Negative Food Effect Research Articles

The use of PBPK/PD to establish clinically relevant dissolution specifications for zolpidem immediate release tablets

BackgroundZolpidem is a non-benzodiazepine hypnotic agent which has been shown to be effective in inducing and maintaining sleep in adults and is one of the most frequently prescribed hypnotics in the world. For drugs that are used to treat sleeping disorders, the time to reach the maximum concentration (Tmax) of the drug in plasma is important to achieving a fast onset of action and this must be maintained when switching from one product to another. ObjectivesThe main objective of the present work was to create a PBPK/PD model for zolpidem and establish a clinically relevant “safe space” for dissolution of zolpidem from the commercial immediate release (IR) formulation. A second objective was to analyze literature pharmacokinetic data to verify the negative food effect ascribed to zolpidem and consider its ramifications in terms of the “safe space” for dissolution. MethodsUsing dissolution, pharmacokinetic and pharmacodynamic data, an integrated PBPK/PD model for immediate release zolpidem tablets was constructed in Simcyp®. This model was used to identify the clinically relevant dissolution specifications necessary to ensure efficacy. ResultsAccording to the simulations, as long as 85% of the drug is released in 45 minutes or less, the impact on the PK and PD profiles of zolpidem would be minimal. According to the FDA, the drug has to dissolve from the test and reference products at a similar rate and to an extent of 85% in not more than 30 minutes to pass bioequivalence via the BCS-biowaiver test. Thus, the BCS-biowaiver specifications are somewhat more stringent than the “safe space” based on the PBPK/PD model. Published data from fasted and fed state pharmacokinetic studies suggest but do not prove a negative food effect of zolpidem. ConclusionsA PBPK/PD model indicates that current BCS-biowaiver criteria are more restrictive for immediate release zolpidem tablets than they need to be. In view of the close relationship between PK and PD, it remains advisable to avoid taking zolpidem tablets with or immediately after a meal, as indicated by the Stilnox® labeling.

Food Effects on Oral Drug Absorption: Application of Physiologically-Based Pharmacokinetic Modeling as a Predictive Tool.

The bioavailability of an orally administered small molecule is often dictated by drug-specific physicochemical characteristics and is influenced by many biological processes. For example, in fed or fasted conditions, the transit time within the gastrointestinal tract can vary, confounding the ability to predict the oral absorption. As such, the effects of food on the pharmacokinetics of compounds in the various biopharmaceutics classification system (BCS) classes need to be assessed. The consumption of food leads to physiological changes, including fluctuations in the gastric and intestinal pH, a delay in gastric emptying, an increased bile secretion, and an increased splanchnic and hepatic blood flow. Despite the significant impact of a drug’s absorption and dissolution, food effects have not been fully studied and are often overlooked. Physiologically-based pharmacokinetic (PBPK) models can be used to mechanistically simulate a compound’s pharmacokinetics under fed or fasted conditions, while integrating drug properties such as solubility and permeability. This review discusses the PBPK models published in the literature predicting the food effects, the models’ strengths and shortcomings, as well as future steps to mitigate the current knowledge gap. We observed gaps in knowledge which limits the ability of PBPK models to predict the negative food effects and food effects in the pediatric population. Overall, the further development of PBPK models to predict food effects will provide a mechanistic basis to understand a drug’s behavior in fed and fasted conditions, and will help enable the drug development process.

Biopharmaceutic In Vitro In Vivo Extrapolation (IVIV_E) Informed Physiologically-Based Pharmacokinetic Model of Ritonavir Norvir Tablet Absorption in Humans Under Fasted and Fed State Conditions.

