A theoretical framework for predicting interplay of food with dissolution, permeability, intestinal metabolism and active transport of drugs: Towards mechanistic biopharmaceutical classification system (mBCS)
Authors: Prasad Bhagwat 
Published: June 2021

Prediction of food‐effect on drug‐absorption rate and extent remains a critical challenge because of the complex interplay of fed condition with drug dissolution, permeability, intestinal metabolism and active transport. A systematic literature search was conducted to identity key covariates associated with the food effect. Particularly, the reported pharmacokinetic (PK) data on food‐effect were critically reviewed for potential drug‐ or system‐dependent mechanisms, e.g., delayed gastric emptying, pH‐dependent solubility and stability, lipophilicity (logP) and bile micelles formation, complexation, altered gastric fluid volume, enzyme or transport inhibition, altered blood‐flow, metabolism and transport. Out of 278 drugs for which food‐effect is reported, 45% showed significant positive food‐effect, 31% showed no effect, whereas, only 23% exhibited negative food‐effect. Lipophilicity (logP) of a drug was the major predictor of the positive food‐effect. Accordingly, drugs were first classified into two groups, i.e., Class I (logP ≥ 4.5) and Class II (logP < 4.5). 77% Class I drugs showed decisively positive food‐effect (e.g., venetoclax, ospemifene, and posaconazole), and termed as Class IA; whereas 23% drugs (i.e., Class IB) showed either none or modest negative food‐effect. Class IB drugs were either acid‐labile or substrates of intestinal transporters (e.g., everolimus, cinnarizine). Interestingly, Class IB drugs were mostly anionic. 31% Class I drugs showed greater than >2‐fold positive food‐effect, whereas only 4% Class II drugs showed >2‐fold increase in the exposure. Class II drugs were further classified into three groups. Class IIA drugs were those which are not substrates of the intestinal enzymes or transporters, nor they form complex with food component or degrade in the intestine. The food‐effect was modest for these drugs, which can be potentially predicted by dissolution testing in the physiologically relevant dissolution media. However, Class IIB drugs exhibited >2‐fold increase in AUC and Cmax. These drugs (e.g., gabapentin, propranolol, and hydralazine) are either substrates of intestinal nutrient transporters or the GI enzymes predominantly located in upper part of intestine, i.e., CYP3A4, esterases, and acetyl transferases. This effect is potentially because of the increased gut and liver blood‐flow in fed condition or due to food‐mediated inhibition of enzyme activity. In contrast, Class IIC drugs exhibited significant negative food‐effect. These drugs (e.g., T‐3256336, clodronate) were substrates of intestinal efflux transporters (e.g., P‐gp, and BCRP), or enzymes predominantly expressed in the lower part of intestine (e.g., UGT2B17), or they form complex. The proposed mechanistic biopharmaceutical classification system (mBCS) can be further extended and applied to predict the food‐effect at quantitative level on i)drug absorption and metabolism as well as GI‐based drug‐interaction, ii) dissolution‐based exposure extrapolation, iii) performance of controlled‐release formulations, and iv) potential challenges in bioequivalent studies.

Support or Funding Information

Department of Pharmaceutics, UW, Seattle and the FDA (# 5U01FD005969).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.