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 AUC_0–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 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 μM, K_i = 33.6 μM) in a non-competitive manner and OAT3 (IC₅₀ = 1.80 μM, K_i = 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.

• 7-hydroxymethotrexate
• Clinical
• OAT1
• OAT3
• transporters

Declaration of interest

T. Kozaki, M. Tagashira, K. Yamanishi, B. Ellis, T. Kayanoki, R. Ooishi, K. Sugiyama, T. Kohira and K. Tsurui are employees of Asahi Kasei Pharma Corporation, which provided the financial support for these studies. K. Tsuruta is an employee of Asahi Kasei Pharma America Corporation, which is a wholly-owned subsidiary of Asahi Kasei Pharma Corporation. S. Matsuda is an employee of Sekisui Medical Company, Ltd., which was contracted by Asahi Kasei Pharma Corporation to conduct the in vitro studies.