Ritonavir is a well-known CYP3A4 and CYP2D6 enzyme inhibitor, frequently used to assess the drug-drug interaction (DDI) liability of susceptible drugs. It is also used as a pharmacokinetic booster to increase exposure to CYP3A4 substrates. This study aimed to develop a mechanistic absorption and disposition model to describe exposure to ritonavir following oral dosing of the commercial amorphous solid dispersion tablet, Norvir, under fasted and fed conditions. A mechanistic description of ritonavir absorption from Norvir tablets may help to improve the design of DDI studies. Key parameters of amorphous ritonavir including free base solubility (solubility of the unbound, un-ionized species), bile micelle partition coefficients, formulation wetting/disintegration, and in vivo precipitation parameters were either obtained from the literature or estimated by modeling in vitro biopharmaceutic experiments. Based on variety of in vitro evidence, a main assumption of the model is that ritonavir does not form a crystalline precipitate while resident in the gastrointestinal tract. In the model, if simulated luminal concentration exceeds the amorphous solubility limit, then precipitation to an amorphous form is immediate. Simulated and observed Cmax and AUC0-t parameters were well captured (within 1.5-fold) for both fasted and fed states in healthy volunteers. By accounting for luminal fluid viscosity differences in the different prandial states (affecting drug diffusivity) as well as the effect of drug free fraction on gut wall permeation rates, it was possible to explain the negative food effect observed for Norvir tablets in humans. In summary, a biopharmaceutic in vitro in vivo extrapolation approach provides confidence in (verification of) key input parameters of the physiologically-based pharmacokinetic ritonavir model which resulted in successful simulation of observed plasma profiles.

Prediction of Negative Food‐Effect on Drug Bioavailability by Mechanistic Biopharmaceutics Classification System (mBCS)‐guided Physiologically‐based Pharmacokinetic modeling

Food can influence drug bioavailability by altering gut physiology and microenvironment. Conventional approaches such as dissolution testing and biopharmaceutics classification system (BCS) often fail to predict food effect on drug bioavailability. To address this, we proposed a mechanistic BCS (mBCS) (Figure 1) based on analysing literature data. The mBCS first classifies drugs based on if their absorption is solubility‐limited (Class I) or permeability‐limited (Class II), which are sub‐grouped based on if the food effect is predictable (IA and IIA) or not predictable (IB, IC, IIB and IIC) using the dissolution testing (Figure 1A). Finally, mBCS allows identifying the mechanisms that lead to unpredictable food‐effect on drug bioavailability. Particularly, out of 288 drugs where the food‐effect data were reported, 105 drugs exhibited negative food effect. Further evaluation suggested that the primary reason for the unpredictable negative food effect is the interplay of intestinal efflux transport and delayed gastric emptying (Figure 1B). For example, amongst all drugs that showed negative food effect, majority (58%) were substrates of GI efflux transporters (e.g., maraviroc, afatinib, furosemide, ixazomib, asciminib, and omadacycline). We thus hypothesized that since gastric emptying time in fed state is higher (>2 h) as compared to the fasting state (15 min), drug co‐administration with food results in decreased concentration gradient across intestinal wall (lumen to blood), which eventually causes desaturation of GI efflux transporters. To test this hypothesis, we developed an mBCS‐guided physiologically based pharmacokinetic (PBPK) model in MATLAB (MathWorks, Natick, MA) by incorporating the regional protein abundance and saturation kinetics (Km and Vmax) of selected drugs (maraviroc, afatinib, and furosemide). The results from maraviroc PBPK modeling are presented below. The model was successful in predicting non‐linear PK within 2‐fold at varied dose ranges (e.g., 0.5, 0.61, 0.88, 1.17, 1.07 and 1.02 folds for 30, 100, 300, 600, 900 and 1200 mg, respectively for maraviroc) in the fasted state. The model successfully captured ~37% reduction in AUC in fed state at lower clinical doses of 100 and 300 mg of maraviroc. Similarly, consistent with the observed clinical data 1, the predicted magnitude of negative food effect was significantly lower (~22 and 18% reduction in AUC) at higher doses of 900 and 1200 mg, respectively. Parameter sensitivity analysis showed that gastric emptying time and kinetic parameters of P‐gp are important mechanisms that regulate non‐linear PK and food effect for maraviroc. Therefore, the proposed mBCS‐guided PBPK modeling approach can be used for prospective prediction of negative food effect, which can also be used to justify clinical trial waiver for the food effect studies.Support or Funding InformationDepartment of Pharmaceutical Sciences, Washington State University, SpokaneMechanistic biopharmaceutics classification system (mBCS) framework (A) and proposed mechanism of interplay between GI efflux and gastric emptying in fasting and fed states for mBCS class‐IIC drugs (B).Figure 1

Investigation of drug partition kinetics to fat in simulated fed state gastric conditions based on drug properties.

