The Role of Lipids in Mitigation of Food Effect

The effect of food as part of the daily diet on drug absorption has been noted since the 1960s (Sjoqvist, 2010). Food can either increase or decrease the oral bioavailability of drugs, potentially leading to a change in their pharmacological effect. Therefore, assessing the food effect on the bioavailability of a drug is important to optimize its efficacy and safety. Since the change in bioavailability can depend on the amount of lipid in the food, the clinical studies for food effects include low and high-fat meals as described by FDA Guidelines.

In this paper, after a general description of the effect of food on gastrointestinal physiology, drugs, and formulation, the role of lipids has been explained along with their digestion and absorption mechanisms. Case studies with self-emulsifying drug delivery systems (SEDDS) have been presented as a way to mitigate the food effect. Current in vitro methods to determine indicators for the food effect during the drug development stage have also been described.

Effect of Food on Gastrointestinal Physiology, Drugs, and Formulations

For certain drugs, interactions with food can lead to reduced drug absorption (negative food effect), delayed absorption rate, or increased absorption (positive food effect). These interactions can result in significant inter and intra-subject variabilities. The most clinically relevant and important change in food-drug interaction is often seen in the extent of bioavailability, as evidenced by changes in Cmax and AUC.

Delayed absorption, occurring due to slowed gastric transit in the fed state, can extend the time to reach peak concentrations in the blood (Tmax). However, in cases where pharmacodynamics relies on overall drug exposure rather than peak plasma levels, delayed absorption may not be clinically significant (O’Shea et al., 2019).

The ingestion of food initiates a series of physiological changes in the gastrointestinal (GI) tract. Table 1 summarizes these changes as the ingested food moves from the esophagus to the stomach, initiating dynamic changes in digestion that can impact drug formulations. The stomach’s volume increases significantly to accommodate undigested food, leading to a dilution of stomach fluids and an increase in luminal pH from 1.5 in the fasted state to 4.5 in the fed state. Gastric fluid, containing acidic and enzymatic components, homogenizes the food and buffers the gastric environment (Varum, 2013). The pH changes can introduce variability in drug dissolution/solubility, affecting the passive diffusion across the intestinal membrane. Additionally, pH and enzymatic changes can influence drug stability in the GI tract, leading to variability in oral bioavailability (Abuhelwa, 2017).

Concurrently, motility and contraction in the stomach during the fed state, responsible for mixing and milling and the mechanical digestion of food, can impact the dissolution and dispersion of drug formulations. Furthermore, the volume, viscosity, and composition of the food, along with the secretion of digestive enzymes, can affect the contraction of the pyloric sphincter, causing a delay in gastric emptying (Varum, 2013).

These observed physiological changes are commonly associated with dietary intake, while the effects of digestive enzymes are specific to the nature of food components (e.g., pepsin for proteins, and lipase for lipids). Specifically, changes in the intestinal secretion of bile and pancreatic lipase are triggered by the intake of dietary lipids.

How do Dietary Lipids affect Bioavailability?

The lipid component of food plays a vital role in enhancing the bioavailability of drugs that are poorly soluble or permeable. This enhancement primarily occurs through:

• increasing the in vivo drug solubilization capacity of the gastrointestinal fluid in response to the secretion of bile salts and digestion of lipid components of food
• creating lipidic microenvironments for poorly water-soluble drugs and
• enhancing passive diffusion across enterocytes and reducing the first-pass effect due to lipid digestion and metabolism (Clarysse et al., 2009; Porter et al., 2007)

Common dietary lipids include fats (such as butter and meat tallow) and vegetable oils. These dietary lipids are composed of triglycerides, which are glycerol esters of fatty acids with varying chain lengths, as shown in Table 2. Most common dietary fats and oils consist of esters of long-chain fatty acids (>C12), with the exception of coconut oil.

When any of these lipids are consumed as part of the daily diet, their digestion begins in the stomach through the activation of gastric lipase due to increased pH. Gastric lipase initiates the hydrolysis of triglycerides into free fatty acids and monoglycerides. As the lipolytic products reach the duodenum, the secretion of pancreatic lipase, co-lipase, and bile salts is triggered (Pentafragka et al., 2020). The majority of lipolysis takes place in the duodenum, forming a complex system of intestinal colloidal phases that facilitate the permeation of dietary lipids into enterocytes via passive diffusion. When a poorly soluble drug is co-administered with such dietary lipids, colloidal structures formed by the lipolytic products and bile salts enable permeation by entrapping the drug molecule and enhancing its solubility in gastrointestinal fluid (O’Driscoll, 2002).

