Modeling Corticosteroid Effects in a Rat Model of Rheumatoid Arthritis II: Mechanistic Pharmacodynamic Model for Dexamethasone Effects in Lewis Rats with Collagen-Induced Arthritis

Abstract

A mechanism-based model for pharmacodynamic effects of dexamethasone (DEX) was incorporated into our model for arthritis disease progression in the rat to aid in identification of the primary factors responsible for edema and bone loss. Collagen-induced arthritis was produced in male Lewis rats after injection of type II porcine collagen. DEX was given subcutaneously in single doses of 0.225 or 2.25 mg/kg or 7-day multiple doses of 0.045 or 0.225 mg/kg at 21 days postdisease induction. Effects on disease progression were measured by paw swelling, bone mineral density (BMD), body weights, plasma corticosterone (CST), and tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, IL-6, and glucocorticoid receptor (GR) mRNA expression in paw tissue. Lumbar and femur BMD was determined by PIXImus II dual-energy X-ray absorptiometry. Plasma CST was assayed by high-performance liquid chromatography. Cytokine and GR mRNA were assayed by quantitative real-time polymerase chain reaction. Indirect response models, drug interaction models, transduction processes, and the fifth-generation model of corticosteroid dynamics were integrated and applied using S-ADAPT software to describe how dexamethasone binding to GR can regulate diverse processes. Cytokine mRNA, GR mRNA, plasma CST, and paw edema were suppressed after DEX administration. TNF-␣ mRNA expression and BMD seemed to increase immediately after dosing but were ultimately reduced. Model parameters indicated that IL-6 and IL-1␤ were most sensitive to inhibition by DEX. TNF-␣ seemed to primarily influence edema, whereas IL-6 contributed the most to bone loss. Lower doses of corticosteroids may be sufficient to suppress the cytokines most relevant to bone erosion.

Antiarthritis Effect of a Novel Bruton's Tyrosine Kinase (BTK) Inhibitor in Rat Collagen-Induced Arthritis and Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling: Relationships between Inhibition of BTK Phosphorylation and Efficacy

“…Although the application of mechanism-based PK/PD modeling in preclinical models of arthritis is relatively new, previous work has provided a better understanding of factors contributing to disease progression in the rat CIA model (Earp et al, 2008a(Earp et al, ,b, 2009). In the current integrated disease progression PK/PD model (Fig.…”

Modeling Corticosteroid Effects in a Rat Model of Rheumatoid Arthritis I: Mechanistic Disease Progression Model for the Time Course of Collagen-Induced Arthritis in Lewis Rats

“…Four additional rats were scanned for the femur, lumbar, and paw regions on days 2, 9, 12, 15, 19, 23, and 27. Four healthy controls were also scanned for the femur, lumbar, and paw regions on days 1, 8, 16, 19, 23, 27, and 35. Paw and body weight data and tissues from preliminary pilot studies in our laboratory and from Earp et al (2008) were also included in the model development. In total, 162 healthy and arthritic rats were used for all paw mRNA measurements.…”

“…The apparent lack of sensitivity of these factors to CST was important in determining how much effect CST had on the biomarkers after DEX was administered and CST concentrations plummeted. If CST entirely explained the degree of remission for both cytokines, then in Earp et al (2008) after DEX was administered predicted IL-6 and IL-1␤ mRNA concentrations would spike well above the observed baseline when DEX concentrations fell and CST concentrations remained low. The parameter IC 50_IL1␤/Rem denotes the amount of Rem necessary to inhibit IL-1␤ mRNA production to 50% of maximal capacity (0.7).…”

“…This investigation aims at 1) developing a mechanistic model to describe the natural time course of the molecular factors that drive chronic inflammatory arthritis in the rat and that are relevant to corticosteroid effect (this study) and 2) integrating drug binding assumptions into the disease progression model to explain pharmacodynamic effects of corticosteroids (CS) and further resolve disease progression parameters (Earp et al, 2008). The molecular factors assayed to describe disease progression include proinflammatory cytokine mRNA for tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, and IL-6 and factors relevant to endogenous corticosteroid dynamics, including glucocorticoid receptor (GR) mRNA and plasma corticosterone (CST).…”

Translational Biomarkers: from Preclinical to Clinical a Report of 2009 AAPS/ACCP Biomarker Workshop

“…A rat model of rheumatoid arthritis showed considerable promise for use of mRNA as a biomarker for disease progression and efficacy of dexamethasone (17). Genes for the pro-inflammatory cytokines, IL-1β, TNF-α, and IL-6 in rat paws exhibited a lengthy lag phase and then rose in anticipation of physical changes in paw edema.…”