The presence of fat in the gastric environment can affect the pharmacokinetic behaviour of drugs with mechanisms which have not been yet fully understood. The objective of the current study was to assess the drug partition to the lipid part of the fed gastric content under different emulsification conditions, using in vitro discriminating setups. The model drugs used in the study were selected on the basis of different physicochemical properties (lipophilicity, ionization, molecular weight and aqueous solubility) and different food effect observed in in vivo human studies. Fed State Simulated Gastric Fluid prepared with skimmed milk (FeSSGFsk) and anhydrous milk fat were used as surrogates for the aqueous and fat portions of the fed gastric environment respectively. An optimized biphasic model was developed so as to predict the differences in partition rate constants to fat, for model drugs of a wide range of the properties mentioned above. The experimental data and the use of statistical analysis revealed that molecular weight, molecular weight and log D pH 5 interaction and negative food effect act as negative factors to the rate constants of fat partition, while absence of food effect and logD pH 5 interaction with aqueous solubility affect the rate constants of partition to fat favourably.

In-vitro-in-silico investigation of the negative food effect of zolpidem when administered as immediate-release tablets.

The main objective of the present work was to combine in-vitro and in-silico tools to better understand the in-vivo behavior of the immediate release (IR) formulation of zolpidem in the fasted and fed states. The dissolution of zolpidem was evaluated using biorelevant media simulating the gastric and intestinal environment in the fasted and fed states. Additionally, the influence of high viscosity and high fat content on the release of zolpidem under fed state conditions was investigated. The in-vitro results were combined with a physiologically based pharmacokinetic (PBPK) model constructed with Simcyp® to simulate the zolpidem pharmacokinetic profile in both prandial states. In vitro biorelevant dissolution experiments representing the fasted and fed states, combinedwith PBPKmodelling, were able to simulate the plasma profiles from the clinical food effect studies well. Experiments reflecting the pH and fat content of themeal led to a good prediction of the zolpidem plasma profile in the fed state, whereas increasing the viscosity of the gastricmedia led to an under-prediction. This work demonstrates that the combination of biorelevant dissolution testing and PBPK modelling is very useful for understanding the in-vivo behavior of zolpidem in the fasted and fed states. This approach could be implemented in the development of other drugs exhibiting negative food effects, saving resources and bringing new drug products to the market faster.

Prediction of Bioequivalence and Food Effect Using Flux- and Solubility-Based Methods.

In this work, two different approaches have been developed to predict the food effect and the bioequivalence of marketed itraconazole (ITRA) formulations. Kinetic solubility and simultaneous dissolution-permeation tests of three (ITRA) formulations (Sporanox capsules and solution and SUBA-ITRA capsules) were carried out in simulated fasted and fed states. Fraction of dose absorbed ratios estimating food effect and bioequivalence were calculated based on these results and were compared to the in vivo study results published by Medicines Agencies. The comparison demonstrated that kinetic solubility and flux values could be used as input parameters for biopharmaceutics modeling and simulations to estimate food effect and bioequivalence. Both prediction methods were able to determine a slightly negative food effect in the case of the Sporanox solution and also a pronounced positive food effect for the Sporanox capsule. Superior bioavailability was predicted when the Sporanox solution was compared to the Sporanox capsule (in agreement with in vivo data).

Designing robust immediate release tablet formulations avoiding food effects for BCS class 3 drugs