Once lipolytic products cross the intestinal membrane, if they are composed of long-chain fatty acids (>C12), they are transported to the endoplasmic reticulum, where they undergo re-esterification to form triglycerides. These triglycerides, along with phospholipids and cholesterol, combine with apolipoprotein to form chylomicrons. When a lipophilic drug is co-administered with dietary lipids containing long-chain fatty acid esters (such as bacon fat, olive oil, and canola oil), it can become part of this process. The chylomicrons carrying the drug are then secreted into the lymphatic vessels before joining the systemic circulation at the thoracic duct’s connection. Lipophilic drugs (such as testosterone undecanoate, halofantrine, cyclosporine, and cannabidiol) participating in chylomicron formation and lymphatic uptake can experience enhanced bioavailability by bypassing the first hepatic metabolism.

Some lipids, such as those in coconut oil, are esters of fatty acids with medium chain length (<C12). These lipids undergo hydrolysis by lipase enzymes in the duodenum in a similar manner. Once the digestive products of these lipids permeate into enterocytes, they are primarily absorbed via the portal route, with minimal lymphatic uptake. Lipids containing medium-chain fatty acids can enhance bioavailability by improving the dissolution of drugs in vivo and enhancing permeation through the modulation of tight junctions (Kirpich et al., 2012).

The enhanced bioavailability for some drugs can depend on the amount of lipids in the food as the stimulation of lymphatic transport can depend on the quantity of administered lipids (Trevaskis, 2008)

Lipid Formulations as a Strategy to Reduce Food Effect

In cases of a positive food effect, increased bioavailability with co-administered food can be variable. Therefore, developing drug formulations that are not influenced by food would be preferable to optimize bioavailability. If the positive food effect is attributed to enhanced drug solubility in the gastrointestinal lumen, solubility-enhancing technologies can mitigate the food effect. These technologies, including lipid-based formulations, amorphous solid dispersion, nanosized drug preparations, prodrugs and salts, and cyclodextrin complexation, have been discussed with examples in a review by Meola et al., 2022. The authors identified lipid-based formulations as the most widely explored technology to enhance bioavailability and reduce the food effect of poorly water-soluble drugs.

When formulating a drug with poor solubility/permeability using lipid vehicles, which share similar chemistry with dietary lipids, the bioavailability enhancement mechanisms for a positive food effect already exist in the formulation. Consequently, the drug does not have to rely on dietary lipids for increased exposure. Therefore, formulating with lipids can serve as a means to control the food effect.

Lipid formulations typically include oily vehicles, surfactants, and cosurfactants to create self-emulsifying drug delivery systems (SEDDS). Similar to dietary lipids, SEDDS can enhance the solubility and dispersibility of the API in the GI tract, trigger lipolysis, improve permeability, and facilitate absorption through the hepatic/ lymphatic route.

Food effect mitigation by SEDDS formulations has been documented for various APIs (see Table 3). In in vivo studies, a significant reduction in positive food effect was observed for APIs falling into BCS II and IV categories. Lipid-based formulations can effectively mitigate positive food effects associated with poor solubility or permeability of APIs. However, if the food effect is attributed to factors like pH differences or specific ingredients in the food affecting the drug, lipids alone may not be sufficient to mitigate the food effect.

A Case Study with Venetoclax to Mitigate the Food Effect with SEDDS

Venetoclax (Venclexta^®/Venclyxto^® tablet) is a BCL-2 inhibitor, indicated for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. It has a MW of 868.44, very low aqueous solubility with LogP 5.5, and it is classified as BCS IV.

According to the FDA-approved product label (Venclexta^® tablet), there is a 5-fold Cmax and AUC increase with a high-fat meal.

Koehls et al (2022) developed a lipophilic salt of the API (venetoclax docusate) and created SEDDS formulations to mitigate the food effect of venetoclax. The formulations include:

1. Long Chain (LC)-SEDDS of 30% of glyceryl mono-oleate (Peceol^®) and 70% of surfactant mix (Kolliphor^®RH40: Tween^®85, 1:1)
2. Medium Chain (MC)-SEDDS of 30 % of MCM (Capmul^® MCM) and 70% of surfactant mix (Kolliphor^®RH40: Tween^®85, 1:1)
3. 100% of surfactant mix (Kolliphor^®RH40: Tween^®85, 1:1)

The bioavailability of these formulations in the fasted state was compared with the bioavailability of the commercial product (Venclyxto® tablet) fed and fasted states in male landrace pigs, Figure 1.

The SEDDS formulations showed an increase in oral bioavailability of venetoclax docusate up to 2.4-fold compared to the commercial amorphous solid dispersion in the fasted state. All SEDDS formulations in the fasted state showed a similar bioavailability compared to Venclyxto^® in the fed state. This study highlights the feasibility of SEDDS not only for enhancing the bioavailability of highly lipophilic and BCS class IV compounds but also for mitigating the food effect.

In Vitro Methods in the Assessment of Food Effect

Assessment of food effect in vivo is usually performed during clinical studies, as described by FDA guidelines: the pharmacokinetic parameters are assessed with a high-fat meal to ensure appropriate dosing. Understanding the food effect at the early stages of drug development is crucial to designing a formulation to mitigate the food effect. In vitro, models can be helpful in their initial prediction. However, the prediction/assessment of food effects in vitro is rather complex. The main limitation of in vitro tests is the lack of simulation of dynamic processes, as food can simultaneously affect the physiology of the GI tract, permeability, and overall absorption by enhancing lymphatic uptake. In vitro methods can help to identify indicators, but overall quantitative prediction still relies on clinical studies. There are multiple parameters that can be determined as indicators for any potential food effect:

• Physicochemical properties of drugs – In a study conducted by Dr. Singh, more than 100 structurally diverse actives with published food effect data were evaluated for the correlation between their aqueous solubility, log P, and dose/solubility ratio with food effect. It was observed that actives with poor aqueous solubility and higher log P exhibited a prominent food effect (Singh, 2005). As suggested by (Bennet, 2023), the Biopharmaceutics Classification System (BCS) can be used in the prediction of food effects. The BCS classification is a system where drugs are classified based on intestinal permeability and aqueous solubility, which are dependent on the physicochemical properties of the drug. BCS II i.e. poorly soluble and highly permeable and IV i.e. poorly soluble and poorly permeable drugs are more prone to food effect
• The effect of pH on solubility and stability of API – Roche compound, RZ-50, were evaluated using compendial and biorelevant media using USP type II and III apparatus, and PK data was obtained from dogs in the postprandial state. Biorelevant fed-state media used with type III apparatus exhibited better IVIVC. There are several examples in published literature demonstrating better IVIVC with biorelevant dissolution testing than traditional dissolution testing.
• Solubility in lipid vehicles – Certain lipophilic drugs exhibit good solubility in lipid vehicles, which can be an indication of enhanced solubility in the GI tract with dietary lipids. It also provides the potential to develop a SEDDS formulation as a food effect mitigation strategy.

Tests to simulate digestion: Digestion of food in the gut is mainly carried out by two processes i.e. mechanical digestion and enzymatic digestion, and in vitro models can help simulate one or both of these digestion processes. The most current methods are:

• In vitro lipolysis tests
• Dynamic gastric/intestinal models

In vitro, lipolysis tests

The pH-stat lipolysis models can be classified into intestinal and gastrointestinal models. The intestinal pH stat model is the most used in vitro model given its simplistic design in terms of setup and operation. The entire process occurs in a jacketed beaker where the first few minutes of the test involve dispersion of the formulation followed by digestion with the addition of porcine pancreatic lipase to mimic the digestion in the small intestine. Throughout the process, pH is maintained using sodium hydroxide, and aliquots collected during the process are centrifuged and evaluated for solubilized activity in the aqueous and oily phases.

In the in vitro lipolysis test, fasted state intestinal media is used considering that poorly soluble drugs are mostly subject to food effects, and developing an optimized formulation using fasted conditions will minimize potential risks associated with food effects (Hywel Williams, 2014).

One of the drawbacks of the pH-stat lipolysis model is that gastric digestion is not accounted for, which is responsible for the digestion of 4-40% triglycerides.(Ragna Berthelson, 2019). Based on the study conducted by (Frederic Carriere, 1993) to evaluate the contribution of gastric and pancreatic lipases in vivo lipolysis, it was concluded that gastric lipase may be responsible for the hydrolysis of 17.5% of the triglyceride acyl chains. Incorporation of the gastric step in the pH-stat lipolysis model can be made possible by starting the test with gastric media and then changing it to intestinal media. Gastric lipase from animal or microbial sources can be used as the closest substitute given their commercial availability. The gastric digestion simulation can also be carried out along with intestinal lipolysis using a 2-step one-compartment model or a 2-step two-compartment model(Ragna Berthelson, 2019).

