Negative Food Effect Research Articles

Self-microemulsifying drug delivery system (SMEDDS) for oral delivery of zafirlukast: Design, formulation, and pharmacokinetic evaluation

The current research aimed to develop a self-microemulsifying drug delivery system (SMEDDS) of zafirlukast to enhance its oral bioavailability by increasing its solubility and overcoming the negative food effect. For the formulation of SMEDDS, the solubility of zafirlukast was determined in different oils, surfactants, and cosurfactants. Based on this study's results, pseudo-ternary phase diagrams were plotted to select the efficient self-emulsification region. Eudragit EPO was employed as a precipitation inhibitor to avoid the supersaturation of zafirlukast in the SMEDDS system. The formulated system was evaluated for transparency, cloud point, optical birefringence, and globule size analysis using techniques like DLS, SANS and TEM. The SMEDDS preconcentrate was solidified by adsorbing it on Neusilin US2 and further formulated as a tablet. It was then evaluated for in vitro drug release against the marketed tablet. The optimized composition of zafirlukast SMEDDS and suspension of the plain drug were evaluated for a pharmacokinetic profile in rats for both fed and fasted conditions. The SMEDDS yielded microemulsion found transparent and homogeneous with globule size less than 50 nm by DLS, SANS and TEM techniques. On dilution with water, the microemulsion was found robust without any phase separation even after 24 h of storage. The tablet form of SMEDDS was stable and passed all the IPQC tests for a tablet. The optimized SMEDDS tablet form exhibited a superior in vitro dissolution profile than a marketed tablet. The pharmacokinetic study of optimized SMEDDS showed improved value for Cmax and AUC in both fed and fasted conditions compared to the plain drug.

Understanding mechanisms of negative food effect for voclosporin using physiologically based pharmacokinetic modeling

Negative food effect refers to a reduction in bioavailability, when a drug is taken with food. Voclosporin, a highly lipophilic cyclic peptide drug for treatment of active lupus nephritis, has shown negative food effect in clinical trials. Here, the cause of the negative food effect of voclosporin was investigated using physiologically based pharmacokinetic (PBPK) modeling to understand the mechanism responsible for oral absorption of voclosporin. Voclosporin is a substrate for P-glycoprotein and CYP3A4, and it has been evaluated for intestinal membrane permeability in human induced pluripotent stem cell-derived intestinal epithelial cells (hiPSC-IECs). The membrane permeability in hiPSC-IECs is integrated into the PBPK model for simulating permeability accurately. The PBPK model simulated the systemic PK profile in fasted state in human. Then, the PBPK model with in vitro adsorption of voclosporin onto food simulated the systemic PK profile in fed state for food effect. In addition, the PBPK model for rats also simulated the plasma profile of voclosporin for the food effect. These results suggest that a possible cause of the negative food effect of voclosporin is the adsorption of voclosporin to food in gastrointestinal tract. These approaches could facilitate understanding of the mechanisms responsible for oral absorption of cyclic peptides.

Food and bile micelle binding of zwitterionic antihistamine drugs.

The food effects on oral drug absorption are challenging to predict from in vitro data. Food intake has been reported to reduce the oral absorption of several zwitterionic antihistamine drugs. However, the mechanism for this negative food effect has not been clear. The purpose of the present study was to evaluate the bile micelle and food binding of zwitterionic antihistamine drugs as a possible mechanism for the negative food effects on their oral drug absorption. Bilastine (BIL), cetirizine (CET), fexofenadine (FEX), and olopatadine (OLO) were employed as model drugs. The fed/fasted AUC ratios of BIL, CET, FEX, and OLO after oral administration are reported to be 0.60 to 0.7, 0.92, 0.76 to 0.85, and 0.84, respectively. The unbound fraction (f u) of these drugs in the fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, containing 3 and 15 mM taurocholic acid, respectively) with or without FDA breakfast homogenate (BFH) was measured by dynamic dialysis. The FeSSIF/ FaSSIF fu ratios were 0.90 (BIL), 0.46 (CET), 0.76 (FEX), and 0.78 (OLO). In the presence of BFH, the fu ratios were reduced to 0.52 (BIL), 0.22 (CET), 0.39 (FEX), and 0.44 (OLO). Despite being zwitterion at pH 6.5, the antihistamine drugs were bound to bile micelles. Bile micelle and food binding were suggested to cause a negative food effect on the oral absorption of these drugs. However, the AUC ratio was not quantitatively predicted by using FeSSIF + BFH.

