Drug Absorption Research Articles

Novel Vesicular Bilosomal Delivery Systems for Dermal/Transdermal Applications.

The application of therapeutically active molecules through the dermal/transdermal route into the skin has evolved as an attractive formulation strategy in comparison to oral delivery systems for the treatment of various disease conditions. However, the delivery of drugs across the skin is limited due to poor permeability. Dermal/transdermal delivery is associated with ease of accessibility, enhanced safety, better patient compliance, and reduced variability in plasma drug concentrations. It has the ability to bypass the first-pass metabolism, which ultimately results in steady and sustained drug levels in the systemic circulation. Vesicular drug delivery systems, including bilosomes, have gained significant interest due to their colloidal nature, improved drug solubility, absorption, and bioavailability with prolonged circulation time for a large number of new drug molecules. Bilosomes are novel lipid vesicular nanocarriers comprising bile salts, such as deoxycholic acid, sodium cholate, deoxycholate, taurocholate, glycocholate or sorbitan tristearate. These bilosomes are associated with high flexibility, deformability, and elasticity attributed to their bile acid component. These carriers are advantageous in terms of improved skin permeation, increased dermal and epidermal drug concentration, and enhanced local action with reduced systemic absorption of the drug, resulting in reduced side effects. The present article provides a comprehensive overview of the biopharmaceutical aspects of dermal/transdermal bilosome delivery systems, their composition, formulation techniques, characterization methods, and applications.

The vehicle of administration, feed or water, and prandial state influence the oral bioavailability of amoxicillin in piglets.

Feed and water components may interact with drugs and affect their dissolution and bioavailability. The impact of the vehicle of administration (feed and water) and the prandial condition of weaner piglets on amoxicillin´s oral bioavailability was evaluated. First, amoxicillin's in vitro dissolution and stability in purified, soft, and hard water, as well as release kinetics from feed in simulated gastric and intestinal media were assessed. Then, pharmacokinetic parameters and bioavailability were determined in fasted and fed pigs using soft water, hard water, or feed as vehicles of administration following a balanced incomplete block design. Amoxicillin showed similar dissolution profiles in soft and hard water, distinct from the dissolution profile obtained with purified water. Complete dissolution was only achieved in purified water, and merely reached 50% in soft or hard water. Once dissolved, antibiotic concentrations decreased by around 20% after 24h in all solutions. Korsmeyer-Peppas model best described amoxicillin release from feed in simulated gastric and intestinal media. Feed considerably reduced antibiotic dissolution in both simulated media. In vivo, amoxicillin exhibited significantly higher bioavailability when delivered via water to fasted than to fed animals, while in-feed administration yielded the lowest values. All treatments showed a similar rate of drug absorption. In conclusion, we demonstrated that water and feed components, as well as feed present in gastrointestinal tract of piglets decrease amoxicillin´s oral bioavailability. Therefore, the use of oral amoxicillin as a broad-spectrum antibiotic to treat systemic infections in pigs should be thoroughly revised.

Recent Updates on Interaction Studies and Drug Delivery of Antimalarials with Serum Albumin Proteins.

This review focuses on recent trends in the binding study of various antimalarial agents with serum albumins in detail. Serum albumin has a significant role in the transport of drugs and endogenous ligands. The nature and magnitude of serum albumin and drug interactions have a tremendous impact on the pharmacological behavior and toxicity of that drug. Binding of drug to serum albumin not only controls its free and active concentration, but also provides a reservoir for a long duration of action. This ultimately affects drug absorption, distribution, metabolism, and excretion. Such interaction determines the actual drug efficacy as the drug action can be correlated with the amount of unbound drug. With the advancement in spectroscopic techniques and simulation studies, binding studies play an increasingly important role in biophysical and biomedical science, especially in the field of drug delivery and development. This review assesses the insight we have gained so far to improve drug delivery and discovery of antimalarials on the basis of a plethora of drug-serum protein interaction studies done so far.

Using An In Vitro Tissue Perfusion System to Detect the Functional Activities of Isolated Intestinal Tubes in Real Time.

Gastrointestinal diseases, which have a high incidence, pose considerable challenges for humans. The small intestine is integral to food and drug digestion and absorption and plays a crucial role in treating these diseases. The intestinal tube movement experiment, a common and essential in vitro method, is utilized to study gastrointestinal dynamics. This includes the preparation of the isolated intestinal tube, as well as the suspension of the prepared intestinal tube in the bath and its connection to a signal detector. This is followed by the recording and analysis of a series of parameters, such as tension, which can be used to assess intestinal motor function, as well as considerations for keeping the intestinal tube active in vitro. The standardized program from sampling to data collection greatly improves the repeatability of the experimental data and ensures the authenticity of the recording of intestinal tension after physiological, pathological, and drug intervention. Here we present the key problems in experimental operation and a valuable reference experimental protocol for studying drugs that regulate gastrointestinal motility.

