title: 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.
authors.affiliation: Laboratory for Safety Assessment & ADME, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation , Tokyo , Japan .
authors.forename: Tomohito
authors.initials: T
authors.lastname: Kozaki
authors.forename: Mizuka
authors.initials: M
authors.lastname: Tagashira
authors.forename: Kei
authors.initials: K
authors.lastname: Yamanishi
authors.forename: Brendan
authors.initials: B
authors.lastname: Ellis
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kayanoki
authors.forename: Rika
authors.initials: R
authors.lastname: Ooishi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sugiyama
authors.forename: Sunao
authors.initials: S
authors.lastname: Matsuda
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Tsuruta
authors.forename: Terutomo
authors.initials: T
authors.lastname: Kohira
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tsurui
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D003710:Demography; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D054513:Group IV Phospholipases A2; D008727:Methotrexate
keywords: 7-hydroxymethotrexate; Clinical; OAT1; OAT3; transporters