On the processes limiting oral drug absorption when amorphous solid dispersions are administered after a high-calorie, high-fat meal: Sporanox® pellets

Objectives1) Identify processes limiting the arrival of itraconazole at the intestinal epithelium when Sporanox® amorphous solid dispersion (ASD) pellets are transferred from the stomach through the upper small intestine, after a high-calorie, high-fat meal. 2) Evaluate whether itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine are useful for the assessment of dose effects in the fed state and food effects on plasma levels. MethodsItraconazole concentrations, apparent viscosity, and solubilization capacity were measured in aspirates from the upper gastrointestinal lumen collected during a recently performed clinical study in healthy adults. Published itraconazole concentrations in plasma, after a high-calorie high-fat meal and Sporanox® ASD pellets, and in contents of the upper small intestine of healthy adults, after administration of Sporanox® ASD pellets in the fasted state, were used to achieve the second objective. ResultsWhen Sporanox® ASD pellets (up to 200 mg) are transferred from the stomach through the upper small intestine, after a high-calorie, high-fat meal, itraconazole concentrations in the colloidal phase or the micellar phase of aqueous contents of the upper small intestine are unsaturated, in most cases. During the first 3 h post-dosing after a high-calorie, high-fat meal, the impact of dose (200 mg vs. 100 mg) on itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine seems to underestimate the impact of dose on plasma levels. When Sporanox® ASD pellets are administered after a high-calorie, high-fat meal at the 200 mg dose level, itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine are, on average, lower than those achieved in fasted state. ConclusionsWhen Sporanox® ASD pellets are transferred from the stomach to the upper small intestine after a high-calorie, high-fat meal, itraconazole's arrival at the intestinal epithelium seems to be limited by its arrival at the colloidal phase of aqueous contents of the upper small intestine. The impact of dose (100 mg vs. 200 mg) on plasma levels after a high-calorie, high-fat meal and during the gastrointestinal transfer of Sporanox® pellets requires consideration of pre-systemic itraconazole metabolism. At the 200 mg dose level, after taking into consideration differences in the volume of the contents of the upper small intestine between the fasted and the fed state during the gastrointestinal transfer of Sporanox® ASD pellets, itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine suggest a mild negative food effect on average plasma levels; published clinical data are inconclusive.

In Vitro Lipolysis Model to Predict Food Effect of Poorly Water-Soluble Drugs Itraconazole, Rivaroxaban, and Ritonavir

It is desirable to predict positive food effect of oral formulations due to food mediated dissolution enhancement of lipophilic drugs. The objective was to assess the ability of in vitro lipolysis to anticipate a positive food effect. Tested formulations included rivaroxaban and itraconazole, where some formulations, but not all, exhibit a positive food effect in vivo in humans. Amorphous solid dispersion formulations of ritonavir, which exhibit a negative food effect in vivo in humans, were also studied. Fe-lipolysis and Fa-lipolysis media representing fed and fasted intestinal conditions were used. Results show frequent agreement between in vitro lipolysis predictions and in vivo human outcomes. For rivaroxaban, food effect of unformulated active pharmaceutical ingredient (API) and products were correctly predicted where 2.5 mg and 10 mg strengths did not show any food effect; however, 20 mg did show a positive food effect. For itraconazole, all four products were correctly predicted, with Sporanox, Sempera, and generic capsules having a food effect, but Tolsura not having a positive food effect. For ritonavir, lipolysis predicted a positive food effect for API and Norvir tablet and powder, but Norvir products have negative food effect in vivo in humans. Overall, the lipolysis model showed favorable predictability and merits additional evaluation.

Impact of prandial state on luminal and permeation-behavior of fosamprenavir oral suspension studied by in vitro tools: Solubility-, bioconversion- and permeation- studies in biomimetic media

