Elimination nonlinear

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-... 

Dose-dependent clearance and distribution was then later observed in a Phase 1 study in children with solid tumors (Sonnichsen et al., 1994). In a study in adults with ovarian cancer, Gianni et al. (1995) used a 3-compartment model with saturable intercompart-mental clearance into Compartment 2 and saturable, Michaelis-Menten elimination kinetics from the central compartment to describe the kinetics after 3 hour and 24 hour infusion. Now at this point one would typically assume that the mechanism for nonlinear elimination from the central compartment is either saturable protein binding or saturable metabolism. But the story is not that simple. Sparreboom et al. (1996a) speculated that since Cremophor EL is known to form micelles in aqueous solution, even many hours after dilution below the critical micellular concentration, and can modulate P-glycoprotein efflux, that the nonlinearity in pharmacokinetics was not due to paclitaxel, but due to the vehicle, Cremophor EL. This hypothesis was later confirmed in a study in mice (Sparreboom et al., 1996b). 

Phenytoin The oral bioavailability of phenytoin is variable because of differences in first-j>ass metabolism. Phenytoin metabolism is nonlinear elimination kinetics shift from first-order to zero-order at moderate to high dose levels. The drug binds extensively to plasma proteins (97-98%), and free (unbound) phenytoin levels in plasma are increased transiently by drugs that compete for binding (eg, sulfonamides, valproic acid). The metabolism of phen)Toin is enhanced in the presence of inducers of liver metabolism (eg, phenobarbital, rifampin) and inhibited by other drugs (eg, cimetidine, isoniazid). Fos-phenytoin is a water-soluble prodrug form of phen)Toin that is used parenterally. 

Anticonvulsant used for tonic-clonic and partial seizures blocks Na" channels in neuronal membranes. Serum levels variable due to first-pass metabolism and nonlinear elimination kinetics. Tox sedation, diplopia, gingival hyperplasia, hirsutism, teratogenic potential. Drug interactions via effects on plasma protein binding or induction of hepatic metabolism. 

As the clearance of rhG-CSF is known to decrease with a rise in dose and is known to be saturable, the average clearance after i.v. administration will be lower than that after s.c. administration. Therefore, the apparent absolute bioavailability with subcutaneous administration calculated from the AUC ratio is expected to be a conservative estimate. In a second study by Flayashi et al., the estimation of rhG-CSF absorption kinetics after s.c. administration with a nonlinear elimination pharmacokinetic model using a modified Wagner-Nelson method was studied... 

Hayashi N, Aso H, Higashida M, et al. (2001). Estimation of rhG-CSF absorption kinetics after subcutaneous administration using a modified Wagner-Nelson method with a nonlinear elimination model. Eur. J. Pharmaceu. Sci. 13 151-158. 

M-CSF, for example, undergoes besides linear renal elimination a nonlinear elimination pathway that follows Michaelis-Menten kinetics and is linked to a receptor-mediated uptake into macrophages. At low concentrations, M-CSF follows linear pharmacokinetics, while at high concentrations, nonrenal elimination pathways are saturated, resulting in nonlinear pharmacokinetic behavior (Fig. 3) [45, 46]. Other examples for receptor-mediated elimination are insulin, t-PA, epidermal growth factor (EGF), ANP, and interleukin-10 [19, 28, 38,44,47]. 

The average clearance Cl and resulting half-life values t,/2 for theophylline in various subpopulations and disease states are summarized in Table 10.3. Although the metabolism of theophylline appears to proceed as a first-order process, single metabolism pathways may already reach saturation within therapeutic concentrations, resulting in nonlinear elimination. Thus, increases in theophylline dose may result in disproportionally larger increases in serum concentrations. " " ... 

Accordingly, the rate of input lit) is obtained from the following equation, which considers both linear and nonlinear elimination ... 

In contrast to other modeling approaches, the disposition decomposition technique enables the elimination kinetics to be isolated and determined nonparametrically without the need for a specific structured modeling of the distribution kinetics. Such objective determination of the nonlinear elimination kinetics is of significant value in the areas of nonlinear drug level predictions and absorption evaluations. Moreover, the nonparametric determination provides a useful visualization of the nonlinear elimination kinetics that may be quite helpful in determining the mechanism of the elimination process. 

CYP2C9 inhibitors, such as amiodarone, azole antifungal drugs and fluvoxamine may inhibit the metabolism of phenytoin. This may cause a particularly dangerous increase in phenytoin steady-state concentrations because of the nonlinear elimination kinetics of this drug. 

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