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Evaluation of drug–drug interaction between the novel cPLA2 inhibitor AK106-001616 and methotrexate in rheumatoid arthritis patients

Abstract 1. Drug interaction potential between AK106-001616, a novel cytosolic phospholipase A2 inhibitor, and methotrexate (MTX) in rheumatoid arthritis patients was investigated. This trial is registered with ClinicalTrials.gov, number NCT00902369. 2. In the clinical study, the 90% confidence intervals (CIs) for the geometric mean ratio (GMR) of AUC0–t of MTX administered after AK106-001616 200 mg compared to the MTX without AK106-001616 were within 80–125%. However, administration of AK106-001616 at doses of 400 and 600 mg exceeded the 125% threshold. As small but statistically significant increases in AUC0–t were observed, we investigated the mechanism for this drug–drug interaction between MTX and AK106-001616. 3. In vitro, AK106-001616 inhibited OAT1 (IC50 = 18.4 μM, Ki = 33.6 μM) in a non-competitive manner and OAT3 (IC50 = 1.80 μM, Ki = 1.49 μM) in a competitive manner. Both transporters are involved in MTX transport in renal proximal tubules. 4. AK106-001616 has a weak drug interaction with MTX. In vitro studies provide a mechanistic understanding of the in vivo inhibition of transporters by AK106-001616.