Fosamprenavir is a prodrug designed to overcome the solubility challenge of the parent drug amprenavir, a protease inhibitor. For the marketed oral suspension (Telzir®) a clinically documented negative food effect has been reported.The present study aims to gain a better mechanistic understanding of the food effect by in vitro tests on solubility, bioconversion, permeability, and dynamic dissolution/bioconversion/permeation studies in a high throughput manner on a microtiter plate (Permeapad® Plate). In order to mimick luminal condition changes in connection with food, various modified versions of fasted and fed state simulated intestinal fluids (FaSSIF-V2) and (FeSSIF–V2) were used. The kinetics of enzymatic cleavage (simulated bioconversion) were studied in these media with a focus on molecularly dissolved drug concentrations using microdialysis. Dynamic dissolution/bioconversion/permeation experiments, indicated the following factors to contribute to reduced permeation in fed state: elevated inorganic phosphate concentrations, higher concentrations of bile salts and lipids and lower intestinal pH. The impact of these effects is difficult to capture in vivo due to their interconnection and large variability between individuals.This study revealed factors leading to an altered luminal behavior of Telzir® oral suspension in fed state, which may contribute to explain the observed reduced amprenavir absorption from the suspension. Especially the high throughput small-scale dissolution/bioconversion/permeation experiments on a microtiter plate were demonstrated an efficient and powerful tool for elucidating the food effects of phosphate-ester prodrug type drug products as far as their altered luminal behavior is concerned.

Food and bile micelle binding of quaternary ammonium compounds.

Physiologically-based biopharmaceutics modeling (PBBM) has been widely used to predict the oral absorption of drugs. However, the prediction of food effects on oral drug absorption is still challenging, especially for negative food effects. Marked negative food effects have been reported in most cases of quaternary ammonium compounds (QAC). However, the mechanism has remained unclear. The purpose of the present study was to investigate the bile micelle and food binding of QACs as a mechanism of the negative food effect. Trospium (TRS), propantheline (PPT), and ambenonium (AMB) were selected as model QAC drugs. The oral absorption of these QACs has been reported to be reduced by 77% (TRS), > 66% (PPT), and 79% (AMB), when taken with food. The fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, containing 3 and 15 mM taurocholic acid, respectively) with or without FDA breakfast homogenate (BFH) were used as the simulated intestinal fluid. The unbound fraction (fu) of the QACs in these media was measured by dynamic dialysis. The fu ratios (FeSSIF/ FaSSIF) were 0.67 (TRS), 0.47 (PPT), and 0.76 (AMB). When BFH was added to FeSSIF, it was reduced to 0.39 (TRS), 0.28 (PPT), and 0.59 (AMB). These results suggested that bile micelle and food binding play an important role in the negative food effect on the oral absorption of QACs.

The Dynamic Intestinal Absorption Model (Diamod®), an in vitro tool to study the interconnected kinetics of gastrointestinal solubility, supersaturation, precipitation, and intestinal permeation processes of oral drugs

This study aimed at developing the Diamod® as a dynamic gastrointestinal transfer model with physically interconnected permeation. The Diamod® was validated by studying the impact of the intraluminal dilution of a cyclodextrin-based itraconazole solution and the negative food effect for indinavir sulfate for which clinical data are available demonstrating that the systemic exposure was strongly mediated by interconnected solubility, precipitation, and permeation processes. The Diamod® accurately simulated the impact of water intake on the gastrointestinal behavior of a Sporanox® solution. Water intake significantly decreased the duodenal solute concentrations of itraconazole as compared to no intake of water. Despite this duodenal behavior the amount of permeated itraconazole was not affected by water intake as observed in vivo. Next to this, the Diamod® accurately simulated the negative food effect for indinavir sulfate. Different fasted and fed state experiments demonstrated that this negative food effect was mediated by an increased stomach pH, entrapment of indinavir in colloidal structures and the slower gastric emptying of indinavir under fed state conditions. Therefore, it can be concluded that the Diamod® is a useful in vitro model to mechanistically study the gastrointestinal performance of drugs.

When Interactions Between Bile Salts and Cyclodextrin Cause a Negative Food Effect: Dynamic Dissolution/Permeation Studies with Itraconazole (Sporanox®) and Biomimetic Media

