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

Abstract

A population pharmacokinetic–pharmacodynamic–disease progression (PK/PD/DIS) model was developed to characterize the effects of anakinra in collagen-induced arthritic (CIA) rats and explore the role of interleukin-1β (IL-1β) in rheumatoid arthritis. The CIA rats received either vehicle, or anakinra at 100 mg/kg for about 33 h, 100 mg/kg for about 188 h, or 10 mg/kg for about 188 h by subcutaneous infusion. Plasma concentrations of anakinra were assayed by enzyme-linked immunosorbent assay. Swelling of rat hind paws was measured. Population PK/PD/DIS parameters were computed for the various groups using non-linear mixed-effects modeling software (NONMEM® Version VI). The final model was assessed using visual predictive checks and nonparameter stratified bootstrapping. A two-compartment PK model with two sequential absorption processes and linear elimination was used to capture PK profiles of anakinra. A transduction-based feedback model incorporating logistic growth rate captured disease progression and indirect response model I captured drug effects. The PK and paw swelling versus time profiles in CIA rats were fitted well. Anakinra has modest effects (Imax = 0.28) on paw edema in CIA rats. The profiles are well-described by our PK/PD/DIS model which provides a basis for future mechanism-based assessment of anakinra dynamics in rheumatoid arthritis.

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

“…Estimates of most DIS-related parameters, such as t onset and k grow , were close to the previously reported values. However, the baseline rat paw volume ( Paw 0 ) in our current study (55.4 mm 2 ) was slightly lower than those in the etanercept (~62.6 mm 2 ) [13] and anakinra (57.1 mm 2 ) studies [14]. This reflects batch-to-batch differences in the rats and emphasized the importance of considering inter-individual variability in our modeling analysis.…”

“…Therefore, such dosing groups were added to our subsequent studies with anakinra [14], methotrexate (MTX) [41], and abatacept. The doses selected in our studies were based on previous findings that showed successful use of the drug in similar animal models [39,42,43].…”

“…The other was a transduction-based feedback model that contained a series of transit compartments which contributed both to the production and the natural edema remission. This model functioned well for characterizing the effects of anakinra in CIA rats [14]. The temporal changes of paw sizes for the three abatacept dosing groups were fitted simultaneously.…”

“…We have also investigated the PK / PD / DIS relationships of therapeutic proteins (etanercept and anakinra) using CIA rats [13,14]. The current study was enacted to seek better understanding of the pharmacology of abatacept with quantitative assessment of its PK / PD properties.…”

Modeling, Simulation, and Translation Framework for the Preclinical Development of Monoclonal Antibodies

“…This type of model can be seen in Liu et al (25) who developed a combined PKPD and disease progression model to evaluate the effect of anakinra in collagen-induced arthritic rats and to explore the effect of interleukin-1β in rheumatoid arthritis. Having a combined PKPD and disease progression model in a validated AMD may be an ideal situation as it allows for an integrated understanding of exposure, response, and disease progression in a single system and reduces uncertainty and variability in the translation.…”