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

1. Drug interaction potential between AK106-001616, a novel cytosolic phospholipase A(2) 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 AUC(0-t) of MTX administered after AK106-001616 200mg compared to the MTX without AK106-001616 were within 80-125%. However, administration of AK106-001616 at doses of 400 and 600mg exceeded the 125% threshold. As small but statistically significant increases in AUC(0-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 mu M, K-i = 33.6 mu M) in a non-competitive manner and OAT3 (IC50 = 1.80 mu M, K-i = 1.49 mu M) 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.