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Research PaperPredicting Effect of Food on Extent of Drug Absorption Basedon Physicochemical PropertiesChong-Hui Gu, 1,4,5 Hua Li, 2 Jaquan Levons, 1 Kimberley Lentz, 3 Rajesh B Gandhi, 1Krishnaswamy Raghavan, 1 and Ronald L. Smith 1Received August 16, 2006; accepted January 3, 2007; published online March 24, 2007Purpose. To develop a statistical model for predicting effect of food on the extent of absorption (areaunder the curve of timeYplasma concentration profile, AUC) of drugs based on physicochemicalproperties.Materials and Methods. Logistic regression was applied to establish the relationship between the effectof food (positive, negative or no effect) on AUC of 92 entries and physicochemical parameters, includingclinical doses used in the food effect study, solubility (pH 7), dose number (dose/solubility at pH 7),calculated Log D (pH 7), polar surface area, total surface area, percent polar surface area, number ofhydrogen bond donor, number of hydrogen bond acceptors, and maximum absorbable dose (MAD).Results. For compounds with MAD Q clinical dose, the food effect can be predicted from the dosenumber category and Log D category, while for compounds with MAD < clinical dose, the food effectcan be predicted from the dose number category alone. With cross validation, 74 out of 92 entries (80%)were predicted into the correct category. The correct predictions were 97, 79 and 68% for compoundswith positive, negative and no food effect, respectively.Conclusions. A logistic regression model based on dose, solubility, and permeability of compounds isdeveloped to predict the food effect on AUC. Statistically, solubilization effect of food primarilyaccounted for the positive food effect on absorption while interference of food with absorption causednegative effect on absorption of compounds that are highly hydrophilic and probably with narrowwindow of absorption.KEY WORDS: food effect prediction; logistic regression; physicochemical properties.INTRODUCTIONFood exerts complicated effect on pharmacokinetic and/or pharmacodynamic profiles of a drug. In this study, the keyphysicochemical parameters that contribute to the food effectwere identified by statistical analysis of the effect of food onthe extent of drug absorption. A prediction model was alsoestablished using logistic regression.The effect of food on oral absorption may be attributedto specific mechanism for an individual compound. Forexample, food may interfere with specific transporters thatare involved in absorption of a specific compound (1). Foodmay increase the splanchnic blood flow rate and increase thebioavailability of compounds that undergo extensive firstpass effect (2). Certain compounds, e.g., tetracycline anddigoxin, can also chelate to specific components of foodleading to reduced bioavailability (3,4). These specific foodeffects may be difficult to predict based on physicochemicaldescriptors of compounds.However, food also exerts general physiological changesand its effect on drug absorption may be statisticallypredicted for compounds with similar physicochemical prop-erties. With food intake, the gastric pH increases initially toabout pH 6, followed by decrease in pH value to 2 inapproximately 1 h because of increased acid secretion (5,6).The bile secretion also increases with food intake, which mayenhance the solubility of lipophilic compounds (6). It wassuggested that the permeability may be reduced in generalfor poorly permeable compound because food impedes thediffusion of the compound to the mucosal surface (7). Largervolume after food intake, which leads to lower concentrationof dissolved compound, also reduces the amount absorbed ina definite period of time. Additionally, general bindingbetween drug and food components and incorporation ofdrug in the micelles of food may also impede the access ofthe drug to the epithelium surface and hence absorption. Itwas also well known that food causes delayed gastricemptying leading to delayed tmax and lower Cmax (8,9),although these parameters were not analyzed in this study.0724-8741/07/0600-1118/0 # 2007 Springer Science + Business Media, LLC 1118Pharmaceutical Research, Vol. 24, No. 6, June 2007 ( # 2007)DOI: 10.1007/s11095-007-9236-11 Biopharmaceutics R&D, Bristol-Myers Squibb Co., New Bruns-wick, New Jersey, USA.2 Global Biometrics Sciences, Bristol-Myers Squibb Co., Hopewell,New Jersey, USA.3 Discovery Metabolism and Pharmacokinetics, Bristol-Myers SquibbCo., Wallingford, Connecticut, USA.4 Present address: Formulation Development, Vertex PharmaceuticalsInc., 130 Waverly Street, Cambridge, Massachusetts 02139, USA.5 To whom correspondence should be addressed. (e-mail:chong-hui_gu@vrtx.com)