The marketed oral solution of itraconazole (Sporanox®) contains 40% (259.2 mM) of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). The obvious role of HP-β-CD is to solubilize itraconazole and to overcome its poor aqueous solubility that restricts its absorption.In this study, we investigated the biorelevance of in vitro experiments by the influence of biomimetic media (containing bile salts and phospholipids) on the predicted itraconazole absorption from the commercial HP-β-CD-based Sporanox® solution. We performed phase-solubility studies of itraconazole and dynamic 2-step-dissolution/permeation studies using a biomimetic artificial barrier, Sporanox® solution, and fasted state simulated intestinal fluid (FaSSIF_V1).Both FaSSIF_V1 and HP-β-CD increased the apparent solubility of itraconazole when used individually. In combination, their solubility-enhancing effects were not additive probably due to the competition of bile salts with itraconazole for the hydrophobic cavity of HP-β-CD. Our combined dissolution/permeation experiments indicated the occurrence of a transient supersaturation from Sporanox® upon two-step dissolution. Through systematic variation of bile salt concentrations in the biomimetic media, it was observed that the extent and the duration of supersaturation depend on the concentrations of bile salts: supersaturation was rather stable in the absence of bile salts and phospholipids. The higher the bile salt concentration, the faster the collapse of the transient supersaturation occurred, an effect which is nicely mirrored by reduced in vitro permeation across the barrier. This is an indication of a negative food effect, which in fact correlates well with what earlier had been observed in clinical studies for Sporanox® solution.In essence, we could demonstrate that in vitro two-stage dissolution/permeation experiments using an artificial barrier and selected biomimetic media may predict the negative effects of the latter on cyclodextrin-based drug formulations like Sporanox® Oral Solution and, at the same time, provide a deeper mechanistic insight.

Dynamic Changes in Gastrointestinal Fluid Characteristics after Food Ingestion Are Important for Quantitatively Predicting the In Vivo Performance of Oral Solid Dosage Forms in Humans in the Fed State.

The aim of this study was to develop a simulation model to predict the in vivo performance of solid oral dosage forms in humans in the fed state. We focused on investigating the effect of dynamic changes in gastrointestinal (GI) fluid characteristics in the fed state on the in vivo performance of solid dosage forms. We used six solid dosage forms containing weak base drugs as model formulations, two with positive food effects in humans, two with negative food effects, and two which are not affected by food ingestion. These model drug formulations were used to perform biorelevant dissolution tests in the stomach and small intestine under both prandial states. The in vitro properties of the drug products obtained from these tests were then coupled with in silico models (fasted or fed) to predict food effects in humans. We successfully incorporated the dynamic changes in GI fluid characteristics and their effects on the in vivo dissolution of drugs into the prediction model for the fed state. This newly designed physiologically based biopharmaceutics modeling approach provided the precise and quantitative prediction of food effects (i.e., changes in Cmax and AUC after food ingestion) in humans while considering the dynamic changes in fluid characteristics in the fed state.

Fast-Fed Variability: Insights into Drug Delivery, Molecular Manifestations, and Regulatory Aspects.

Among various drug administration routes, oral drug delivery is preferred and is considered patient-friendly; hence, most of the marketed drugs are available as conventional tablets or capsules. In such cases, the administration of drugs with or without food has tremendous importance on the bioavailability of the drugs. The presence of food may increase (positive effect) or decrease (negative effect) the bioavailability of the drug. Such a positive or negative effect is undesirable since it makes dosage estimation difficult in several diseases. This may lead to an increased propensity for adverse effects of drugs when a positive food effect is perceived. However, a negative food effect may lead to therapeutic insufficiency for patients suffering from life-threatening disorders. This review emphasizes the causes of food effects, formulation strategies to overcome the fast-fed variability, and the regulatory aspects of drugs with food effects, which may open new avenues for researchers to design products that may help to eliminate fast-fed variability.

Mechanistic analysis for positive and negative food effects on oral absorption of poorly soluble drugs from cyclodextrin containing formulations: Study with a mini-scale in vitro system

The aim of this study is to understand the basic mechanism of the food effect on oral drug absorption from cyclodextrin (CyD) containing formulations. Danazol (DNZ) and Albendazole (ABZ) were used as model drugs with poor water solubility. Both drugs were suspended or dissolved in Fasted State or Fed State Simulated Intestinal Fluid (FaSSIF or FeSSIF) containing various concentrations of 2-Hydroxypropyl-beta-cyclodextrin (HP-βCyD). Drugs were applied to a μFlux system as a suspension or solution and the dissolved concentration and the permeated amount were monitored. Dissolved drug concentration was analyzed based on the chemical equilibrium to calculate the concentrations of free drug, drug-CyD complex and drug-bile acid micelle complex. Mathematical analysis revealed that the bile acid also interacted with HP-βCyD to displace the drug and reduced the solubilizing capacity of HP-βCyD. The permeation rate of DNZ was faster in FaSSIF than in FeSSIF at 1% HP-βCyD while it became faster in FeSSIF at 2% HP-βCyD, suggesting that complexes with HP-βCyD and with the bile acid micelle can diffuse through the unstirred water layer to contribute to the permeation by providing a free DNZ at the vicinity of the membrane. In contrast, the permeation of ABZ follows the free drug concentration since its permeation is rate-limited by the membrane permeation itself. In vivo rat study with 1% HP-βCyD showed the higher absorption of DNZ in FaSSIF than in FeSSIF, corresponding well to the in vitro results. With 2% HP-βCyD, almost the same absorption profiles were observed in FaSSIF and FeSSIF despite the faster membrane permeation in FeSSIF, possibly due to the slower dissolution of DNZ in FeSSIF. In conclusion, in vitro study with a mini-scale system such as a μFlux system is useful to understand the complicated interactions of the drug with CyDs and/or bile acids and is helpful for designing efficient and robust formulations of poorly soluble drugs using CyDs as an excipient.

