A proof-of-concept and drug-drug interaction study of pamapimod, a novel p38 MAP kinase inhibitor, with methotrexate in patients with rheumatoid arthritis.
This study evaluated the potential pharmacokinetic interaction of pamapimod, a p38 mitogen-activated protein kinase inhibitor, and methotrexate (MTX) when administered concomitantly in patients with rheumatoid arthritis (RA); the study also evaluated the pharmacodynamic effects of pamapimod. Twenty-two RA patients on a stable regimen of MTX (10-25 mg/wk; administered on days 1 and 8) were randomized to receive 300 mg of pamapimod (n = 17) or placebo (n = 5) once daily (qd) for 10 days (days 5-14). Blood and urine samples were collected pre- and postdose on days 1 (MTX alone), 7 (pamapimod alone), and 8 (MTX and pamapimod coadministered). No clinically significant changes were observed in plasma exposures and renal clearance of pamapimod, MTX, or their metabolites, whether administered separately or concomitantly. The combination of pamapimod (300 mg qd) for 10 days and weekly MTX was generally well tolerated. Parameters of RA disease--namely, tender joint count, swollen joint count, erythrocyte sedimentation rate, and C-reactive protein--generally decreased between days 5 and 14. The results of this study suggest that dose adjustments for either drug are not necessary when concomitantly administered and that pamapimod can decrease pharmacodynamic markers of disease activity.
Zhang
Xiaoping
X
Department of Clinical Pharmacology, Hoffmann-La Roche Inc, 340 Kingsland Street, Nutley, NJ 07110, USA. amy.zhang@roche.com
Huang
Yue
Y
Navarro
Mercidita T
MT
Hisoire
Grace
G
Caulfield
John P
JP
D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D011728:Pyridones / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000097:blood
D018501:Antirheumatic Agents; D011728:Pyridones; D011743:Pyrimidines; C533858:pamapimod; D048051:p38 Mitogen-Activated Protein Kinases; D008727:Methotrexate