Background/Purpose: Baricitinib (Bari) is an oral inhibitor of Janus kinases (JAK) selective for JAK 1 and 2. It has demonstrated dose-dependent efficacy in patients with moderate-to-severe rheumatoid arthritis (RA) who have an inadequate response to methotrexate in multiple phase 2 studies. The objective of this analysis was to characterize the dose/exposure-response (D/E-R) relationship of Bari to optimize selection of doses and dose regimens for the phase 3 program.

Methods: Pharmacokinetics (PK) and efficacy data are available in patients with RA from two Phase 2 studies, Study JADA (n=278, Keystone E, et al.) and Study JADN (n=143, Tanaka Y, et al.), respectively. Study JADA used doses of 1, 2, 4, and 8 mg QD for up to 24 weeks and 2 mg BID for 12 weeks, and Study JADN used doses of 1, 2, 4, and 8 mg QD for up to 12 weeks. A Population PK (PopPK) model was developed to characterize plasma concentration-time profiles and identify potential covariates using NONMEM (version 7.2). A semi-mechanistic population PK/pharmacodynamic (PK/PD) model was developed to describe the time course and D/E-R relationship for the key efficacy endpoints, ACR20/50/70 and DAS28-CRP response rates. A placebo effect was accounted for in both PD models. A sequential PK and PK/PD analysis approach was used. The developed PK/PD model was subsequently applied to simulate ACR20/50/70 and DAS28-CRP response rates following various doses and dosing regimens (QD vs BID) to help optimizing dose selection for phase 3 studies.

Results: The models adequately described the PK and the longitudinal dose/exposure-response relationships for ACR20/50/70 and DAS28-CRP for all regimens tested in the phase 2 studies. The mean terminal half-life of BARI was estimated to be approximately 14 hours. Renal function was identified as a significant covariate on the clearance of BARI. No patient factors had a significant impact on the PK/PD relationship. PD steady state was attained approximately 12 weeks after treatment for all endpoints. Based on the dose/response curve, 4 mg approached the maximum effect and offered additional efficacy benefits over 2 mg. Simulations suggested that at the same total daily doses, QD and BID dosing regimens achieved similar average plasma concentrations at steady state. In addition, the efficacy responses were comparable between the QD and BID dosing regimens for all efficacy endpoints at the same total daily doses based on the simulations.

Conclusion: Based on modeling and simulations with phase 2 data over a dose range of 1-8 mg (QD and BID), 4 mg and 2 mg QD were selected for further investigation for the BARI phase 3 studies, with 4 mg QD identified as the preferred phase 3 dose. At the same total daily dose, splitting the dose into a BID regimen does not provide any advantage over QD dosing for any of the efficacy endpoints.

References:

Keystone E, et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis. 2015;74(2):333-340.

Tanaka Y, et al. Efficacy and safety of baricitinib in Japanese RA patients during a 52 week extension phase. Art Rheum. 2014;66(11):S652.

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/evaluate-the-dose-efficacy-response-relationship-of-baricitinib-in-patients-with-rheumatoid-arthritis/