Edaravone for the Treatment of Motor Neurone Disease: A Critical Review of Approved and Alternative Formulations against a Proposed Quality Target Product Profile.

Edaravone is one of two main drugs for treating motor neurone disease (MND). This review proposes a specific quality target product profile (QTPP) for edaravone following an appraisal of the issues accounting for the poor clinical uptake of the approved IV and oral liquid edaravone formulations. This is followed by a review of the alternative oral formulations of edaravone described in the published patent and journal literature against the QTPP. A total of 14 texts published by six research groups on 18 novel oral formulations of edaravone for the treatment of MND have been reviewed. The alternative oral formulations included liquid and solid formulations developed with cyclodextrins, lipids, surfactants, co-surfactants, alkalising agents, tablet excipients, and co-solvents. Most were intended to deliver edaravone for drug absorption in the lower gastrointestinal tract (GIT); however, there were also four formulations targeting the oral mucosal absorption of edaravone to avoid first-pass metabolism. All the novel formulations improved the aqueous solubility, stability, and oral bioavailability (BA) of edaravone compared to an aqueous suspension of edaravone. A common limitation of the published formulations is the lack of MND-patient-centred data. Except for TW001, no other formulations have been trialled in MND patients. To meet the QTPP of an oral edaravone formulation for MND patients, it is recommended that a tablet of appropriate size and with acceptable taste and stability be designed for the effective sublingual or buccal absorption of edaravone. This tablet should be designed with input from the MND community.

Advances in Modeling Approaches for Oral Drug Delivery: Artificial Intelligence, Physiologically-Based Pharmacokinetics, and First-Principles Models.

Oral drug absorption is the primary route for drug administration. However, this process hinges on multiple factors, including the drug's physicochemical properties, formulation characteristics, and gastrointestinal physiology. Given its intricacy and the exorbitant costs associated with experimentation, the trial-and-error method proves prohibitively expensive. Theoretical models have emerged as a cost-effective alternative by assimilating data from diverse experiments and theoretical considerations. These models fall into three categories: (i) data-driven models, encompassing classical pharmacokinetics, quantitative-structure models (QSAR), and machine/deep learning; (ii) mechanism-based models, which include quasi-equilibrium, steady-state, and physiologically-based pharmacokinetics models; and (iii) first principles models, including molecular dynamics and continuum models. This review provides an overview of recent modeling endeavors across these categories while evaluating their respective advantages and limitations. Additionally, a primer on partial differential equations and their numerical solutions is included in the appendix, recognizing their utility in modeling physiological systems despite their mathematical complexity limiting widespread application in this field.

Recent Progress in Multifunctional Stimuli-Responsive Combinational Drug Delivery Systems for the Treatment of Biofilm-Forming Bacterial Infections.

Drug-resistant infectious diseases pose a substantial challenge and threat to medical regimens. While adaptive laboratory evolution provides foresight for encountering such situations, it has inherent limitations. Novel drug delivery systems (DDSs) have garnered attention for overcoming these hurdles. Multi-stimuli responsive DDSs are particularly effective due to their reduced background leakage and targeted drug delivery to specific host sites for pathogen elimination. Bacterial infections create an acidic state in the microenvironment (pH: 5.0-5.5), which differs from normal physiological conditions (pH: 7.4). Infected areas are characterized by the overexpression of hyaluronidase, gelatinase, phospholipase, and other virulence factors. Consequently, several effective stimuli-responsive DDSs have been developed to target bacterial pathogens. Additionally, biofilms, structured communities of bacteria encased in a self-produced polymeric matrix, pose a significant challenge by conferring resistance to conventional antimicrobial treatments. Recent advancements in nano-drug delivery systems (nDDSs) show promise in enhancing antimicrobial efficacy by improving drug absorption and targeting within the biofilm matrix. nDDSs can deliver antimicrobials directly to the biofilm, facilitating more effective eradication of these resilient bacterial communities. Herein, this review examines challenges in DDS development, focusing on enhancing antibacterial activity and eradicating biofilms without adverse effects. Furthermore, advances in immune system modulation and photothermal therapy are discussed as future directions for the treatment of bacterial diseases.

