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Four basic models for characterizing indirect pharmacodynamic responses after drug administration have been developed and compared. The models are based on drug effects (inhibition or stimulation) on the factors controlling either the input or the dissipation of drug response. Pharmacokinetic parameters of methylprednisolone were used to generate plasma(More)
Corticosteroid (CS) pharmacogenomics was studied using gene microarrays in rat liver. Methylprednisolone (MPL) was administered intravenously at 50 mg/kg. Rats were sacrificed and liver excised at 17 time points over 72 h. RNAs from individual livers were used to query Affymetrix GeneChips that contain sequences for 8000 genes. Cluster analysis revealed six(More)
This study describes a pharmacokinetic (PK) model to account for serum recombinant human erythropoietin (rHuEpo) concentrations in healthy volunteers following intravenous (IV) and subcutaneous (SC) dosing; it also characterizes the pharmacodynamics (PD) of SC rHuEpo effects on reticulocytes, red blood cells (RBC), and hemoglobin (Hb) in blood. Data were(More)
FTY720 (2-amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) is a new sphingosine-1-phosphate receptor agonist being developed for multiple sclerosis and prevention of solid organ transplant rejection. A physiologically based pharmacokinetic model was developed to predict the concentration of FTY720 in various organs of the body. Single oral(More)
The most common approach to in vivo pharmacokinetic and pharmacodynamic modeling involves sequential analysis of the plasma concentration versus time and then response versus time data, such that the plasma kinetic model provides an independent function, driving the dynamics. However, response versus time data, even in the absence of measured drug(More)
The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEpo) were investigated in monkeys. A two-compartment model with dual input and nonlinear disposition could adequately characterize the PK of rHuEpo upon three intravenous and six s.c. administrations. The kinetic model suggests rapid zero-order absorption of part of(More)
Drugs that bind with high affinity and to a significant extent (relative to dose) to a pharmacologic target such as an enzyme, receptor, or transporter may exhibit nonlinear pharmacokinetic (PK) behavior. Processes such as receptor-mediated endocytosis may result in drug elimination. A general PK model for characterizing such behavior is described and(More)
Pharmacodynamics is the study of the time course of pharmacological effects of drugs. The field of pharmacodynamic modeling has made many advances, due in part to the relatively recent development of basic and extended mechanism-based models. The purpose of this article is to describe the classic as well as contemporary approaches, with an emphasis on(More)
Erythropoietin (EPO) has a highly conserved structure among mammals, and thus recombinant human EPO (rHuEPO) has biological activity in various species. This study explores the interspecies relationships of the pharmacokinetics (PK) and pharmacodynamics (PD) of rHuEPO. The PK parameters such as clearance (CL) and volume of distribution (V(ss)) after i.v.(More)
A mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) model was developed for recombinant human erythropoietin (rHuEPO) to account for receptor-mediated endocytosis via erythropoietin receptor (EPOR) as a primary mechanism for nonlinear disposition of rHuEPO as well as activation of erythropoietic stimulation. Time profiles of rHuEPO concentrations(More)