Pharmacokinetic and Pharmacodynamic Modeling

Pegfilgrastim plasma concentrations were modeled using a two-compartment model with a delayed, first-order absorption process. The clearance of pegfilgrastim was described by parallel linear and neutrophil-mediated clearance pathways  

The neutrophil-mediated clearance was expressed as a Michaelis-Menten function, because G-CSF receptor binding is subject to saturation. The product of kcat and the ratio of ANC and ANC at baseline is the maximum velocity of drug elimination from this pathway, km is the Michaelis constant, and C is the pegfilgrastim concentration. CL2 denotes the linear clearance pathway. 

This PK/PD model was fit to the individual and naive-averaged PK profiles from monkeys. The km for the nonlinear pathway was 5.3 ng/mL for cynomolgus 

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Rohatagi, S. A future in pharmacokinetic and pharmacodynamic modeling. Curr Drug Discov 2004,... 

Pharmacokinetics and Pharmacodynamics, Modelling, Simulation, and Data Analysis 335... 

Leung, W.W. and D.J. Paustenbach. 1995. Physiologically based pharmacokinetic and pharmacodynamic modeling in health risk assessment and characterization of hazardous substances. Toxicol. Lett. 79 55-65. 

Excerpted primarily from Yang, R.S.H., M.E. Andersen, J.E. Dennison, Y.C. Ou, K.H. Liao, and B. Reisfeld, 2004. Physiologically based pharmacokinetic and pharmacodynamic modeling. Pp. 391-405 in Mouse Models of Cancer. E.C. Holland, ed., Wiley New York. Reprinted with permission copyright 2004, Wiley. 

M.C. Wacholtz, N. Minton, and W.J. Jusko. 2004. Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after single and multiple doses in healthy volunteers. 

Holford, N.H. and L.B. Sheiner. 1981. Pharmacokinetic and pharmacodynamic modeling in vivo. Crit. Rev. Bioeng. 

Nestorov, I. A. Sensitivity analysis of pharmacokinetic and pharmacodynamic models in clinical trial simulation and design. In Kimko, H. C., Duffull, S. B eds. Simulation for designing clinical trials. A pharmacokinetic-pharmacodynamic modeling perspective. (Drugs and the pharmaceutical sciences, volume 127) Marcel Dekker, New York, 2003. 

In general, multiple (up to 30-40) blood samples can be obtained per subject to measure dmg and metabolite concentrations as well as biomarkers in these phase I clinical trials. Furthermore, pharmacodynamic measurements can be included to get a first impression on the drug effect in humans, however, limited by the fact that healthy volunteers were studied and not patients. As strict inclusion and exclusion criteria are used, the demographic characteristics of the healthy volunteers do not provide sufficient spread to investigate the effect of intrinsic factors. Therefore, phase I trials provide very rich data to develop pharmacokinetic and pharmacodynamic models on biomarker, but cannot be used to develop models for efficacy, safety, influence of patient factors on PK and/or PD and disease progression. 

Colburn WA (1981) Simultaneous pharmacokinetic and pharmacodynamic modeling. J Pharmacokin Biopharm 9 367 Dingemanse J, Van Bree JB, Danhof M (1989) Pharmacokinetic modeling of anticonvulsant reponse of Phenobarbital in rats. J Pharmacol Exp Ther 249 601-608 Hoffman A, Goldberg A (1994) The relationship between receptor-effector unit heterogeneity and the shape of the concentration-effect profile pharmacodynamic implications. J Pharmacokinet Biopharm 22 449-468... 

Frederick CB, Potter DW, Chang-Mateu MI, Andersen ME. 1992. A physiologically based pharmacokinetic and pharmacodynamic model to describe the oral dosing of rats with ethyl acrylate and its implications for risk assessment. Toxicol Appl Pharmacol 114 246-260. 

Reisfeld B, Mayeno AN, Lyons MA, Yang RSH. 2007. Physiologically-based pharmacokinetic and pharmacodynamic modeling, in computational toxicology. In Ekins S, editor, Risk assessment for pharmaceutical and environmental chemicals. Hoboken (NJ) John Wiley Sons, p 33-69. 

Timchalk C, Poet TS. 2008. Development of a physiologically based pharmacokinetic and pharmacodynamic model to determine dosimetry and cholinesterase inhibition for a binary mixture of chlorpyrifos and diazinon in the rat. Neurotoxicology 29 428 443. 

Gearhart, J. M., Jepson, G.W., Clewell, H.J., III, Andersen, M.E., Conolly, R.B. (1990). Physiologically based pharmacokinetic and pharmacodynamic model for the inhibition of acetylcholinesterase by diisopropylfluorophosphate. Toxicol. Appl. Pharmacol. 106 295-310. 

Le Coz F, Funck-Brentano C, Morell T, Ghadanfar MM, JaUlon P. Pharmacokinetic and pharmacodynamic modeling of the effects of oral and intravenous administrations of dofetilide on ventricular repolarization. Clin Pharmacol Ther 1995 57(5) 533-42. 

McDougal JN, Zheng Y, Zhang Q, Conolly R. Biologically based pharmacokinetic and pharmacodynamic models of skin. In Riviere JE, editor, Dermal absorption models in toxicology and pharmacology. New York Taylor and Francis, 2006. p. 89-112. 

The most common approach to in vivo pharmacokinetic and pharmacodynamic modeling involves sequential analysis of the concentration versus time and effect versus time data, such that the kinetic model provides an independent variable, such as concentration, driving the dynamics. Only in limited situations could it be anticipated that the effect influences the kinetics, for example effects on blood flow or drug clearance itself. 

As discussed earlier, high-affinity anti-drug antibodies produce effects on the pharmacokinetics and pharmacodynamics of drugs in animals and humans. For new therapeutic applications, these effects need to be fully tested in animals before administration to humans. In addition, from a basic science viewpoint, it will be necessary to develop relevant pharmacokinetic and pharmacodynamic models of... 

The relationships between antibody dose, antibody affinity (or catalytic antibody K,.j. and their effects on the drug s pharmacokinetics and pharmacodynamics are poorly understood. For instance, if the drug effect compartment is associated with the pharmacokinetic peripheral compartment, the time needed to reverse drug effects with antibodies would be predicted to be slower than if the effect compartment is associated with the pharmacokinetic central compartment. In addition, it appears that high-affmity antibodies block the metabolism and/or change the metabolic profile of drugs (Owens and Mayersohn 1986 Valentine et al. 1994). These are complex changes that need to be studied in detail, and pharmacokinetic and pharmacodynamic models of these effects need to be developed in animal models before use in humans. 

W. A. Colburn, Simultaneous pharmacokinetic and pharmacodynamic modeling. J Phar-macokinet Biopharm 9 367-388 (1981). 

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