Pharmacokinetics population kinetics

Pharmacokinetic/pharmacodynamic model using nonlinear, mixed-effects model in two compartment, best described time course of concentration strong correlation with creatinine clearance predicted concentration at the efi ect site and in reduction of heart rate during atrial fibrillation using population kinetic approach... 

There have been attempts to study the pharmacokinetics of macromolecules by applying the sparse sampling strategy and population kinetic methods described in Chapter 10 (36, 77). In one study, erythropoietin was administered SC to 48 healthy adult male... 

P. Veng-Pedersen, S. Chapel, N. H. Al-Huniti, R. L. Schmidt, E. M. Sedars, R. J. Hohl, and J. A. Widness, Pharmacokinetic tracer kinetics analysis of changes in erythropoietin receptor population in phlebotomy-induced anemia and bone marrow ablation. Biopharm Drug Dispos 25(4) 149-156 (2003). 

Metabolism and pharmacokinetic studies have greater relevance when conducted in both sexes of young adult animals of the same species and strain used for other toxicity tests with the test substance. The number of animals used in metabolism and pharmacokinetic studies would be sufficient to reliably estimate population variability. This usually means a separate (but parallel) set of groups of animals in rodent studies. A single set of intravenous and oral dosing results from adult animals, when combined with some in vitro kinetic results, may provide an adequate data set for the design and interpretation of short-term, subchronic and chronic toxicity studies. 

Renwick (1991, 1993) analyzed interindividual differences of healthy volunteers by comparing the maximum and mean values of pharmacokinetic parameters (7 substances) and pharmacodynamic parameters (6 substances). The data indicated that toxicokinetic differences were slightly greater than toxicodynamic differences. With one exception, the ratios between the maximum and mean value for a substance s kinetic parameter ranged from 1.8 to 4.2 with most values between 3 and 4, and it was concluded that a factor of 3-4 would be sufficient to consider toxicokinetic differences for 99% of the healthy, adult population and for 80% of the substances. The ratios between the maximum and mean value for a substance s dynamic parameter ranged from 1.5 to 6.9 with most values between 1.7 and 2.7. Based on the analyses, Renwick proposed to subdivide the interindividual factor of 10 into a factor of 4 for pharmacokinetic differences and a factor of 2.5 for pharmacodynamic differences. The aim of the subdivision of the 10-fold factor was to allow the incorporation of suitable compound-specific data for one particular aspect of uncertainty. 

WeU accepted Provides rich and high quahty data Can establish a causal link between altered pharmacokinetics and the variable of interest Early results from specific studies enable expansion of patient population in Phase 3 studies not usually difficult to perform Relatively straightforward and simple data analysis Not usually useful for screening Frequent sampling is very difficult in patients in large clinical trials or in children Relationship between altered pharmacokinetics and clinical response may not be established Study sample usually does not represent the target population Small sample may fail to elicit extremes of altered kinetics... 

Pharmacokinetics in specific populations to demonstrate the effect of age and disease on kinetics, for example, young, elderly, patients with renal failure, liver disease, cardiac failure... 

The structural submodel describes the central tendency of the time course of the antibody concentrations as a function of the estimated typical pharmacokinetic parameters and independent variables such as the dosing regimen and time. As described in Section 3.9.3, mAbs exhibit several parallel elimination pathways. A population structural submodel to mechanistically cover these aspects is depicted schematically in Fig. 3.14. The principal element in this more sophisticated model is the incorporation of a second elimination pathway as a nonlinear process (Michaelis-Menten kinetics) into the structural model with the additional parameters Vmax, the maximum elimination rate, and km, the concentration at which the elimination rate is 50% of the maximum value. The addition of this second nonlinear elimination process from the peripheral compartment to the linear clearance process usually significantly improves the fit of the model to the data. Total clearance is the sum of both clearance parts. The dependence of total clearance on mAb concentrations is illustrated in Fig. 3.15, using population estimates of the linear (CLl) and nonlinear clearance (CLnl) components. At low concentra-... 

V. V. Estimation of population characteristics of pharmacokinetic parameters from routine clinical data. J Pharmaco-kinet Biopharm 1977, 5 445—479. 

Nonlinear mixed-effects modeling methods as applied to pharmacokinetic-dynamic data are operational tools able to perform population analyses [461]. In the basic formulation of the model, it is recognized that the overall variability in the measured response in a sample of individuals, which cannot be explained by the pharmacokinetic-dynamic model, reflects both interindividual dispersion in kinetics and residual variation, the latter including intraindividual variability and measurement error. The observed response of an individual within the framework of a population nonlinear mixed-effects regression model can be described as... 

Potency/biological activity Pharmacokinetic profile Absorption time from tissue vs. IV Circulating half-life Distribution and elimination kinetics Toxicological profile Immunogenic potential Patient population characteristics Disease state Pathophysiology Age... 

Population pharmacokinetic parameters quantify population mean kineticS/ between-subject variability (intersubject variability)/ and residual variability. Residual variability includes within-subject variability/ model misspecification/ and measurement error. This information is necessary to design a dosage regimen for a drug. If all patients were identical/ the same dose would be appropriate for all. However/ since... 

Although population pharmacokinetic parameters have been estimated either by fitting all individuals data together as if there were no kinetic differences, or by fitting each individual s data separately and then combining the individual parameter estimates, these methods have certain theoretical problems that can only be aggravated when the deficiencies of typical clinical data are present. The nonlinear mixed-effect analysis avoids many of these deficiencies and... 

Sheiner, L.B. Beal, S.L. Evaluation of methods for estimating population pharmacokinetic parameters. I. Biexponential model and experimental pharmacokinetic data. J. Pharmaco-kinet. Biopharm. 1981, 9 (5), 635-651. 

Collart, L. Blaschke, T.H. Bouch, F. Prober, C.G. Potential of population pharmacokinetics to reduce the frequency of blood required for estimating kinetic parameters in neonates. Dev. Pharmacol. Ther. 1992, 18 (1-2), 71-80. 

Sheiner, L.B. Beal, S.L. Estimation of pooled pharmacokinetic parameters describing populations. In Kinetic Data Analysis Endrenyi, L., Ed. Plenum Press, Newyork, 1981 271-284. 

Lin et al. (submitted) examined the pharmacokinetics of imi-pramine and desipramine in 28 African Americans, 33 Asians, 28 Caucasians, and 30 Mexican Americans. The only significant differences in kinetic parameters were noted in the black cohort. African Americans displayed larger areas under the curve for and had higher maximum concentrations of desipramine. This study is concordant with that by Gaviria et al. (1986) in that no significant differences between Caucasian and Mexican American subjects were demonstrated. The increased area under the curve and maximum concentration in the African American group coincide with the slower metabolism seen with populations genetically similar to African blacks and with other reports of slow metabolism in African Americans (Strickland et al. 1991). 

L. B. Sheiner and S. L. Beal, Estimation of pooled pharmacokinetic parameters describing populations, in Kinetic Data Analysis, L. Endrenyi (Ed.). Plenum Press, New York, 1981, pp. 271-284. 

Initial doses of vancomycin can be computed for adult patients using estimated kinetic parameters derived from population pharmacokinetic data. Clearance is estimated using the patient s creatinine clearance in the following equation" Cl (in mL/min/kg) = 0.695(CrCl in mL/min/kg) -L 0.05. The volume of distribution is computed assuming the standard value of 0.7 L/kg = 0.7(Wt),... 

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