Background/Purpose: Abnormal B cell activation is an essential part of autoimmune inflammation. B cell depletion is proven to be an efficacious treatment in patients as well as in preclinical rodent rheumatoid arthritis models. Bruton’s Tyrosine Kinase (BTK) is downstream of B cell receptor and critical in B-cell development and activation, making it a potential therapeutic target for autoimmune inflammatory diseases. Here we evaluated a novel and selective small molecule BTK inhibitor in disease mechanism and pharmacokinetics (PK)/pharmacodynamics (PD) models to understand the level and duration of compound exposure on activation biomarker PD effect that leads to efficacy.  

Methods:  Female Lewis rats were treated with the BTK inhibitor (3, 10, 30, 100 mg/kg PO QD) prophylactically starting from the day of immunization in the rat collagen induced arthritis (CIA) model.  Disease severity was evaluated in life by measuring paw thickness and clinical scores and terminal by micro-CT imaging of ankle and knee joints for bone erosion. The effect of the BTK inhibitor on B cells was evaluated by ex vivo whole blood B cell CD86 PK/PD assay. Blood was collected from rats at 0, 0.5, 4, 8, and 24 hours after compound dosing.  B cells were stimulated in vitro in whole blood by crosslinking of BCR with dextran conjugated anti-IgD. Activation biomarker CD86 expression on B cells was quantified by flow cytometry. Rat plasma compound concentrations were determined by protein precipitation followed by liquid chromatography – tandem mass spectrometry. A PK/PD-CIA model was built linking the effect of compound exposure with CD86 biomarker expression in the ex vivo whole blood assay and paw inflammation in the rat CIA. PK was best described using a zero-order dissolvation linked with a first-order absorption compartment and a concentration dependent elimination rate. For CD86 expression a direct-effect model was used. Paw inflammation in the rat CIA modeling was performed based on the assumption that the biomarker PD effect drove the disease inhibition.

Results: The BTK inhibitor showed an exposure-dependent suppression of joint inflammation in the rat CIA model with an EAUC50  of 56 uM.h, and blocking of CD86 upregulation in ex vivo whole blood B cell biomarker activation assay (IC50= 918 nM). Micro-CT imaging revealed reduced bone erosion in both ankle and knee joints by the inhibitor, and the bone effect correlated well with the reduction on joint inflammation.  The integrated PK/PD-CIA model was used to simulate the full range of target engagement by the inhibitor as measured by the CD86 assay. A good correlation between average CD86 inhibition over a 24 hour time period and the paw thickness inhibition in the rat CIA model was found.  An average of 60% CD86 suppression led to a 90% suppression of disease development in the rat CIA model.

Conclusion: The selective and novel BTK inhibitor is efficacious in the rat CIA model. Pharmacological evaluation of compounds in disease mechanism and target pathway relevant PK/PD and efficacy models can provide valuable data in building a translational PK/PD/efficacy platform from preclinical in vitro and in vivo models to human diseases in drug discovery.

---

« Back to 2014 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/explore-translational-pharmacokineticspharmacodynamics-responseefficacy-relationship-of-a-novel-brutons-tyrosine-kinase-inhibitor-in-rat-collagen-induced-arthritis-model/