Nonlinear clearance

Studies interested in the determination of macro pharmacokinetic parameters, such as total body clearance or the apparent volume of distribution, can be readily calculated from polyexponential equations such as Eq. (9) without assignment of a specific model structure. Parameters (i.e., Ah Xt) associated with such an equation are initially estimated by the method of residuals followed by nonlinear least squares regression analyses [30],... 

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... 

Caffeine pharmacokinetics are nonlinear. For example, when comparing a 500 mg dose to a 250 mg dose, the clearance is reduced and elimination half-life is prolonged with the higher dose (Kaplan et al. 1997). Thus, larger doses prolong the action of the drug. Active metabolites of caffeine are paraxanthine, and to a lesser degree, theobromine, and theophylline. Urinary metabolites are I-methylxanthine, l-methyluric acid, and an acetylated uracil derivative. 

Pharmacokinetics Ticlopidine is rapidly absorbed (more than 80%), with peak plasma levels occurring at approximately 2 hours after dosing, and is extensively metabolized. Administration after meals results in a 20% increase in the area under the plasma concentration-time curve (AUC). Ticlopidine displays nonlinear pharmacokinetics and clearance decreases markedly on repeated dosing. Ticlopidine binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein at concentrations attained with the recommended dose, 15% or less in plasma is bound to this protein. 

Pharmacokinetics The pharmacokinetics of pegfilgrastim were studied in 379 patients with cancer. The pegylated version of filgrastim demonstrated nonlinear pharmacokinetics, and clearance decreased with increases in dose. Neutrophil receptor binding is an important component of pegfilgrastim clearance, and serum clearance is directly related to the number of neu-... 

Paroxetine at low concentration is dependent on CYP 2D6 for its clearance. However, this enzyme is almost completely saturated by paroxetine at low concentrations, which accounts for the nonlinear pharmacokinetics of paroxetine and why its half-life goes from 10 to 20 hours when the dose is advanced from 10 to 20 mg per day. At higher concentrations, paroxetine is most likely dependent on CYP 3A3/4 for its clearance. This dose-dependent change in the clearance of paroxetine probably accounts for the higher incidence of withdrawal reactions with this SSRI than might otherwise be expected for a drug with a half-life of 20 hours at steady-state on 20 mg per day (296, 297). 

For drugs that exhibit capacity-limited elimination (eg, phenytoin, ethanol), clearance will vary depending on the concentration of drug that is achieved (Table 3-1). Capacity-limited elimination is also known as saturable, dose- or concentration-dependent, nonlinear, and Michaelis-Menten elimination. 

Actisomide was included in a set of drugs for computational predictions of human drug clearance using different allometry methods (08MI1, 09JPS2472) and for computational predictions of volume of distribution using linear and nonlinear models (09JMC4488). 

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-... 

Fig. 12.9 Nonlinear relationship between dose and antibody clearance following administration of single doses of trastuzumab in patients with HER2/overexpressing metastatic breast cancer. (Figure produced from data reported in [117]).

Dose-ranging PK and PD studies of pegfilgrastim have been conducted in mice, rats, and monkeys. Similar to filgrastim, the PK of pegfilgrastim are nonlinear after SC administration the clearance of pegfilgrastim decreases with increasing... 

Modihcations of this model, including a nonlinear temperature prohle in the melt him, channel curvature effects, and an approximate method to account for the flight clearance effect, are presented by Tadmor and Klein (1), together with expressions for power calculations. Numerous other improvements of the melting model have been suggested in the literature (33,41 -6). A detailed discussion of these, however, is beyond the scope of this text. 

Phenytoin is an anticonvulsant that has been shown to be preferentially hydroxy-lated in the pro-(.S ) ring by CYP2C9 (77), which accounts for approximately 80% of its clearance in man (78). The use of phenytoin is complicated by virtue of its nonlinear kinetics, long half-life, and narrow therapeutic margin. However, it has been used to confirm the in vitro finding that phenytoin and tolbutamide are metabolized by the same P450 enzyme (79). 

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