Zero-order absorption models model parameter estimation

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... 

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. 

Standard linear regression and method of residual analyses of two-compartment IV infusion (zero-order absorption) data is limited to samples collected during the postinfusion period. Plasma concentrations during the infusion period do not lend themselves to a linear analysis for a two-compartment model. Estimation of parameters from measured postinfusion plasma samples is quite similar to the two-compartment bolus IV (instantaneous absorption) case. Proper parameter evaluation ideally requires at least three to five plasma samples be collected during the distribution phase, and five to seven samples be collected during the elimination phase. Area under the curve (AUC) calculations can also be used in evaluating some of the model parameters. 

The principal parameter used to indicate the rate of drug absorption is Cmax, even though it is also influenced by the extent of absorption the observed fmaX is less reliable. Because of the uncertainty associated with Cmax, it has been suggested (Endrenyi Yan, 1993 Tozer, 1994) that Cmax/AUCo-loq/ where AUCo-loq is the area under the curve from time zero to the LOQ of the acceptable analytical method, may more reliably measure the rate of drug absorption, except when multiexponential decline is extensive. Estimation of the terms should be based on the observed (measured) plasma concentrationtime data and the use of non-compartmental methods rather than compart-mental pharmacokinetic models. MRTs, from time zero to the LOQ of the analytical method, for the test and reference products can be compared, assuming that first-order absorption and disposition of the drug apply (Jackson Chen, 1987). 

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