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1.  Modeling Pharmacokinetics/Pharmacodynamics of Abatacept and Disease Progression in Collagen-Induced Arthritic Rats - A Population Approach 
The PK / PD of abatacept, a selective T-cell co-stimulation modulator, was examined in rats with collagen-induced arthritis (CIA) using a nonlinear mixed effect modeling approach. Male Lewis rats underwent collagen induction to produce rheumatoid arthritis. Two single-dose groups received either 10 mg/kg intravenous (IV) or 20 mg/kg subcutaneous (SC) abatacept, and one multiple-dose group received one 20 mg/kg SC abatacept dose and four additional 10 mg/kg SC doses. Effects on disease progression (DIS) were measured by paw swelling. Plasma concentrations of abatacept were assayed by enzyme-linked immunosorbent assay (ELISA). The PK / PD data were sequentially fitted using NONMEM VI. Goodness-of-fit was assessed by objective functions and visual inspection of diagnostic plots. The PK of abatacept followed a two-compartment model with linear elimination. For SC doses, short-term zero-order absorption was assumed with F = 59.2 %. The disease progression component was an indirect response model with a time-dependent change in paw edema production rate constant (kin) that was inhibited by abatacept. Variation in the PK data could be explained by inter-individual variability in clearance (CL) and central compartment volume (V1), while the large variability of the PD data may be the result of paw edema production (kin0) and loss rate constant (kout). Abatacept has modest effects on paw swelling in CIA rats. The PK / PD profiles were well described by the proposed model and allowed evaluation of inter-individual variability on drug- and DIS-related parameters.
PMCID: PMC3947259  PMID: 24233383
Abatacept; arthritis; model; pharmacokinetics; pharmacodynamics; disease progression
2.  Fifth-Generation Model for Corticosteroid Pharmacodynamics: Application to Steady-State Receptor Down-Regulation and Enzyme Induction Patterns during Seven-Day Continuous Infusion of Methylprednisolone in Rats 
A fifth-generation model for receptor/gene-mediated corticosteroid effects was proposed based on results from a 50 mg/kg IV bolus dose of methylprednisolone (MPL) in male adrenalectomized rats, and confirmed using data from other acute dosage regimens. Steady-state equations for receptor down-regulation and tyrosine aminotransferase (TAT) enzyme induction patterns were derived. Five groups of male Wistar rats (n=5/group) were subcutaneously implanted with Alzet mini-pumps primed to release saline or 0.05, 0.1, 0.2, and 0.3 mg/kg/hr of MPL for 7 days. Rats were sacrificed at the end of the infusion. Plasma MPL concentrations, blood lymphocyte counts, and hepatic cytosolic free receptor density, receptor mRNA, TAT mRNA, and TAT enzyme levels were quantitated. The pronounced steroid effects were evidenced by marked losses in body weights and changes in organ weights. All four treatments caused a dose-dependent reduction in hepatic receptor levels, which correlated with the induction of TAT mRNA and TAT enzyme levels. The 7 day receptor mRNA and free receptor density correlated well with the model predicted steady-state levels. However, the extent of enzyme induction was markedly higher than that predicted by the model suggesting that the usual receptor/gene-mediated effects observed upon single/intermittent dosing of MPL may be countered by alterations in other aspects of the system. A mean IC50 of 6.1 ng/mL was estimated for the immunosuppressive effects of methylprednisolone on blood lymphocytes. The extent and duration of steroid exposure play a critical role in mediating steroid effects and advanced PK/PD models provide unique insights into controlling factors.
PMCID: PMC4207287  PMID: 12194533
pharmacodynamics; pharmacogenomics; methylprednisolone; tyrosine amino-transferase
3.  Assessing the Dynamics of Nuclear Glucocorticoid-Receptor Complex: Adding Flexibility to Gene Expression Modeling1 
A retrospective analysis was performed to modify our fourth-generation pharmacodynamic model for glucocorticoid receptor (GR) dynamics with incorporation of more physiological features. This modified model was developed by integrating previously reported free cytosolic GR and GR mRNA data following single (10, 50 mg/kg) and dual (50 mg/kg at 0 and 24 hr) intravenous doses of methylprednisolone (MPL) in adrenalectomized (ADX) male Wistar rats with several in vitro studies describing real-time kinetics of the transfer of rat steroid-receptor complex from the cell cytosol to the nucleus. Additionally, free hepatic cytosolic GR and its mRNA data from a chronic infusion dosing study of MPL (0.1 and 0.3 mg/kg/hr) in male ADX Wistar rats were used to verify the predictability of the model. Incorporation of information regarding in vitro receptor kinetics allowed us to describe the receptor-mediated pharmacogenomic effects of MPL for a larger variety of genes in rat liver from microarray studies. These included early responsive gene like CCAAT/enhancer binding protein-β (CEBP-β), a transcription factor, as well as the later responsive gene for tyrosine aminotransferase (TAT), a classical biomarker of glucocorticoid (GC) genomic effects. This more mechanistic model of GR dynamics can be applied to characterize profiles for a greater number of genes in liver.
