Absorption zero-order

For a typical drug with zero-order absorption, the concentrations after oral administration rise to a sharp peak and then quickly decline with no intermediate plateau. Examples of insoluble drugs whose absorption processes follow zero-order kinetics are cyclosporine (Grevel et al., 1986) and griseofulvin (Bates and Carrigan, 1975). 

Simultaneous Lrst- (with and without lag time) and zero-order absorption... 

Expressions similar to Equation (8.30) may be obtained for drugs that do not exhibit first order absorption and elimination characteristics by substituting the appropriate kinetic relationships in Equation (8.29). For example, for a drug that exhibits zero order absorption and first order elimination kinetics, Equation (8.29) becomes ... 

The mismatch of surpassing 100% absorption of the active metabolite is probably due to method constraints in combination with the immediate release data, as the deconvolution method requires data from a formulation with zero order absorption for the impulse function, e.g. an oral solution (oral bolus input) the immediate release formulation only provides an approximation to the required properties. 

Zero-order absorption processes apply to iron, to depot i.m. formulations and to drug implants, e.g. antipsychotics and sex hormones. 

The derivative spectrophotometry methods provide higher selectivity and higher sensitivity than do the methods based on normal (zero-order) absorption spectra. The increase in selectivity (with reduction or elimination of the effect of the spectrum of one substance on the spectrum of another one) results from reducing the band-width in the derivative spectra. An appropriate order of derivative spectrum may give complete separation of the spectra owing to the corresponding components of the system). 

Fig. 2.2. Zero-order absorption spectra (a) and their derivatives 1st order (b), 2nd order (c), 3rd order (d), and 4th order (e). Broken lines - substance 1 and substance 2 continuous line - mixture of substances 1 and 2.

The typical absorption profiles are represented by the first-order absorption and the zero-order absorption. Atypical absorption profiles can be described by parallel first-order absorption, mixed first-order and zero order absorption, or Weibull-type absorption. 

The plasma drug profiles in 50 subjects, following oral administration of the drug X and assuming a zero-order absorption process, are plotted in Figure 13.3. Corresponding NONMEM control file and data set are in Appendix 13.2. 

FIGURE 133 Plot of simulated plasma concentrations of drug X in 50 subjects, following a single oral dose, assuming a zero-order absorption type. Normal left panel) and semilog right panel) scale. Thick line represents population predictions for a typical subject. 

Example 4 Mixture of First-Order Absorption and Zero-Order Absorption Models... 

Sometimes, two first-order absorption processes do not adequately describe the data and the absorption profiles are better described by a combination of first-order and zero-order processes (40, 56-59). Lag time may be added for each type of absorption, which then will determine whether the two processes are simultaneous or sequential. Moreover, if the first-order rate constant is finked to the zero-order input parameters, the model can be interpreted as the consequence of dissolution-limited absorption. The ordering of the processes (first-order absorption first, or zero-order absorption first) is usually empirical or data driven. Pathophysiology and/or physicochemical characteristics of the compound may help in deciding the order. 

APPENDIX 13.2 ZERO-ORDER ABSORPTION NONMEM Input... 

PROB Zero-Order Absorption INPUT ID TIME DV AMT CMT RATE EVID MDV DATA EX2 DATA.csv IGNORE= ... 

APPENDIX 13.4 MIXTURE OF FIRST-ORDER AND ZERO-ORDER ABSORPTION... 

Wade et al. (1993) simulated concentration data for 100 subjects under a one-compartment steady-state model using either first-or zero-order absorption. Simulated data were then fit using FO-approximation with a first-order absorption model having ka fixed to 0.25-, 0.5-, 1-, 2-, 3-, and 4 times the true ka value. Whatever value ka was fixed equal to, clearance was consistently biased, but was relatively robust with underpredictions of the true value by less than 5% on average. In contrast, volume of distribution was very sensitive to absorption misspecification, but only when there were samples collected in the absorption phase. When there were no concentration data in the absorption phase, significant parameter bias was not observed for any parameter. The variance components were far more sensitive to model misspecification than the parameter estimates with some... 

Perfusion versus Permeation Transport Infusion (Zero-Order Absorption)... 

The second type of absorption model that is commonly applied is zero-order absorption. Zero-order refers to the case where the absorption rate is... 

First-order absorption is the final approach that will be considered. Analogous to the zero-order absorption case, first-order absorption refers to the fact that the absorption rate (r fo) is taken to be proportional to the amount of drug remaining to be absorbed Aran) raised to the first power (or power of one), giving... 

Figure 10.11 Graphical representation of a steady or zero-order absorption rate.

ONE-COMPARTMENT IV INFUSION (ZERO-ORDER ABSORPTION) MODEL... 

Zero-order absorption occurs when drug enters the systemic circulation at a constant rate. An IV infusion, in which a drug solution is delivered directly into the systemic circulation at a steady flow rate, represents an idealized zero-order absorption case. Because of this, standard zero-order absorption models are typically called IV infusion models and are designed specifically for the IV infusion case. This particular section deals with the one-compartment IV infusion model, so as in the previous one-compartment bolus IV model, the body is modeled as a single compartment with the implication that the distribution process is essentially instantaneous. As with the other standard models, the exact meaning of the assumptions inherent in this model are described next. Model equations then are introduced that allow the prediction of plasma concentrations for drugs with known PK parameters, or the estimation of PK parameters from measured plasma concentrations. Modification of the one-compartment IV infusion (zero-order absorption) model to approximate other types of steady drug delivery are described in Section 10.8.5. 

The standard one-compartment IV infusion (or zero-order absorption) model makes three inherent assumptions about the ADME processes that occur during and after drug delivery ... 

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