic Liver Disease and Optimal Dose Adjustment Guide With Concomitantly Administered CYP3A and CYP2C9 Inhibitors

“…The following intrinsic and extrinsic factors had no significant effect on avatrombopag PK: age, race, renal function, liver function, prothrombin international normalization ratio, and concomitant administration of proton pump inhibitors or H 2 blockers. Although coadministration with strong CYP3A inhibitors/inducers was shown to affect avatrombopag PK in previous clinical study and physiologically based PK simulations, the effect of concomitant administration of these drugs could not be estimated in the population PK analysis due to the very limited number of subjects in the PK data set receiving concomitant CYP3A inhibitors/inducers, which is attributed to the short treatment duration of 5 days with avatrombopag.…”

“…Concomitant drugs used for the simulation were itraconazole (CYP3A inhibitor), verapamil (CYP3A inhibitor), fluconazole (CYP2C9 and CYP3A dual inhibitor), sulfaphenazole (CYP2C9 inhibitor), and rifampin (CYP3A4 and CYP2C9 dual inducer) . The apparent clearance values used in the simulations following coadministration of inhibitors/inducers were obtained from the actual clinical data and physiologically based PK simulation data . PD simulations were performed using the dose regimens included in phase 3 studies of avatrombopag, with and without concomitant medication, with dosing 60 mg for 5 days for patients with baseline platelet count of <40 × 10 9 /L and 40 mg for 5 days for patients with baseline between 40 and <50 × 10 9 /L.…”

“…In a clinical drug‐drug interaction study in healthy subjects, coadministration with CYP2C9 and CYP3A inhibitors/inducers was shown to affect avatrombopag pharmacokinetics (PK). Fluconazole (a dual inhibitor of CYP2C9 and CYP3A) and rifampin (a dual inducer of CYP2C9 and CYP3A4) resulted in an approximately 2‐fold increase and 0.5‐fold decrease in avatrombopag area under the plasma drug concentration‐time curve, respectively; no clinically important drug interactions were observed following coadministration with CYP3A or P‐glycoprotein inhibitors …”

New Small Molecule Drugs for Thrombocytopenia: Chemical, Pharmacological, and Therapeutic Use Considerations

“…Platelet count steadily declines within 7 days of the procedure and platelet count returns to baseline in about 35 days. Elimination half-life of the drug is ~19 h. The most frequent side effects of ≥3% are pyrexia, nausea, fatigue, abdominal pain, headache, and peripheral edema [52,55,56,57]. Similar to drugs with the same mechanism of action, avatrombopag is associated with a slight risk of thrombotic and thromboembolic complications, particularly portal vein thrombosis (1 case out of 430 participants in clinical trials ADAPT-1 (NCT01972529) and ADAPT-2 (NCT01976104)) [58].…”

“…Avatrombopag is a substrate of CYP2C9 and CYP3A, which metabolize the drug to the corresponding 4-hydroxylated products with the former enzyme playing more predominant role (Figure 3) [52,55,56,57]. Given this metabolic profile, drug-drug interactions between avatrombopag and rifampin, enzalutamide, fluconazole, and mifepristone were reported.…”