Food induced viscosity in the gastrointestinal tract is reported to reduce the bioavailability of tablets containing BCS class 3 drugs, mainly by retarding their disintegration and dissolution of the active pharmaceutical ingredient. The role of formulation factors in minimizing this negative food effect is largely unknown. Combinations of disintegrants were studied together with soluble and insoluble fillers and trospium chloride as model drug substance. Different batches of tablets were compressed at 10 kN and 30 kN, by incorporating different combinations of croscarmellose sodium (CSS), cross-linked (CPD) and sodium starch glycolate (SSG) at low level i.e, 2% + 2% and high level i.e, 4% + 4% of compressional weight, while taking lactose as a soluble filler and dibasic calcium phosphate (DCP) and microcrystalline cellulose (MCC) as insoluble fillers. Under low viscous conditions, disintegration of DCP based tablets was faster compared to lactose based tablets, but under high viscous conditions, simulating the effect of an ingested FDA meal, the disintegration behavior was reverted. Increased compressional force prolonged the disintegration of lactose and DCP based formulations under fasted conditions. However, when evaluated under food viscosity conditions, DCP based tablets compressed at higher force showed rapid disintegration while no effect of increased compressional force in lactose based tablets was observed. MCC based tablets in particular showed largely prolonged disintegration times in viscous media irrespective of the disintegrant type and levels investigated. Disintegrant combinations possessing wicking ability with minimum or no gelling were found to reduce disintegration times. The disintegrant combination of CPD + CCS was effective in reducing disintegration and enhancing dissolution besides not being affected by changes in compressional force and their total proportion in the tablet. In conclusion, it is recommended to evaluate formulations under increased viscosity conditions during the development phase of tablets with an objective to minimize the negative effect of food viscosity on disintegration and dissolution.

Human intestinal fluid factors affecting intestinal drug permeation in vitro

Intestinal permeability assessment is an important aspect of drug development, which strongly depends on the solvent system used in the intestinal donor compartment. For this purpose, human intestinal fluids (HIF) can be considered as the golden standard. A recent study demonstrated a reduced apparent permeation across rat intestinal tissue from fed versus fasted state HIF for 9 out of 16 compounds tested. Commercially available fed and fasted state simulated fluids (FeSSIF and FaSSIF) reproduced this food effect for only 3 out of 16 compounds. To elucidate this observed difference, the current study assessed the impact of relevant intestinal fluid factors (bile salt, phospholipids, cholesterol, free fatty acids (FFA), monoacylglycerides (MAG)) and 2-factor interactions at a fixed pH of 6.5 on drug permeation across both rat tissue (Ussing chambers setup) and an artificial membrane (dialysis setup). Four representative compounds were selected for the permeation experiments: for propranolol and indomethacin, a food-induced permeation reduction was previously seen in both HIF and SIF; for metoprolol and darunavir, a reduction was only seen in HIF. Using a fractional 25–1 design of experiments (DoE) approach, 16 SIF combinations were defined as donor media for permeation studies.In the Ussing chambers (rat tissue), FFA and MAG reduced the permeation for all 4 compounds. Only for propranolol and indomethacin, permeation was further reduced by bile salts and phospholipids. This explains why the use of FeSSIF vs FaSSIF, lacking FFA and MAG, predicted a negative food effect for propranolol and indomethacin but not for metoprolol and darunavir. In the dialysis set-up using an artificial membrane, significantly higher permeation rates compared to the Ussing chambers were observed. Under those conditions, FFA and MAG no longer reduced permeation, while bile salts and phospholipids still did. This may indicate that lipidic structures can provide depot release in the case of a dynamic equilibrium between free and entrapped drug.

Synthesis and Physicochemical Evaluation of Entecavir-Fatty Acid Conjugates in Reducing Food Effect on Intestinal Absorption.

The oral bioavailability of entecavir (EV), an anti-viral agent commonly prescribed to treat hepatitis B infections, is drastically reduced under a post-prandial state. This is primarily due to its low permeability in the gastrointestinal tract. To reduce the food effect on the intestinal absorption of the nucleotide analogue, four lipidic prodrugs were synthesized via the esterification of the primary alcohol of EV with fatty acids (hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid). EV-3-dodecanoate (or EV-C12) exhibited high solubility in a fed state simulated intestinal fluid (78.8 μg/mL), with the acceptable calculated logP value (3.62) and the lowest hydrolysis rate (22.5% for 12 h in simulated gastric fluid, pH 1.2). Therefore, it was chosen as a candidate to improve intestinal absorption of EV, especially under a fed state condition. Physical characterization using scanning electron microscopy, a differential scanning calorimeter, and X-ray powder diffraction revealed that EV-C12 had a rectangular-shaped crystalline form, with a melting point of about 170 °C. In a release test in biorelevant media, such as fasted and fed state-simulated intestinal and/or gastric fluid, more than 90% of the prodrug was released within 2 h in all media tested. These data suggest that this lipidic prodrug might have the potential to alleviate the negative food effect on the intestinal absorption of EV with increased therapeutic efficacy and patient compliance.

Formulation strategy towards minimizing viscosity mediated negative food effect on disintegration and dissolution of immediate release tablets

Food induced viscosity can delay disintegration and subsequent release of API from solid dosage form which may lead to severe reduction in the bioavailability of BCS type III compounds. Formulations of such tablets need to be optimized in view of this postprandial viscosity factor. In this study, three super disintegrants, croscarmellose sodium (CCS), cross-linked polyvinylpolypyrrolidone (CPD), and sodium starch glycolate (SSG) were assessed for their efficiency under simulated fed state. Tablets containing these disintegrants were compressed at 10 and 30 KN, while taking lactose as a soluble filler. In addition to other compendial tests, disintegration force of these formulations was measured by texture analysis. Comparison of parameters derived from force – time curves revealed a direct relation of maximum disintegration force (Fmax) and disintegration force development rate (DFDR) with compressional force in fasted state, whereas an inverse relationship of Fmax and DFDR with compressional force was observed in fed state. The gelling tendency of disintegrants influenced the rate of release of API in simulated fed and fasted states when compressional force was changed. These observations recommend the evaluation of formulations in simulated fed state, in the development stage, with an objective of minimizing the negative impact of food induced viscosity on disintegration. Use of disintegrants that act without gelling or can counteract the effect of gelling is recommended for tablet formulations with reduced disintegration time (DT) and mean dissolution time (MDT) in fed state, respectively.

Efficacy, safety, tolerability, and pharmacokinetics of EPI-506 (ralaniten acetate), a novel androgen receptor (AR) N-terminal domain (NTD) inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC) progressing after enzalutamide and/or abiraterone.

5032 Background: EPI-506 (ralaniten acetate) is a first-in-class small molecule transcription inhibitor of the AR NTD. Nonclinical studies demonstrated activity against both full length and resistance-related AR species, including AR-v7. Methods: Open-label, single-arm, Phase 1/2 study evaluating EPI-506 administered orally once-daily. The Phase 1 is a 3+3 design to establish the safety, pharmacokinetic (PK) profile, and recommended phase 2 dose of EPI-506. Anti-tumor activity is also evaluated. Inclusion criteria included: mCRPC with progression after ≥1 line of hormonal therapy or chemotherapy, and progression on enzalutamide and/or abiraterone. Results: Eighteen patients (pts) have been enrolled in the dose escalation phase over 5 dose levels (80, 160, 320, 640, 1280 mg). Median age was 71 (range 58-87). Prior treatments included enzalutamide only (N = 7), abiraterone only (N = 2) or both (N = 9). Six pts have had prior chemotherapy. Seven pts have discontinued due to disease progression and 2 pts due to adverse events (AEs): Grade 4 elevated amylase (related) and Grade 4 gastrointestinal bleeding (unrelated). Median exposure was 98.5 days (range 26-338). Most frequently reported treatment emergent AEs were diarrhea (N = 7), nausea (N = 5) and fatigue (N = 3). One Grade 3 AE (AST elevation) at 1280 mg and one Grade 4 AE (increased amylase) at 640 mg were reported. PK data demonstrate a dose-proportional profile for Cmax and AUC coupled with an initial negative food effect up to 640 mg. At week 4 of continuous dosing, 3 of 18 evaluable pts demonstrated PSA declines ranging from 9 to 18% receiving doses ≥640 mg. Conclusions: EPI-506 is well-tolerated with a favorable safety profile. PK indicates dose-proportionality. PSA declines have been observed at doses associated with sub-therapeutic exposure in preclinical studies. This study is the first to evaluate targeting the AR NTD, a region critical for transcriptional function of all known AR species. Clinical trial information: NCT02606123.

Food effects in paediatric medicines development for products Co-administered with food

A small amount of food is commonly used to aid administration of medicines to children to improve palatability and/or swallowability. However the impact of this co-administered food on the absorption and subsequent pharmacokinetic profile of the drug is unknown. Existing information on food effects is limited to standard protocols used to evaluate the impact of a high fat meal in an adult population using the adult medication. In the absence of a substantial body of data, there are no specific guidelines available during development of paediatric products relating to low volumes of potentially low calorie food.This paper brings together expertise to consider how the impact of co-administered food can be risk assessed during the development of a paediatric medicine. Two case studies were used to facilitate discussions and seek out commonalities in risk assessing paediatric products; these case studies used model drugs that differed in their solubility, a poorly soluble drug that demonstrated a positive food effect in adults and a highly soluble drug where a negative food effect was observed. For poorly soluble drugs risk assessments are centred upon understanding the impact of food on the in vivo solubility of the drug which requires knowledge of the composition of the food and the volumes present within the paediatric gastrointestinal tract. Further work is required to develop age appropriate in vitro and in silico models that are representative of paediatric populations.For soluble drugs it is more important to understand the mechanisms that may lead to a food effect, this may include interactions with transporters or the impact of the food composition on gastro-intestinal transit or even altered gastric motility. In silico models have the most promise for highly soluble drug products although it is essential that these models reflect the relevant mechanisms involved in potential food effects.The development of appropriate in vitro and in silico tools is limited by the lack of available clinical data that is critical to validate any tool. Further work is required to identify globally acceptable and available vehicles that should be the first option for co-administration with medicines to enable rapid and relevant risk assessment.

Mechanistic investigation of the negative food effect of modified release zolpidem

AimsWhen administered orally as either an immediate or modified release dosage form, zolpidem demonstrates a negative food effect, i.e. decrease in Cmax and AUC. The aim of the study was to arrive at a better understanding of the absorption of this BCS class I compound in vivo and to simulate the observed plasma profiles using in vitro and in silico methods. MethodsPharmacokinetic profiles of zolpidem are presented from a bioavailability (8mg intravenous; 10mg immediate release Stilnox®; 10mg and 12.5mg modified release Ambien® CR) and from a food effect study (12.5mg modified release Ambien® CR). The dissolution behavior of the 12.5mg strength was investigated using compendial methods in the USP apparatus II and using biorelevant methods in the USP apparatus III and IV. The mean plasma profiles as well as selected individual plasma profiles were simulated with Simcyp® and GastroPlus™. The absorption behavior was additionally investigated using the Qgut model, which entails algebraic deconvolution of all individual profiles, incorporating both first pass gut and liver extraction. ResultsIt was possible to simulate the mean plasma profiles using a “middle-out” approach, based on in vitro data combined with pharmacokinetic parameters obtained after intravenous administration, using PBPK software (Simcyp® and GastroPlus™), resulting in average fold error (AFE) values <1.5. Deconvolution verified that the in vivo absorption rate from the modified release formulation is controlled by the formulation in the fasted state, whereas in the fed state, the absorption rate is mainly controlled by gastric emptying. One-stage in vitro tests suggested that interactions with meal components, resulting in incomplete release, may be the source of the negative food effect for both the immediate and modified release formulations. ConclusionsThe present study demonstrated that a combination of biorelevant dissolution testing with modeling approaches enables a mechanistic understanding of the absorption of zolpidem from various formulations and can serve as a useful biopharmaceutical approach for the development of modified release solid oral dosage forms.

Supersaturation of zafirlukast in fasted and fed state intestinal media with and without precipitation inhibitors

Poor water solubility is a bottle neck in the development of many new drug candidates, and understanding and circumventing this is essential for a more effective drug development. Zafirlukast (ZA) is a leukotriene antagonist marketed for the treatment of asthma (Accolate®). ZA is poorly water soluble, and is formulated in an amorphous form (aZA) to improve its solubility and oral bioavailability. It has been shown that upon dissolution of aZa, the concentration of ZA in solution is supersaturated with respect to its stable crystalline form (ZA monohydrate), and thus, in theory, the bioavailability increases upon amorphization of ZA. The polymers hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone (PVP), often used as stabilizers of the supersaturated state, are in the excipient list of Accolate®. It is not recommended to take Accolate® with food, as this reduces the bioavailability by 40%.The aim of this study was to investigate the effect of simulated fasted and fed state intestinal media as well as the effect of HPMC and PVP on the supersaturation and precipitation of ZA in vitro.Supersaturation of aZA was studied in vitro in a small scale setup using the μDiss Profiler™. Several media were used for this study: One medium simulating the fasted state intestinal fluids and three media simulating different fed state intestinal fluids. Solid state changes of the drug were investigated by small angle x-ray scattering. The duration wherein aZA was maintained at a supersaturated state was prolonged in the presence of HPMC and lasted more than 20h in the presence of PVP in a fasted state intestinal medium. The presence of PVP increased the concentration of drug dissolved in the supersaturated state. The duration of supersaturation was shorter in fed than in a fasted state simulated intestinal media, but the concentration during supersaturation was higher. It was thus not possible to predict any positive or negative food effects from the dissolution/precipitation curves from different media. Lipolysis products in the fed state simulated media seemed to cause both a negative effect on the duration of supersaturation, and an increased drug concentration during supersaturation. In contrast, when testing the effect of a fed state simulated medium compared to the fasted state medium, in the presence of PVP, a clear negative effect was seen on the dissolution/precipitation curved of the fed state medium. The drug concentration during supersaturation was marginally different in the two media, but a precipitation of ZA was seen in the fed state medium, which was not observed in the fasted state medium. Solid state transformation from aZA to ZA monohydrate (mhZA) upon precipitation of the supersaturated solutions was confirmed by small angle x-ray scattering. All of these results can explain the described in vivo behavior of ZA. For ZA simple dissolution experiments in vitro can be used to examine supersaturation, effectiveness of PI and potential food effects on these.

A Food Effect Study of an Oral Thrombin Inhibitor and Prodrug Approach To Mitigate It.

LB30870, a new direct thrombin inhibitor, showed 80% reduction in oral bioavailability in fed state. The present study aims to propose trypsin binding as a mechanism for such negative food effect and demonstrate a prodrug approach to mitigate food effect. Effect of food composition on fed state oral bioavailability of LB30870 was studied in dogs. Various prodrugs were synthesized, and their solubility, permeability, and trypsin binding affinity were measured. LB30870 and prodrugs were subject to cocrystallization with trypsin, and the X-ray structures of cocrystals were determined. Food effect was studied in dogs for selected prodrugs. Protein or lipid meal appeared to affect oral bioavailability of LB30870 in dogs more than carbohydrate meal. Blocking both carboxyl and amidine groups of LB30870 resulted in trypsin Ki values orders of magnitude higher than that of LB30870. Prodrugs belonged to either Biopharmaceutical Classification System I, II, or III. X-ray crystallography revealed that prodrugs did not bind to trypsin, but instead their hydrolysis product at the amidine blocking group formed cocrystal with trypsin. A prodrug with significantly less food effect than LB30870 was identified. Binding of prodrugs to food components such as dietary fiber appeared to counteract the positive effect brought with the prodrug approach. Further formulation research is warranted to enhance the oral bioavailability of prodrugs. In conclusion, this study is the first to demonstrate that the negative food effect of LB30870 can be attributed to trypsin binding. Trypsin binding study is proposed as a screening tool during lead optimization to minimize food effect.

Evaluation of the Use of Göttingen Minipigs to Predict Food Effects on the Oral Absorption of Drugs in Humans

This study investigated the oral absorption of drugs in minipigs to predict food effects in man. The protocol was based on a previously described model in dogs and further investigated the food source (i.e., US FDA breakfast or a nutritional drink) and food quantities. Two poorly soluble compounds were investigated [pravastatin (negative food effect) and atazanavir (positive food effect)] in Göttingen minipigs after seven different food regimens. The gastric emptying rate was evaluated by coadministration of acetaminophen. In short, the results demonstrated longer gastric emptying times in minipigs when compared with humans, within a range from 2.3 to 8.4 h dependent on the food regimen. There were no significant differences in drug absorption between fed and fasted state for the two compounds. The study showed that the dog protocol could not be transferred directly to minipigs, but needs further investigation and adjustments in order to get a valid model using Göttingen minipigs for the evaluation of food effects on drug absorption in humans.

Viscosity-mediated negative food effect on oral absorption of poorly-permeable drugs with an absorption window in the proximal intestine: In vitro experimental simulation and computational verification

Concomitant food intake can diminish oral absorption of drugs with limited permeability and an absorption window in the proximal intestine, due to viscosity-mediated decrease in dosage form disintegration time and drug dissolution rate. Three poorly-permeable drugs (atenolol, metformin hydrochloride, and furosemide) exhibiting negative food effect, and one highly-soluble and highly-permeable (metoprolol tartrate), serving as a negative control, were selected for the study. In vitro and in silico tools were used to evaluate the influence of media viscosity on drug bioperformance under fasted and fed conditions. The obtained results demonstrated that increased medium viscosity in the presence of food is one of the key factors limiting oral absorption of drugs with limited permeability and absorption restricted to the upper parts of the intestine, while having negligible effect on pharmacokinetic profile of drugs with pH- and site-independent absorption. Dissolution medium pH 4.6 with the addition of hydroxypropyl methylcellulose was suggested to simulate postprandial gastric conditions for drugs whose solubility under these conditions is not the limiting factor for drug absorption. In addition, drug formulation was found to be an interfering factor in relation to the impact of medium viscosity on the rate and extent of drug absorption.

Suitability of a Minipig Model in Assessing Clinical Bioperformance of Matrix and Multiparticulate Extended-Release Formulations for a BCS Class III Drug Development Candidate

Preclinical studies in dogs are often employed as part of formulation screening process. However, the shorter transit time and colonic length in dogs may result in underestimation of absorption, especially for extended-release (ER) formulations. In the recent years, minipigs have attracted attention as an alternative animal model. However reports on studies with ER formulations are limited. In this manuscript, we report the first comprehensive comparison of minipig and clinical data for two types of ER formulations. Matrix tablets and multiparticulates in capsules of a BCS Class III compound were tested in the Yucatan minipig model. The relative performance of the formulations in minipigs in the fasted state was reasonably aligned with the clinical observations. The minipig model was able to rank order the formulations, reflecting the targeted release rate, in a manner consistent with the clinical data. Minipigs also reflected the loss of bioavailability relative to the immediate-release formulation. A level C in vitro/in vivo correlation was demonstrated for both the minipig and clinical data. However, an assessment of food effect in the minipig model appeared challenging, especially for the matrix formulation for which a negative food effect was observed in minipigs compared with the positive food effect in the clinic.

Ion Pairing with Bile Salts Modulates Intestinal Permeability and Contributes to Food–Drug Interaction of BCS Class III Compound Trospium Chloride

In the current study the involvement of ion pair formation between bile salts and trospium chloride (TC), a positively charged Biopharmaceutical Classification System (BCS) class III substance, showing a decrease in bioavailability upon coadministration with food (negative food effect) was investigated. Isothermal titration calorimetry provided evidence of a reaction between TC and bile acids. An effect of ion pair formation on the apparent partition coefficient (APC) was examined using (3)H-trospium. The addition of bovine bile and bile extract porcine led to a significant increase of the APC. In vitro permeability studies of trospium were performed across Caco-2-monolayers and excised segments of rat jejunum in a modified Ussing chamber. The addition of bile acids led to an increase of trospium permeation across Caco-2-monolayers and rat excised segments by approximately a factor of 1.5. The addition of glycochenodeoxycholate (GCDC) was less effective than taurodeoxycholate (TDOC). In the presence of an olive oil emulsion, a complete extinction of the permeation increasing effects of bile salts was observed. Thus, although there are more bile acids in the intestine in the fed state compared to the fasted state, these are not able to form ion pairs with trospium in fed state, because they are involved in the emulsification of dietary fats. In conclusion, the formation of ion pairs between trospium and bile acids can partially explain its negative food effect. Our results are presumably transferable to other organic cations showing a negative food effect.