PBPK modeling: What is the role of CYP3A4 expression in the gastrointestinal tract to accurately predict first-pass metabolism?

Gastrointestinal first-pass metabolism plays an important role in bioavailability and in drug-drug interactions. Physiologically-based pharmacokinetic (PBPK) modeling is a powerful tool to integrate these processes mechanistically. However, a correct bottom-up prediction of GI first-pass metabolism is challenging and depends on various model parameters like the level of enzyme expression and the basolateral intestinal mucosa permeability (P).

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Metabolism in Pregnant Subjects and Fetuses.

This study aimed to develop a physiologically based pharmacokinetic (PBPK) model that simulates metabolically cleared compounds' pharmacokinetics (PK) in pregnant subjects and fetuses. This model accounts for the differences in tissue sizes, blood flow rates, enzyme expression levels, plasma protein binding, and other physiological factors affecting the drugs' PK in both the pregnant woman and the fetus. The PBPKPlus™ module in GastroPlus was used to model the PK of metoprolol, midazolam, and metronidazole for both non-pregnant and pregnant groups.

Drug-drug interaction prediction of ziritaxestat using a physiologically based enzyme and transporter pharmacokinetic network interaction model.

Ziritaxestat, an autotaxin inhibitor, was under development for the treatment of idiopathic pulmonary fibrosis. It is a substrate of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein and a weak inhibitor of the CYP3A4 and OATP1B1 pathways. We developed a physiologically based pharmacokinetic (PBPK) network interaction model for ziritaxestat that incorporated its metabolic and transporter pathways, enabling prediction of its potential as a victim or perpetrator of drug-drug interactions (DDIs).

Small scale design of experiment investigation of equilibrium solubility in simulated fasted and fed intestinal fluid.

It is widely recognised that drug solubility within the gastrointestinal tract (GIT) differs from values determined in a simple aqueous buffer and to circumvent this problem measurement in biorelevant fluids is determined. Biorelevant fluids are complex mixtures of components (sodium taurocholate, lecithin, sodium phosphate, sodium chloride, pancreatin and sodium oleate) at various concentrations and pH levels to provide systems simulating fasted (FaSSIF) or fed (FeSSIF) intestinal media. Design of Experiment (DoE) studies have been applied to investigate FaSSIF and FeSSIF and indicate that a drug's equilibrium solubility varies over orders of magnitude, is influenced by the drug type and individual or combinations of media components, with some of these interactions being drug specific.

Topography of Simulated Intestinal Equilibrium Solubility.

Oral administration of a solid dosage form requires drug dissolution in the gastrointestinal tract before absorption. Solubility is a key factor controlling dissolution, and it is recognized that, within the intestinal tract, this is influenced by the luminal fluid pH, amphiphile content, and composition. Various simulated intestinal fluid recipes have been introduced to mimic this behavior and studied using a range of different experimental techniques.

Dual Level Statistical Investigation of Equilibrium Solubility in Simulated Fasted and Fed Intestinal Fluid.

The oral route is the preferred option for drug administration but contains the inherent issue of drug absorption from the gastro-intestinal tract (GIT) in order to elicit systemic activity. A prerequisite for absorption is drug dissolution, which is dependent upon drug solubility in the variable milieu of GIT fluid, with poorly soluble drugs presenting a formulation and biopharmaceutical challenge. Multiple factors within GIT fluid influence solubility ranging from pH to the concentration and ratio of amphiphilic substances, such as phospholipid, bile salt, monoglyceride, and cholesterol.

Statistical investigation of the full concentration range of fasted and fed simulated intestinal fluid on the equilibrium solubility of oral drugs.

Upon oral administration the solubility of a drug in intestinal fluid is a key property influencing bioavailability. It is also recognised that simple aqueous solubility does not reflect intestinal solubility and to optimise in vitro investigations simulated intestinal media systems have been developed. Simulated intestinal media which can mimic either the fasted or fed state consists of multiple components each of which either singly or in combination may influence drug solubility, a property that can be investigated by a statistical design of experiment technique.