Research on molecular characteristics of ADME-related genes in kidney renal clear cell carcinoma

Genes involved in drug absorption, distribution, metabolism, and excretion (ADME) are named ADME genes. However, the comprehensive role of ADME genes in kidney renal clear cell carcinoma (KIRC) remains unclear. Using the clinical and gene expression data of KIRC patients downloaded from The Cancer Genome Atlas (TCGA), ArrayExpress, and the Gene Expression Omnibus (GEO) databases, we cluster patients into two patterns, and the population with a relatively poor prognosis demonstrated higher level of immunosuppressive cell infiltration and higher proportion of glycolytic subtypes. Then, 17 ADME genes combination identified through the least absolute shrinkage and selection operator algorithm (LASSO, 1000 times) was utilized to calculate the ADME score. The ADME score was found to be an independent predictor of prognosis in KIRC and to be tightly associated with the infiltration level of immune cells, metabolic properties, tumor-related signaling pathways, genetic variation, and responses to chemotherapeutics. Our work revealed the characteristics of ADME in KIRC. Assessing the ADME profiles of individual patients can deepen our comprehension of tumor microenvironment (TME) features in KIRC and can aid in developing more personalized and effective therapeutic strategies.

Enhancing hair regeneration: Recent progress in tailoring nanostructured lipid carriers through surface modification strategies.

Hair loss is a prevalent problem affecting millions of people worldwide, necessitating innovative and efficient regrowth approaches. Nanostructured lipid carriers (NLCs) have become a hopeful option for transporting bioactive substances to hair follicles because of their compatibility with the body and capability to improve drug absorption. Recently, surface modification techniques have been used to enhance hair regeneration by improving the customization of NLCs. These techniques involve applying polymers, incorporating targeting molecules, and modifying the surface charge. The conversation focuses on how these techniques enhance stability, compatibility with the body, and precise delivery to hair follicles within NLCs. Moreover, it explains how surface-modified NLCs can improve the bioavailability of hair growth-promoting agents like minoxidil and finasteride. Furthermore, information on how surface-modified NLCs interact with hair follicles is given, uncovering their possible uses in treating hair loss conditions. This review discusses the potential of altering the surface of NLCs to customize them for enhanced hair growth. It offers important information for upcoming studies on hair growth.

Contemporary Nanoemulsion Research: Extensive Examination of Self-Nanoemulsifying Drug Delivery Systems

Abstract: The administration of new pharmaceutical compounds orally can pose certain challenges in terms of drug absorption, bioavailability, and pharmacokinetic profile. However, a widely recognized method for enhancing bioavailability involves lipid-based drug delivery systems. Lipid-based drug delivery systems (LBDDS) are the most favourable method for formulating medicines that have low solubility in water. Nanotechnology exerts a significant impact on the therapeutic efficacy of hydrophobic medicines and has emerged as a crucial method in the field of drug delivery research. Self-nanoemulsifying drug delivery systems (SNEDDs) are an important approach that combines the advantages of lipid-based drug delivery systems (LBDDS) and nanotechnology. SNEDDs are currently the favoured method for enhancing the formulation of pharmaceuticals that have low solubility in water. SNEDDs are homogenous mixtures that can self-emulsify spontaneously with gentle stirring, forming an oil-in-water emulsion that conveniently protects and creates a pathway for the lipophilic drug. The small particle size of <200nm increases the solubilisation capacity of the drug by increasing its surface area. SNEDDs have demonstrated the ability to enhance the bioavailability of medicines that are not easily soluble in water. SNEDDs stand apart from other solubility enhancement approaches due to their inclusion of biodegradable components, their ease of large-scale manufacture, and their numerous potential for drug targeting. The aim of the present review was to provide basic knowledge about formulation, applications, and benefits of using SNEDDs. A detailed manuscript has been prepared by doing a literature survey on databases like Google Scholar, SCOPUS, and Pubmed to review the current state of nanotechnology applications, industrial developments, and challenges for using SNEDDS as a novel delivery system is provided in this manuscript.

Cutting-edge Advances in Nanocarrier-Facilitated Topical Drug Delivery Systems for Targeted Skin Cancer Therapy: A Comprehensive Review.

Skin cancer is one of the most common and complex types of the disease, resulting in a high mortality rate worldwide. Skin cancer can be treated with chemotherapy, surgery, radiotherapy, etc. In most cases, a patient's condition and the type of skin cancer determine the recommended treatment options. As a result of poor penetration of the drug into stratum corneum or lesions, low efficacy, and higher concentrations of active pharmaceutical ingredients required to achieve a therapeutic effect, the efficacy of skin cancer therapy has been limited. The high dose requirement, as well as poor bioavailability at the site of action, causes skin inflammation, which greatly hinders drug absorption. This review mainly focuses on research on nanocarriers for sitespecific and controlled delivery of therapeutics for skin cancer treatment. The information related to various nanocarriers systems for skin cancer will be illustrated. This also focused on patents, clinical trials, and research carried out in the field of liposomes, niosomes, ethosomes, nanoparticles, microemulsion, nanoemulsions, gels, nanogels, hydrogels, dendrimers, and nanofibers for treating skin cancer. Nanotechnology-based therapy has shown great promise in controlling skin cancer and can be used to deliver drugs more effectively.

