Simulating Drug Absorption Using the Simcyp Simulator
The Simcyp® Simulator’s models allows simulation of absorption through oral, dermal, and pulmonary routes.
Oral delivery is the preferred route of administration for most 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.
The ADAM model incorporates physiological factors which affect absorption including gastric emptying time, intestinal and colonic transit times, enterohepatic recirculation, GI tract surface area, region-specific gut wall permeability, enterocytic blood flow and region-specific luminal pH. The effects of food on oral absorption are also accommodated.
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 (large tablets, 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. Precipitation of solutions can also be handled.
The Simcyp skin absorption model is based on a modified Shatkin & Brown model. It can be used for dosing of substrate and/or inhibitors. Permeability constants and diffusion and partition coefficients can be calculated using physicochemical data.
Skin is considered as a two compartment model with two distinct layers, the stratum corneum and the viable epidermis + dermis. The thickness and amount of fat in each skin layer and their related inter-individual variability values are also accounted for. The model also incorporates variability in local blood flow.
The Simcyp Simulator includes five dosing application sites for both male and female subjects.
The Simcyp Simulator uses a first order absorption model to describe absorption across the lung for any substrate and/or inhibitors. This model can be used with the full physiologically-based pharmacokinetics (PBPK) model as well as the one-compartment distribution model.
When determining the dosing scheme, the user assigns the proportion of the dose which is inhaled; the remaining dose is swallowed. The inhaled dose goes directly to the lungs where absorption is simulated. The proportion of the dose which is swallowed goes to the GI tract where oral absorption can be simulated using any of the Simcyp oral absorption models (first order, CAT and ADAM)
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