Are Physiologically-based Pharmacokinetic Models Reporting the Right Cmax? Central Venous Versus Peripheral Sampling Site

Physiologically based pharmacokinetic (PBPK) models can over-predict maximum plasma concentrations (Cmax) following intravenous administration. A proposed explanation is that invariably PBPK models report the concentration in the central venous compartment, rather than the site where the samples are drawn. The purpose of this study was to identify and validate potential corrective models based on anatomy and physiology governing the blood supply at the site of sampling and incorporate them into a PBPK platform. Four models were … Continued

Modeling and Simulation to Support Phase 2 Dose Selection for RG7652, a Fully Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9

RG7652 is a fully humanized monoclonal antibody targeting human PCSK9, a regulator of serum low density lipoprotein cholesterol (LDLc) levels. RG7652 prevents degradation of the hepatic LDLc receptors by blocking PCSK9 binding and thereby resulting in efficient LDLc uptake by hepatocytes. The pharmacokinetics of RG7652 have been evaluated in healthy subjects after single and multiple … Continued

Mechanistic Models Describing Active Renal Reabsorption and Secretion: A Simulation-based Study

The objective of the present study was to evaluate mechanistic pharmacokinetic models describing active renal secretion and reabsorption over a range of Michaelis-Menten parameter estimates and doses. Plasma concentration and urinary excretion profiles were simulated and renal clearance (CLr) was calculated for two pharmacokinetic models describing active renal reabsorption (R1/R2), two models describing active secretion (S1/S2), and a model containing both processes. A range of doses (1-1,000 mg/kg) was evaluated, and Vmax and Km parameter estimates were varied over a … Continued

Study Reanalysis Using a Mechanism-based Pharmacokinetic/Pharmacodynamic Model of Pramlintide in Subjects with Type 1 Diabetes

This report describes a pharmacokinetic/pharmacodynamic model for pramlintide, an amylinomimetic, in type 1 diabetes mellitus (T1DM). Plasma glucose and drug concentrations were obtained following bolus and 2-h intravenous infusions of pramlintide at three dose levels or placebo in 25 T1DM subjects during the postprandial period in a crossover study. The original clinical data were reanalyzed … Continued

Simulation of Monoclonal Antibody Pharmacokinetics in Humans Using a Minimal Physiologically-based Model

Compared to small chemical molecules, antibodies and Fc-containing derivatives (mAbs) have unique pharmacokinetic behavior characterized by relatively poor cellular permeability, minimal renal filtration, binding to FcRn, target-mediated drug disposition, and disposition via lymph. A minimal physiologically based pharmacokinetic (PBPK) model to describe the pharmacokinetics of mAbs in humans was developed. Within the model, the body is divided into three physiological compartments; plasma, a single tissue compartment and lymph. The … Continued

Changes in Individual Drug-independent System Parameters during Virtual Pediatric Pharmacokinetic Trials: Introducing Time-varying Physiology into a Pediatric PBPK Model

Although both POPPK and physiologically based pharmacokinetic (PBPK) models can account for age and other covariates within a pediatric population, they generally do not account for real-time growth and maturation of the individuals through the time course of drug exposure; this may be significant in prolonged neonatal studies. The major objective of this study was to introduce … Continued

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