title: 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 (I ( max ) = 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.
authors: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14260, USA.
authors: Dongyang
authors: D
authors: Liu
authors: Hoi-Kei
authors: HK
authors: Lon
authors: Debra C
authors: DC
authors: Dubois
authors: Richard R
authors: RR
authors: Almon
authors: William J
authors: WJ
authors: Jusko
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000097:blood / Q000188:drug therapy*; D001835:Body Weight / Q000187:drug effects; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical / Q000706:statistics & numerical data*; D004487:Edema / Q000188:drug therapy; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein