Is the One-Compartment Model with First Order Absorption a Useful Approximation?

PURPOSE

The one-compartment model with first order absorption (ka1C) has been extensively used to fit oral data. But when the disposition parameters of the drug are not available, the bias in the parameter estimates remains unclear. In this paper, the effect of potential misspecification of the area under the curve (AUC) and the mean absorption time (MAT) was evaluated for three relatively slowly absorbed drugs/formulations.

METHODS

Assuming a three-compartment disposition model with an input (absorption) rate described as a sum of two inverse Gaussian functions (2IG3C) as the true model, the deviations of AUC and MAT estimated with simpler models were analyzed. Simpler models, as the ka1C model (Bateman function), the one-compartment model with IG input function (IG1C) and the gamma density function were fitted to the oral data alone, and compared to the fits obtained with the 2IG3C model which also uses the 3C disposition parameters of the drug. Data from pharmacokinetic studies of trospium, propiverine and ketamine in healthy volunteers were analyzed using a population approach.

RESULTS

The Bateman function (ka1C) allowed a robust estimation of the population mean AUC, but the individual estimates were highly biased. It failed in evaluating MAT. The simple alternative models did not improve the situation.

CONCLUSIONS

The Bateman function appears to be useful for estimating the population mean value of AUC after oral administration. The results reemphasize the fact that insight into the absorption process can be only gained when also intravenous reference data are available.