Expanding Arsenal against Ocular Diseases through Nanoemulsion: Success So Far and the Road Ahead.

The eye is a most delicate organ protected by several complex biological barriers that are static and dynamic. The presence of these ocular barriers retards drug absorption from topically applied dosage forms at the conjunctival sac. The efficient topical delivery of the drug into the globe is more difficult to achieve and there is a need to develop a topical formulation that may reduce the use of injections and increase patient compliance with decreased frequency of administration. In the advancements of research in nanotechnology, nanoemulsions can be used as biocompatible carriers to deliver the drug to the ocular cavity. The lipophilic globules can increase the solubility of hydrophobic cargos which provides increased permeation ability and ocular bioavailability which can sustain drug release and corneal retention. Because of their small size, these formulations do not cause blurring of vision. Nanoemulsions (NEs) over the past decade have been used to treat several ocular diseases in the anterior eye segment. This review summarizes the economic burden, pathology of ocular diseases, formulation considerations for ocular formulations, and recent advances of these NEs as effective carriers for ocular drug delivery highlighting their performance in pre-clinical studies.

Benefits of combining supersaturating and solubilizing formulations – Is two better than one?

A variety of enabling formulations has been developed to address poor oral drug absorption caused by insufficient dissolution in the gastrointestinal tract. As the in vivo performance of these formulations is a result of a complex interplay between dissolution, digestion and permeation, development of suitable in vitro assays that captures these phenomena are called for. The enabling-absorption (ENA) device, consisting of a donor and receiver chamber separated by a semipermeable membrane, has successfully been used to study the performance of lipid-based formulations. In this work, the ENA device was prepared with two different setups (a Caco-2 cell monolayer and an artificial lipid membrane) to study the performance of a lipid-based formulation (LBF), an amorphous solid dispersion (ASD) and the potential benefit of combining the two formulation strategies. An in vivo pharmacokinetic study in rats was performed to evaluate the in vitro-in vivo correlation. In the ENA, high drug concentrations in the donor chamber did not translate to a high mass transfer, which was particularly evident for the ASD as compared to the LBF. The solubility of the polymer used in the ASD was strongly affected by pH-shifts in vitro, and the ph_dependence resulted in poor in vivo performance of the formulation. The dissolution was however increased in vitro when the ASD was combined with a blank lipid-based formulation. This beneficial effect was also observed in vivo, where the drug exposure of the ASD increased significantly when the ASD was co-administered with the blank LBF. To conclude, the in vitro model managed to capture solubility limitations and strategies to overcome these for one of the formulations studied. The correlation between the in vivo exposure of the drug exposure and AUC in the ENA was good for the non pH-sensitive formulations. The deconvoluted pharmacokinetic data indicated that the receiver chamber was a better predictor for the in vivo performance of the drug, however both chambers provided valuable insights to the observed outcome in vivo. This shows that the advanced in vitro setting used herein successfully could explain absorption differences of highly complex formulations.

Exploration of Abiraterone acetate loaded Nanostructured lipid carriers for bioavailability improvement and circumvention of fast-fed variability.

Abiraterone acetate (ABA), a biopharmaceutical class IV drug suffers from solubility and permeability pitfalls resulting in limited oral bioavailability and positive food effect, i.e. multi-fold enhancement in drug absorption in the presence of food. This poses difficulties to physicians towards the estimation of dose and dosage regimen required for efficacious therapy of prostate cancer (PCa). Nanostructured lipid carriers (NLC) have demonstrated tremendous outcomes in enhancing the oral bioavailability of various entities along with food effect attenuation. In this study, Quality by design and multivariate analysis was employed for optimization of ABA loaded NLC (ABA NLC). The optimal size, PDI and zeta potential obtained using QbD were 134.6nm, 0.163 and -15.7mV respectively. Ex vivo qualitative and quantitative intestinal permeability studies demonstrated improved traversion of NLC through the intestinal segments. In vitro dissolution profile in biorelevant fast and fed gastric and intestinal media revealed minimal differences for ABA NLC compared to ABA. In vivo pharmacokinetics was performed to decipher the efficacy of ABA NLC in mitigating the food effect of ABA. The studies demonstrated 14.51-fold and 1.94-fold improvement in oral bioavailability during fasted and fed state respectively as compared to free ABA. The absorption mechanism of ABA NLC using chylomicron flow blocking approach conveyed lymphatic uptake as the major mechanism. Cmax fast/fed ratio was 0.9758 whereas, AUC fast/fed ratio was 0.9386, which being nearly equivalent, confirmed the food effect attenuation. Therefore, the results of the study demonstrate optimal pharmacokinetics of ABA NLC and its utility in circumventing the fast fed variability.

