Background/Purpose:  Baricitinib is an oral selective inhibitor of Janus kinases 1/2 and has demonstrated dose-dependent efficacy in moderate-to-severe RA patients who were DMARD-naïve or with inadequate response to previous conventional or biological disease-modifying anti-rheumatic drugs (cDMARD/bDMARD-IR), in multiple phase 2 and 3 studies. The objective was to characterize the exposure-efficacy relationships and time course of 20, 50, and 70% improvement in the American College of Rheumatology criteria (ACR 20, 50, and 70, respectively) and disease activity score based on 28 joints and high sensitivity C-reactive protein (DAS28-hsCRP), in a combined phase 2/3 analysis.

Methods:  The database comprised 7 baricitinib phase 2 and 3 studies in RA patients receiving placebo, 1, 2, 4, 7, 8 and 10 mg QD or 2-mg BID up to 24 weeks. The corresponding pharmacokinetics (PK), ACR 20/50/70 and DAS28-hsCRP response rates were analyzed by both quartile analysis and population pharmacokinetics/pharmacodynamics (PK/PD) modeling. For the quartile analysis, average steady-state concentrations from patients receiving 2- and 4-mg in 4 phase 3 studies were grouped into quartiles and correlated with the percentage of patients achieving ACR 20/50/70 and DAS28-hsCRP ≤3.2 and <2.6, at Week 12 and 16. Exposure-response models were also developed to describe the time-course and the exposure-response relationships of ACR 20/50/70 and DAS28-hsCRP following administration of baricitinib or placebo. Patient specific factors affecting the ACR 20/50/70 and DAS28-hsCRP response rates were explored.

Results:  Plasma baricitinib concentrations were best characterized by a 2-compartment model with clearance partitioned between renal and non-renal components. Quartile exposure response analysis indicated that clinically relevant higher rates of ACR20/50/70 and DAS28-hsCRP responses were observed in the 3 upper quartiles compared to the lowest quartile. The PK/PD models adequately characterized the time course and exposure-responses of ACR20/50/70 and DAS28-hsCRP. Both baricitinib and placebo exhibited an indirect inhibitory effect on disease progression of ACR and DAS28-hsCRP. The model-estimated maximum response rates for ACR 20, 50, and 70 were 87%, 64%, and 39%, respectively, and 59% and 43% for DAS28-hsCRP ≤3.2 and <2.6, respectively. Model-estimated exposure response curves demonstrated that exposures from the 4-mg dose resided on the plateau of the response curves and exposures from 2-mg were lower and closer to the ascending portion of the curves for both ACR responses and DAS28-hsCRP states.

Conclusion:  The final models successfully described and predicted the time-dependent changes in ACR20/50/70 and DAS28-hsCRP across the range of doses tested. A 4 mg QD dose was predicted to achieve close to maximal response.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bari-00074565/