Application of tiny-TIM as a mechanistic tool to investigate the in vitro performance of different itraconazole formulations under physiologically relevant conditions

The increasing number of poorly water-soluble compounds in drug development is one of the major challenges in oral drug delivery nowadays. For rational formulation development, biopharmaceutical tools are needed that closely simulate the conditions present within the human gastrointestinal (GI) tract in order to early predict the potential effect of important factors like meal intake or acid-reducing agents on oral bioavailability. The tiny-TIM system equipped with the advanced gastric compartment is one of the most realistic in vitro models for the simulation of the physiological processes occurring in human stomach and small intestine. In the present study, this model was applied to study the in vitro performance of an ASD-based formulation of itraconazole under different clinically relevant conditions. Apart from the assessment of the bioaccessible fraction (i.e., the fraction available for drug absorption), the implementation of two additional sampling ports enabled the measurement of intraluminal concentration profiles. Along with solubility experiments in biorelevant media, deeper mechanistic insights into drug product performance in different prandial states as well as in case of gastric pH modification could be generated. The comparison of the in vitro data with published in vivo data revealed that the model successfully predicted the effect of food intake as well as of modified gastric pH conditions on the bioavailability of itraconazole from this formulation. In contrast, the negative food effect observed for an oral solution formulation could not be predicted. For this cyclodextrin-based formulation, the formulation effect on permeation needs to be considered. Nonetheless, the data presented in this study showed that tiny-TIM is an interesting tool to mechanistically study the impact of different physiological conditions on drug release from oral drug products.

Machine learning predicts the effect of food on orally administered medicines

Food-mediated changes to drug absorption, termed the food effect, are hard to predict and can have significant implications for the safety and efficacy of oral drug products in patients. Mimicking the prandial states of the human gastrointestinal tract in preclinical studies is challenging, poorly predictive and can produce difficult to interpret datasets. Machine learning (ML) has emerged from the computer science field and shows promise in interpreting complex datasets present in the pharmaceutical field. A ML-based approach aimed to predict the food effect based on an extensive dataset of over 311 drugs with more than 20 drug physicochemical properties, referred to as features. Machine learning techniques were tested; including logistic regression, support vector machine, k-Nearest neighbours and random forest. First a standard ML pipeline using a 80:20 split for training and testing was tried to predict no food effect, negative food effect and positive food effect, however this lead to specificities of less than 40%. To overcome this, a strategic ML pipeline was devised and three tasks were developed. Random forest achieved the strongest performance overall. High accuracies and sensitivities of 70%, 80% and 70% and specificities of 71%, 76% and 71% were achieved for classifying; (i) no food effect vs food effect, (ii) negative food vs positive food effect and (iii) no food effect vs negative food effect vs positive food effect, respectively. Feature importance using random forest ranked the features by importance for building the predictive tasks. The calculated dose number was the most important feature. Here, ML has provided an effective screening tool for predicting the food effect, with the potential to select lead compounds with no food effect, reduce the number of animal studies, and accelerate oral drug development studies.

Meta-Analysis of Food Effect on Oral Absorption of Efflux Transporter Substrate Drugs: Does Delayed Gastric Emptying Influence Drug Transport Kinetics?

