Physiologically Based Pharmacokinetics of Dexamethasone in Rats.

Blood and multitissue concentration-time profiles for dexamethasone (DEX), a synthetic corticosteroid, were measured in male rats after subcutaneous bolus and infusion dosing. A physiologically based pharmacokinetics (PBPK) model was applied for 12 measured tissues. Tissue partition coefficients (K p ) and metabolic clearance were assessed from infusion studies. Blood cell to plasma partitioning (0.664) and plasma free fraction (0.175) for DEX were found to be moderate. DEX was extensively partitioned into liver (K p = 6.76), whereas the calculated K p values of most tissues ranged between 0.1 and 1.5. Despite the moderate lipophilicity of DEX (log P = 1.8), adipose exhibited very limited distribution (K p = 0.17). Presumably due to P-glycoprotein-mediated efflux, DEX concentrations were very low in brain compared with its expected high permeability. Infusion studies yielded K p values from male and female rats at steady state that were similar. In silico K p values calculated for different tissues by using GastroPlus software were similar to in vivo values except for adipose and liver. Glucocorticoid receptors are found in diverse tissues, and these PBPK modeling results may help provide exposure profiles driving pharmacodynamic effects of DEX. SIGNIFICANCE STATEMENT: Our physiologically based pharmacokinetics model describes the experimentally determined tissue and plasma dexamethasone (DEX) pharmacokinetics (PK) profiles in rats reasonably well. This model can serve for further investigation of DEX tissue distribution in rats as the PK driving force for PD effects in different tissues. No major sex differences were found for DEX tissue distribution. Knowledge gained in this study may be translatable to higher-order species including humans.

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

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-1ß (IL-1ß) 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.