Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment.
OBJECTIVE
To investigate the effects of methotrexate (MTX) on the pharmacokinetics (PK) of CP-690,550, a novel Janus kinase (JAK) inhibitor in development as a therapy for rheumatoid arthritis (RA), to determine the effects of multiple doses of CP-690,550 on the PK of MTX, and to evaluate the short-term safety and tolerability of co-administration of CP-690,550 and MTX.


METHODS
This was a fixed-dose drug-drug interaction study. Twelve patients diagnosed with RA for at least 6 months were enrolled in a Phase I, open-label study of the PK of multiple doses of CP-690,550 (30 mg b.i.d.) and single doses of MTX (15-25 mg per week).


RESULTS
All patients completed the study and were evaluated for PK and safety. CP-690,550 exposure was not affected by co-administration with MTX; AUC(12) ratio (CP-690,550 + MTX/CP-690,550) was 103.06% [90% confidence interval (CI) 99.00, 107.29]. MTX exposure decreased by 10%; AUC(12) ratio (CP-690,550 + MTX/MTX) was 89.53% (90% CI 77.38, 103.57), which was not considered clinically significant. Co-administration of CP-690,550 and MTX was safe and well tolerated. There were no serious adverse events or withdrawals from the study and there was no trend in the incidence or severity of adverse events across treatments.


CONCLUSIONS
Co-administration of CP-690,550 and MTX was safe and well tolerated. There was no clinically significant effect on the PK profile of either drug. Therefore, dose adjustments should not be required when co-administering CP-690,550 and MTX.
Cohen
Stanley
S
Metroplex Clinical Research Center, Dallas, TX, USA.
Zwillich
Samuel H
SH
Chow
Vincent
V
Labadie
Robert R
RR
Wilkinson
Bethanie
B
D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000008:administration & dosage*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D008875:Middle Aged; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*; D016896:Treatment Outcome
D018501:Antirheumatic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D053616:Janus Kinase 3; D008727:Methotrexate