Population pharmacokinetics time dependencies

Rostami-Hodjegan A, Wohf K, Hay AWM, Raistrick D, Calvert R Tucker GT (1999). Population pharmacokinetics in opiate users characterization of time dependent changes. British Journal of Clinical Pharmacology, 47, 974-86... 

Rostami-Hodjegan, A. et ah, Population pharmacokinetics of methadone in opiate users characterization of time-dependent changes, Br. J. Clin. Pharmacol., 48 43-52, 1999. 

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-... 

The rate at which any of the enantiomers is eliminated depends upon the urinary pH. At high pHs, excretion time is prolonged. At low pH ranges, excretion is accelerated. In controlled laboratory studies, where volunteer subjects were given either bicarbonate or ammonium chloride, the higher the urine pH, the more slowly the ephedrine and pseudoephedrine were excreted. Conversely, when the urine pH is low, excretion is accelerated (71). The importance of these observations is hard to assess, because without the addition of bicarbonate, urine pH values in the general population rarely approach 8.0. A study of pseudoephedrine pharmacokinetics in 33 volunteers who were not treated with drugs to alter urine pH found that these parameters could not be... 

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