PubMed · 13914533
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D H SMYTH. 1961. Intestinal absorption.. https://pubmed.ncbi.nlm.nih.gov/13914533/
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We have assessed two commercial software tools employing physiologically based models for prediction of intestinal absorption in human. IDEA 2.0 and GASTROPLUS 3.1.0 were compared both in their ability to predict fraction absorbed for a set of 28 drugs and in terms of the functionality offered. The emphasis was placed on the practical usefulness to pharmaceutical drug discovery. Predictions were assessed for three levels of input data (i) pure in silico input, (ii) thermodynamic solubility and in silico permeability, (iii) thermodynamic solubility and human colon carcinoma cell line (CACO-2) permeability. We found the pure in silico prediction ability of the tools to be comparable with 70% correct classification rate. With measured input data the IDEA prediction rate improved to 79% while GASTROPLUS stayed at 70%. In terms of functionality GASTROPLUS is a powerful system for the trained user. Open access to model parameters, diagnostic tools and the ability to integrate data make it particularly suitable for the later stages of discovery and development. IDEA is web based and presents a simple interface suitable for widespread use with minimal training. However the limited functionality and inconvenient handling of multiple compound batches currently restrict the usefulness of version 2.0 for drug discovery.
The requirement to assess "rate" in bioequivalence tests using indirect metrics reinforces ambiguities as to whether such testing is intended to assure both pharmaceutical quality with respect to drug release characteristics as well as clinical safety and efficacy. Using a one-compartment open pharmacokinetic model with first-order absorption and error-free data, the effects of systematically changing the ratio of the absorption rate constants of test and reference formulations on various indirect metrics of rate of drug absorption [maximum plasma concentration (Cmax), time to reach Cmax (tmax), mean residence time (MRT), partial area under the plasma concentration-time curve (AUC(t))] were evaluated as a function of the ratio of absorption rate constant to elimination rate constant. This simple simulation illustrates the pitfall of judging the performance of different indirect rate metrics on the basis of a fixed universal acceptance interval for bioequivalence. However, turning the issue on its head, since rate, as indicated by a rate constant, cannot be assessed accurately using indirect metrics and may have little clinical relevance, regulatory guidelines should emphasize the use of Cmax and other measures taken from the plasma drug concentration-time curve as empirical indices of safety and efficacy. The acceptance limits should then depend on clinical criteria and the variability of the reference formulation.
A noncompartmental approach for determination of the apparent zero-order absorption rate constant (k0) has been developed. The procedure evolves from the convolution integral and requires individual oral-dose plasma concentrations values and calculation of area intervals under the plasma concentration-time curves after intravenous administration. The proposed method was evaluated and compared with the Wagner-Nelson, Loo-Riegelman, deconvolution, nonlinear regression, and moment methods using errorless and errant simulation data from one- or two-compartment models. The area function method is generally equal to the best of these techniques (nonlinear regression) and superior to the weaker methods (moment, deconvolution, Loo-Riegelman), especially for errant two-compartment data. Coupled with a companion procedure for constructing fraction absorbed versus time plots and assessing first-order absorption rate constants, the area function methods offer direct and accurate means of discerning drug absorption kinetics without the need for assignment of a disposition model for drugs with linear elimination kinetics.