The oral route of drug administration is the most convenient method of drug delivery, but it is associated with variable bioavailability. Food is one of the major factors that affect oral drug absorption by influencing drug properties (e.g., solubility and dissolution rate) and physiological factors (e.g., metabolism and transport across the gastrointestinal tract). The aim of this work was to investigate the effect of food on the high-affinity intestinal efflux transporter substrate drugs. We hypothesized that transport efficiency is higher in the fed state as compared to the fasted state because of the lower intestinal lumen drug concentration due to prolonged gastric emptying time. A systematic analysis of reported clinical food-effect (FE) studies on 311 drugs was performed and the association of the efflux transport efficiency was investigated on the FE magnitude, i.e., changes in maximal plasma concentration and area under the plasma concentration–time profile curve for both solubility and permeability-limited drugs. In total, 124 and 88 drugs showed positive and negative FE, respectively, whereas 99 showed no FE. As expected, the solubility-limited drugs showed positive FE, but interestingly, drugs with a high potential for efflux transport, were associated with negative FE. Moreover, a high-fat diet was associated with a higher magnitude of negative FE for high-affinity efflux transporter substrates as compared to a low-fat diet. To account for changes in drug absorption after food intake, the prolonged gastric emptying time should be considered in the physiologically based pharmacokinetic (PBPK) modeling of orally absorbed efflux transporter substrate drugs.

Physiologically Based Pharmacokinetic (PBPK) Modeling for Betrixaban and the Impact of P-Glycoprotein Inhibition on Betrixaban Pharmacokinetics

Introduction: Betrixaban is a factor Xa inhibitor indicated for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness. A physiologically based pharmacokinetic (PBPK) model for betrixaban provided the mechanistic understanding of the contribution of P-glycoprotein (P-gp), as well as CYP3A4, to the disposition of betrixaban, and predictions of the effects of drug-drug interactions mediated by P-gp and/or CYP3A4. The PBPK model specifically evaluated contribution of the interaction with the P-gp transporter to the disposition of betrixaban, as well as the effects of co-administration of P-gp inhibitors (ketoconazole, verapamil, clarithromycin) on betrixaban pharmacokinetics (PK). Further, in vitro and clinical studies confirmed the lack of a significant interaction of betrixaban with CYP3A4.Methods: The base PBPK model was developed using physiochemical data, in vitro metabolism andtransport data generated using recombinant CYP enzymes and human hepatocytes, and relevant clinical data (eg, observed renal clearance). The model was verified by comparing model predictions with PK data derived from single oral doses of betrixaban (from 80 to 550 mg) in healthy volunteers. The combined contribution of intestinal and hepatic P-gp transport to the disposition of betrixaban was verified by comparing model predictions to the observed ketoconazole and verapamil clinical drug-drug interaction data from healthy volunteers. The verified PBPK model was prospectively employed to predict the impact of a strong P-gp inhibitor (clarithromycin) and a moderate P-gp inhibitor (diltiazem) on betrixaban PK, and to predict the impact of food intake on betrixaban PK and compare it against the observed data in phase 3 studies. The Simcyp Population-Based Simulator (v15 release 1) was used for all simulations.Results: The major clearance pathway for betrixaban was biliary clearance (assigned to hepatic P-gp) as scaled from uptake data generated in human hepatocytes, accounting for ~80% of clearance after IV administration (CLIV). CYP3A4 played virtually no role in the disposition of betrixaban. The base PBPK model incorporating an intestinal P-gp component within the ADAM model resulted in simulations that predicted concentrations very close to the clinically observed pharmacokinetic non-linearity arising from multiple oral dosing of betrixaban in the dose range of 80 to 550 mg in healthy volunteers. The model predicted that the inhibition of intestinal and hepatic P-gp transport of betrixaban would result in the geometric mean area under the curve (AUC) and maximal concentration (Cmax) ratios due to concurrent ketoconazole treatment of 2.4 and 2.5, respectively, which were consistent with the observed ratios of 2.1 and 2.3. The predicted betrixaban geometric mean AUC and Cmax ratios due to concurrent verapamil treatment were 2.3 and 3.1, respectively, compared with the observed ratios of 3.0 and 4.7. The model qualitatively predicted the negative impact of food intake on betrixaban exposure (Figure). The predicted AUC and Cmax for patients treated with betrixaban in the fed state in the phase 3 study were within 1.5-fold of the observed values. In the final application of the PBPK model to predict the impact of the strong and moderate P-gp inhibitors, the predicted AUC and Cmax ratios due to clarithromycin treatment were 3.76 and 3.11, respectively, and due to diltiazem treatment were 1.1 and 1.1, respectively.Conclusions: The PBPK model for betrixaban adequately predicted the clinically observed PK non-linearity and accounted for the observed drug-drug interaction effects due to co-administration of betrixaban with ketoconazole and verapamil in healthy volunteers. The PBPK model did not predict a role for CYP3A4 in the clearance of betrixaban and accurately predicted a negative food effect. Intestinal and hepatic P-gp were identified as major contributors to the observed non-linearity in the kinetics of betrixaban and observed drug-drug interaction effects with P-gp inhibitors. [Display omitted] DisclosuresLeeds:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership. Ke:Portola Pharmaceuticals, Inc.: Consultancy. Rowland Yeo:Portola Pharmaceuticals, Inc.: Consultancy. Curnutte:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership. Conley:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership, Patents & Royalties.

