Quantitative Dynamic Models of Arthritis Progression in the Rat

Abstract

Purpose This comparison employs mathematical disease progression models to identify a rat model of arthritis with the least inter-animal variability and features lending to better study designs. Methods Arthritis was induced with either collagen (CIA) or mycobacterium (AIA) in either Lewis or Dark Agouti (DA) rats. Disease progression was monitored by paw edema and body weight. Models with production, loss, and feedback components were constructed and population analysis using NONMEM software was employed to identify inter-animal variability in the various disease progression parameters. Results Onset time was the only parameter different within all four groups (DA–AIA 11.5 days, DA–CIA 16.5 days, Lewis–AIA 11.9 days, Lewis–CIA 13.9 days). The loss-of-edema rate constant was 20% slower in DA (0.362 h−1) than Lewis (0.466 h−1) rats. Most models exhibited peak paw edema 20 days post-induction. Edema in CIA returned to 150% of the initial value after the disease peaked. DA rats displayed more severe overall responses. Conclusions No statistical differences between groups were observed for inter-animal variation in disease onset, progression and severity parameters. Onset time varies and should be noted in the design of future studies. DA rats may offer a more dynamic range of edema response than Lewis rats.

Modeling pharmacokinetics/pharmacodynamics of abatacept and disease progression in collagen-induced arthritic rats: a population approach

“…The CIA rat model is the most frequently used experimental model to mimic the human disease with an advantage of a relatively short time-frame and readily measured disease markers [11–15]. This CIA model shares many similar disease characteristics with human RA, such as synovial immune infiltration, pannus formation and joint destruction, and it also exhibits many common immunological factors seen in human RA, including rheumatoid factor (RF) and anti-collagen type II (anti-CII) antibodies.…”

“…However, these are not present in the AIA model [32]. Our previous publication has showed that the CIA Lewis rat model is preferable to the AIA model for PK / PD assessment of RA therapeutics [15], and therefore this animal model was selected in the current study.…”

“…Edema was indicated by swelling of the rat hind paws and was measured with digital calipers (VWR Scientific, Rochester, NY) as previously described [11–15]. Edema was indicated by the sum of the paw and ankle area measurements for each hind foot.…”

Population pharmacokinetic–pharmacodynamic–disease progression model for effects of anakinra in Lewis rats with collagen-induced arthritis

“…Three different PD models, indirect response model I combined with simple feedback model (model A) [23], feedback model containing natural growth (model B) [24], and transduction-based feedback model (model C, Fig. 1–final model), were tested.…”

Drug Development of Therapeutic Monoclonal Antibodies

“…Other models, such as the collageninduced arthritis model, have also been used to evaluate antiinflammatory MAbs [39], and is still used today [40,41]. Data collected from preclinical pharmacology studies can be used to relate systemic MAb exposure to inflammation [42] as well as disease progression, which can subsequently be linked to human exposure and response [43,44].…”