In two studies performed by Metter Klitgaard and group (Mette klitgaard, 2020) and (Philip Carsten Christophersen, 2014) and group, it was confirmed that gastrointestinal models were more predictive of the in vivo performance.

A high throughput (HTP) lipolysis model can be used to expedite in vitro lipolysis testing especially when large numbers of formulations have to be evaluated. Its potential for in vivo correlation or its ability to determine food effects has not been studied to date. However, an in vitro model with pH-stat has been used to assess the viability of the HTP model ( (Mette D. Mosgaard, 2015).

Dynamic Gastric/Intestinal Models

The dynamic gastric model (DGM) consists of two sections simulating the stomach and the antrum which aim to mimic complex mixing, biochemical processes, and emptying patterns of the human stomach (Laura M. Masona, 2016). It does not account for the intestinal digestion process. The model is computer-controlled and was originally designed for the food industry. It is widely used in pharmaceutical research to predict in vivo behavior, especially in fasted and fed conditions. Its use has been reported for oral formulations like immediate release, sustained release, and amorphous dispersions, especially to predict food effects and in vivo performance. However, in the case of lipid-based formulations, the DGM has been mainly used to study the effect of mechanical stress on the emulsification of self-emulsifying drug delivery systems (SEDDS) (Ragna Berthelson, 2019).

Similar to DGM, the TNO gastrointestinal models (TIM) are dynamic, computer-controlled systems that allow the evaluation of a formulation in the entire digestive system, including the stomach and the small and large intestines. The temperature is controlled by water jackets, and the peristaltic movement is simulated in each compartment by alternatively contracting pumps and valves. They are designed to allow for the addition of all relevant secretions (enzymes, electrolytes, bile salts, etc.) and control the transit time from one compartment to another. Samples can be taken from any compartment throughout the digestion process to get a real-time analysis. Like the DGM, real food can be used to evaluate fed-state conditions. However, this system does not replace an in vivo study as it cannot mimic absorption or metabolism through gastric cell walls. Moreover, it is a complex system that needs experience, and expertise and comes with a price tag that may not be feasible and/or desired in a standard laboratory setting (Ragna Berthelson, 2019). The first version the company developed was abbreviated as TIM-1. They later developed a simpler version called Tiny–TIM.

In a study, TIM-1 and tiny-TIM models were evaluated for bioaccessibility under fasted and fed states using four poorly soluble actives like ciprofloxacin, posaconazole, nifedipine, & fenofibrate. In the fed state, dosage forms were given with high-fat meals, along with relevant digestion medium. Fasted state tests, on the other hand, were done with water and gastric juice only. Gastric emptying and pH were also adjusted for fed and fasted states to reflect the different conditions in our bodies under each state. Based on the results, the absence and presence of food effects were correctly predicted by both systems for ciprofloxacin and posaconazole, respectively. Differences in bioaccessibility, when comparing immediate release with the extended-release formulations of ciprofloxacin and nifedipine formulations, were also observed with both systems. Moreover, for fenofibrate, higher bio-accessibility was evident using nanoparticle formulation compared with the micro-particle formulation in both systems (Miriam Verweia, 2016). In another study, acetaminophen immediate-release tablets were studied to simulate the impact of food and establish level A IVIVC to help predict the in vivo bioavailability. Results showed good IVIVC and the TIM model exhibited higher efficiency in mimicking the in vivo performance of the acetaminophen tablets compared to the USP II method (Sabah Souliman, 2006).

Concluding Remarks

Lipids play an important role in food effects as they can alter the solubility and absorption of drugs. This effect can be particularly pronounced in poorly soluble/permeable drugs. Therefore, lipid formulations can be a feasible approach to mitigate the food effects of such drugs. In vitro models such as pH-stat lipolysis and dynamic gastric/intestinal models can serve as helpful tools to assess food effects. However, the overall quantitative prediction of the food effect on the pharmacology of a drug still relies on clinical studies.

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Author Details 

Inayat Ellis, PhD- Scientific Affairs Director, Pharmaceutical Division, Gattefossé USA; Masumi Dave, PhD- Application Laboratory Manager, Pharmaceutical Division, Gattefossé USA

Publication Details 

This article appeared in American Pharmaceutical Review:

 Vol. 27, No. 3

April 2024

Pages: 53-57

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