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

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.

Biliary Excretion-Mediated Food Effects and Prediction.

Many orally administered drugs with negative food effects (i.e., lower exposure under fed conditions) are often primarily or partially eliminated by biliary excretion. The aim of this study is to assess the potential correlation between a negative food effect and biliary excretion. Correlation analysis was conducted using a training dataset containing 27 drugs which met the following criteria: (1) immediate-release formulations, (2) shows a negative food effect, (3) > 10% biliary clearance, and (4) does not undergo extensive metabolism. A correlation between fed-state biliary clearance (CLb,fed) and fasted-state biliary clearance (CLb,fast) (y = 1.81*x, R2 = 0.68) was observed. The 1.8-fold increase in biliary clearance was then used as a correction factor to improve physiologically based pharmacokinetic (PBPK) prediction of food effects for 12 test drugs. The mean deviations of predicted fed/fasting AUC ratio and Cmax ratio from clinically observed values were reduced from 32.4 to 17.2% and from 63.3 to 54.3%, respectively. In contrast to the positive food effects on most biopharmaceutics classification system (BCS) class II drugs for which food-stimulated bile flow increases drug solubility and absorption, our results suggest that the elimination of biliary excreted drugs is increased by food-stimulated bile flow, resulting in negative food effects.

Use of Physiologically Based Pharmacokinetic (PBPK) Modeling for Predicting Drug-Food Interactions: an Industry Perspective

The effect of food on pharmacokinetic properties of drugs is a commonly observed occurrence affecting about 40% of orally administered drugs. Within the pharmaceutical industry, significant resources are invested to predict and characterize a clinically relevant food effect. Here, the predictive performance of physiologically based pharmacokinetic (PBPK) food effect models was assessed via de novo mechanistic absorption models for 30 compounds using controlled, pre-defined in vitro, and modeling methodology. Compounds for which absorption was known to be limited by intestinal transporters were excluded in this analysis. A decision tree for model verification and optimization was followed, leading to high, moderate, or low food effect prediction confidence. High (within 0.8- to 1.25-fold) to moderate confidence (within 0.5- to 2-fold) was achieved for most of the compounds (15 and 8, respectively). While for 7 compounds, prediction confidence was found to be low (> 2-fold). There was no clear difference in prediction success for positive or negative food effects and no clear relationship to the BCS category of tested drug molecules. However, an association could be demonstrated when the food effect was mainly related to changes in the gastrointestinal luminal fluids or physiology, including fluid volume, motility, pH, micellar entrapment, and bile salts. Considering these findings, it is recommended that appropriately verified mechanistic PBPK modeling can be leveraged with high to moderate confidence as a key approach to predicting potential food effect, especially related to mechanisms highlighted here.

Prediction of negative food effect induced by bile micelle binding on oral absorption of hydrophilic cationic drugs

The purpose of the present study was to quantitatively predict the negative food effect induced by bile micelle binding on the oral absorption of hydrophilic cationic drugs. The intrinsic membrane permeability and bile micelle unbound fraction of 12 model drugs (7 tertiary amines, 3 quaternary ammoniums, and 2 neutral drugs) were calculated from the experimental Caco-2 permeability data (Papp) under fasted and fed conditions. From these input data, the fraction of a dose absorbed (Fa) was predicted using the gastrointestinal unified theoretical framework, a mechanism-based oral absorption model. The predicted Fa ratio (fed/fasted) was then compared with the in vivo fed/fasted area under the plasma concentration–time curve ratio (AUCr). The AUCr values of tertiary amines and neutral drugs were appropriately predicted (absolute average fold error (AAFE) = 1.19), whereas those of quaternary ammoniums were markedly underestimated (AAFE = 4.70). The Papp ratio (fed/fasted) predicted AUCr less quantitatively (AAFE = 1.30 for tertiary amines and neutral drugs). The results of the present study would lead to a better understanding of negative food effect on oral drug absorption.