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Oral absorption
Oral delivery is the preferred route of administration for the majority of drugs. Therefore, in the preclinical phase of development, a key consideration for many new chemical entities is their rate and extent of intestinal absorption. In turn, these features depend upon the physicochemical properties of the drug itself, the dosage form, and the physiological characteristics of the patient.
Advanced Dissolution, Absorption and Metabolism (ADAM)
ADAM is a mechanistic physiologically-based model within the Simcyp Population-based ADME Simulator that predicts variability in human oral drug bioavailability from physiochemical and in vitro data.
Drug particles, dissolved drug and water (or other dissolution medium) are considered to flow through a series of nine gut segments from the stomach to the colon (Figure 1).
In the gastric segment, dissolution and chemical break down of drug are considered.
The small intestine is divided into 7 sub-segments each having the same transit time. Within each compartment drug can:
- dissolve, re-precipitate or chemically degrade (according to pH)
- be absorbed (if in solution)
- be metabolised within enterocytes
- if not absorbed, pass on to subsequent segment (in both solid and dissolved form)
The colon segment can also be selected for the evaluation of further factors affecting drug absorption.
Figure 1 The Simcyp ADAM mechanistic absorption model.
The ADAM model incorporates physiological factors which affect absorption including gastric emptying time, intestinal and colonic transit times, GI tract surface area, regio-specific gut wall permeability, enterocytic blood flow and regio-specific luminal pH. The effects of food on oral absorption are also accommodated.
An example simulation illustrating the effects of variability in permeability and intestinal transit time on the extent (fa) and rate (ka) of drug absorption is shown in Figure 2.
Metabolism by gut wall enzymes and active transport can also affect bioavailability. The ADAM model incorporates the distribution and interplay of cytochrome P450 enzymes and saturable efflux transport (P-gp) in the GI tract.
Figure 2. Effects of variability in effective permeability (P eff ) and intestinal transit time (T si) on the fraction of drug absorbed into enterocytes (fa) (Jamei et al., 2004).
Within the Simcyp simulator, P eff can be entered either as a measured value or predicted using data from in vitro experiments (with Caco-2, PAMPA or MDCK cells) or physicochemical properties (polar surface area and the number of hydrogen bond donors).
Dosage form and dissolution
Capsules or tablets must disintegrate and a drug must dissolve from particles before drug absorption can occur. The ADAM model simulates these processes following administration of diverse solid dosage forms (immediate release, enteric-coated and controlled/modified release formulations) with or without pH triggering mechanisms. Dissolution rate is predicted using the Wang-Flanagan model, accounting for luminal fluid volumes and dynamics, and regio-specific solubility.
