Modelling of drug absorption as a transport-limited process
Jan Freijer, Teun Post, Bart Ploeger, Joost DeJongh, Meindert Danhof
LAP&P Consultants, Leiden, The Netherlands
Objectives: To explore the properties of an oral absorption model that considers the transport limitation between the sites of administration and absorption. The model is evaluated in the context of the mixed-effects approach.
Introduction:
Absorption of orally administered drugs from the GI tract is an important determinant of the onset of the drug effect. Not surprisingly, much emphasis is on modelling of the absorption process. Models of systemic drug absorption are frequently based on a direct or a delayed (lag time) first-order rate process. These models assume instantaneous presence of the drug in the absorption compartment and subsequently an exponential decrease of the absorption rate with time, thus implying an unrealistically sharp entrance front of the drug at the absorption site. In practice, the use of the first-order approach to predict plasma concentrations frequently yields a considerable mismatch between predicted and measured concentration profiles, particularly for the upswing of the plasma concentration after administration.Methods:
Weiss and co-workers [1] have proposed the Inverse Gaussian Density (IGD) input function as an alternative for the first-order absorption model to describe the absorption-time curve. Recent work [2-3] has shown that this type of absorption model can indeed adequately describe the upswing in the concentration-time curve when combined with compartmental pharmacokinetic (PK) models. Furthermore, from transport physics a mechanism is known that can explain the Inverse Gaussian shape of the absorption-time curve. The IGD absorption model was implemented in NONMEM to analyse the PK of two different drugs using data from various phase I trials.Results and conclusions:
The appealing aspect of the IGD input function is that it contains just two parameters (transport velocity and dispersion length). Additionally, the parameter values can be translated into the appearance of the plasma concentration curves after single dose administration. The two parameters in this model, transport velocity and dispersion length seem to be related to the characteristics of GI tract passage and chemical properties of the drugs studied. It is concluded that the IGD input function is an absorption model that possesses promising properties for evaluating and optimising transport-limited absorption processes.References
[1]Weiss, M (1996) A novel extravascular input function for the assessment of drug absorption in bioavailability studies. Pharmaceutical Research 13: 1547-1553.
[2]Higaki, K, Yamashita, S, Amidon, GL (2001). Time-dependent oral absorption models. Journal of Pharmacokinetics and Pharmacodynamics 28:109-128.
[3]Tatsunami, S, Sako, K, Kuwabara, R, Yamada, K (1998). Using Gaussian-like input rate function in the two-compartment model. Formulation and application to analysis of Didanosine plasma concentration in two Japanese hemophiliacs. Int.J.Clin.Pharm.Res. 18:129-135.