Does fed‐state associated prolonged gastric emptying affect drug transport kinetics in intestine?

Abstract

In vitro dissolution testing to estimate the likelihood of food-effect for the solubility-limited drugs is recommended by the regulatory agencies; however, the effect of changes in physiology such as delayed gastric emptying after food intake cannot be simulated in a dissolution apparatus. To address this, we performed metanalysis of food-effect studies and investigated the effect of food on drug bioavailability due to the changes in physiology and drug properties in fed-state. Our specific aims were to: i) identify the determinants of food-effect on drug absorption, ii) determine the magnitude by which fed-state associated physiological changes affect the absorption of efflux transporter substrates, and iii) measure the effect of high-fat versus low-fat diets on the magnitude of food-effect for the efflux transporter substrates. A systematic meta-analysis of clinical food-effect studies on 311 drugs was performed to evaluate the association of food-effect magnitude with drug- and physiology-specific properties (i.e., change in maximal plasma concentration, Cmax, and area under the plasma concentration-time profile curve, AUC). Of the studied drugs, 124 and 88 drugs showed positive and negative food-effects, respectively, whereas 99 showed no food-effect. Five deterministic properties that influence food-effect were identified, i.e., logP, log dose number, metabolic extraction ratio (EH), and saturation indices of intestinal apical uptake and efflux transporters (Equation 1). In particular, a majority of the drugs with efficient efflux transport (saturation index ≥2) showed negative food-effect. Since these data cannot be explained by dissolution testing, the negative food-effect for the efflux transporter substrates is likely a result of prolonged gastric emptying time in fed-state that leads to increased efflux transport efficiency (luminal drug concentration < Michaelis-Menten constant, Km) (Figure 1A). For example, drugs with saturation index ≥2, such as didanosine, voriconazole, erythromycin, omadacycline, and asciminib, showed 50-67% decrease in Cmax and AUC. Moreover, prolonged gastric emptying time with high-fat diet is associated with a greater negative food-effect as compared to low-fat diet conditions in these transporter substrates. For example, omadacycline, eltrombopag, indinavir, and asciminib showed significantly decreased Cmax (P <0.01) and AUC (P <0.001) with high-fat diet (Figure 1B). The present study is the first to confirm the impact of fed-state associated prolonged gastric emptying time on the saturable kinetics of efflux transporter substrates. Preclinical validation of the postulated mechanism is ongoing in our laboratory. The understanding and integration of changes in physiology and drug properties will allow prospective prediction of food-effect on oral drug absorption.