PMCID: PMC4184272  PMID: 17285360
glucocorticoids; glucocorticoid receptor; nuclear localization; pharmacodynamics; methylprednisolone; pharmacogenomics
4.  Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids 
Receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase (TAT) were evaluated in normal rats. A group of normal male Wistar rats were injected with 50 mg/kg methylprednisolone (MPL) intramuscularly at the nadir of their plasma corticosterone (CST) rhythm (early light cycle) and sacrificed at various time points up to 96 h post-treatment. Blood and livers were collected to measure plasma MPL, CST, hepatic glucocorticoid receptor (GR) mRNA, cytosolic GR density, TAT mRNA, and TAT activity. The pharmacokinetics of MPL showed bi-exponential disposition with two first-order absorption components from the injection site and bioavailability was 21%. Plasma CST was reduced after MPL dosing, but resumed its daily circadian pattern within 36 h. Cytosolic receptor density was significantly suppressed (90%) and returned to baseline by 72 h resuming its biphasic pattern. Hepatic GR mRNA follows a circadian pattern which was disrupted by MPL and did not return during the study. MPL caused significant down-regulation (50%) in GR mRNA which was followed by a delayed rebound phase (60–70 h). Hepatic TAT mRNA and activity showed up-regulation as a consequence of MPL, and returned to their circadian baseline within 72 and 24 h of treatment. A mechanistic receptor/gene-mediated pharmacokinetic/pharmacodynamic model was able to satisfactorily describe the complex interplay of exogenous and endogenous corticosteroid effects on hepatic GR mRNA, cytosolic free GR, TAT mRNA, and TAT activity in normal rats.
PMCID: PMC4180077  PMID: 17593325
Methylprednisolone; Corticosteroids; Pharmacokinetics; Pharmacodynamics; Tyrosine aminotransferase; Glucocorticoid receptors
5.  Mechanism-based disease progression modeling of type 2 diabetes in Goto-Kakizaki rats 
The dynamics of aging and type 2 diabetes (T2D) disease progression were investigated in normal [Wistar-Kyoto (WKY)] and diabetic [Goto-Kakizaki (GK)] rats and a mechanistic disease progression model was developed for glucose, insulin, and glycosylated hemoglobin (HbA1c) changes over time. The study included 30 WKY and 30 GK rats. Plasma glucose and insulin, blood glucose and HbA1c concentrations and hematological measurements were taken at ages 4, 8, 12, 16 and 20 weeks. A mathematical model described the development of insulin resistance (IR) and β-cell function with age/growth and diabetes progression. The model utilized transit compartments and an indirect response model to quantitate biomarker changes over time. Glucose, insulin and HbA1c concentrations in WKY rats increased to a steady-state at 8 weeks due to developmental changes. Glucose concentrations at 4 weeks in GK rats were almost twice those of controls, and increased to a steady-state after 8 weeks. Insulin concentrations at 4 weeks in GK rats were similar to controls, and then hyperinsulinemia occurred until 12–16 weeks of age indicating IR. Subsequently, insulin concentrations in GK rats declined to slightly below WKY controls due to β-cell failure. HbA1c showed a delayed increase relative to glucose. Modeling of HbA1c was complicated by age-related changes in hematology in rats. The diabetes model quantitatively described the glucose/insulin inter-regulation and HbA1c production and reflected the underlying pathogenic factors of T2D—IR and β-cell dysfunction. The model could be extended to incorporate other biomarkers and effects of various anti-diabetic drugs.
PMCID: PMC3727409  PMID: 21127951
Type 2 diabetes; Disease progression modeling; Insulin resistance; β-cell function
6.  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-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.
PMCID: PMC3407879  PMID: 22002845
Anakinra; Pharmacokinetics; Pharmacodynamics; Rheumatoid arthritis; Population model
7.  Dynamic modeling of methylprednisolone effects on body weight and glucose regulation in rats 
Influences of methylprednisolone (MPL) and food consumption on body weight (BW), and the effects of MPL on glycemic control including food consumption and the dynamic interactions among glucose, insulin, and free fatty acids (FFA) were evaluated in normal male Wistar rats. Six groups of animals received either saline or MPL via subcutaneous infusions at the rate of 0.03, 0.1, 0.2, 0.3 and 0.4 mg/kg/h for different treatment periods. BW and food consumption were measured twice a week. Plasma concentrations of MPL and corticosterone (CST) were determined at animal sacrifice. Plasma glucose, insulin, and FFA were measured at various times after infusion. Plasma MPL concentrations were simulated by a two-compartment model and used as the driving force in the pharmacodynamic (PD) analysis. All data were modeled using ADAPT 5. The MPL treatments caused reduction of food consumption and body weights in all dosing groups. The steroid also caused changes in plasma glucose, insulin, and FFA concentrations. Hyper-insulinemia was achieved rapidly at the first sampling time of 6 h; significant elevations of FFA were observed in all drug treatment groups; whereas only modest increases in plasma glucose were observed in the low dosing groups (0.03 and 0.1 mg/kg/h). Body weight changes were modeled by dual actions of MPL: inhibition of food consumption and stimulation of weight loss, with food consumption accounting for the input of energy for body weight. Dynamic models of glucose and insulin feedback interactions were extended to capture the major metabolic effects of FFA: stimulation of insulin secretion and inhibition of insulin-stimulated glucose utilization. These models of body weight and glucose regulation adequately captured the experimental data and reflect significant physiological interactions among glucose, insulin, and FFA. These mechanism-based PD models provide further insights into the multi-factor control of this essential metabolic system.
PMCID: PMC3407886  PMID: 21394487
Glucocorticoids; Methylprednisolone; Pharmacodynamics; Food intake; Body weight; Glucose; Insulin; Free fatty acids

Results 1-7 (7)