Discussion on the effects of acupuncture-medication combination

This article summarizes and discusses the collaborative effects of acupuncture and medication in treatment, including four aspects, named "acupuncture synergizing the effects of medication", "medication advancing the effects of acupuncture", "coordination of acupuncture and medication", and "antagonism of acupuncture and medication". Regarding "acupuncture synergizing the effects of medication", the actions of acupuncture are predominant, which affects the absorption and metabolism of drugs in the body, increases drug concentration in blood, enhances the targeting effect of drugs, guides meridian tropism, alleviates the drug dose and adverse reactions, avoids the first pass effect and accelerates the drug bioavailability. As for "medication advancing the effects of acupuncture", the synergistic effect of acupuncture is obtained by medication, besides, the medication itself may supplement the drug property to the needles during acupuncture pretreatment so as to increase the therapeutic effect. In terms of "coordination of acupuncture and medication", and "antagonism of acupuncture and medication", there are the underlying co-effects of acupuncture and medication in the body, and the action targets may be same or different between them, thus, it needs to be further explored.

Prediction method of pharmacokinetic parameters of small molecule drugs based on GCN network model.

Accurately predicting plasma protein binding rate (PPBR) and oral bioavailability (OBA) helps to better reveal the absorption and distribution of drugs in the human body and subsequent drug design. Although machine learning models have achieved good results in prediction accuracy, they often suffer from insufficient accuracy when dealing with data with irregular topological structures. In view of this, this study proposes a pharmacokinetic parameter prediction framework based on graph convolutional networks (GCN), which predicts the PPBR and OBA of small molecule drugs. In the framework, GCN is first used to extract spatial feature information on the topological structure of drug molecules, in order to better learn node features and association information between nodes. Then, based on the principle of drug similarity, this study calculates the similarity between small molecule drugs, selects different thresholds to construct datasets, and establishes a prediction model centered on the GCN algorithm. The experimental results show that compared with traditional machine learning prediction models, the prediction model constructed based on the GCN method performs best on PPBR and OBA datasets with an inter-molecular similarity threshold of 0.25, with MAE of 0.155 and 0.167, respectively. In addition, in order to further improve the accuracy of the prediction model, GCN is combined with other algorithms. Compared to using a single GCN method, the distribution of the predicted values obtained by the combined model is highly consistent with the true values. In summary, this work provides a new method for improving the rate of early drug screening in the future.

Modeling drug transport and absorption in subcutaneous injection of monoclonal antibodies: Impact of tissue deformation, devices, and physiology

The pharmaceutical industry has experienced a remarkable increase in the use of subcutaneous injection of monoclonal antibodies (mAbs), attributed mainly to its advantages in reducing healthcare-related costs and enhancing patient compliance. Despite this growth, there is a limited understanding of how tissue mechanics, physiological parameters, and different injection devices and techniques influence the transport and absorption of the drug. In this work, we propose a high-fidelity computational model to study drug transport and absorption during and after subcutaneous injection of mAbs. Our numerical model includes large-deformation mechanics, fluid flow, drug transport, and blood and lymphatic uptake. Through this computational framework, we analyze the tissue material responses, plume dynamics, and drug absorption. We analyze different devices, injection techniques, and physiological parameters such as BMI, flow rate, and injection depth. Finally, we compare our numerical results against the experimental data from the literature.

Knockout Transporter Cell Lines to Assess Substrate Potential Towards Efflux Transporters

P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance transporter 2 (MRP2) are efflux transporters involved in the absorption, excretion, and distribution of drugs. Bidirectional cell assays are recognized models for evaluating the potential of new drugs as substrates or inhibitors of efflux transporters. However, the assays are complicated by a lack of selective substrates and/or inhibitors, as well simultaneous expression of several efflux transporters in cell lines used in efflux models. This project aims to evaluate an in vitro efflux cell assay employing model substrates and inhibitors of P-gp, BCRP and MRP2 with knockout (KO) cell lines. The efflux ratios (ER) of P-gp (digoxin, paclitaxel), BCRP (prazosin, rosuvastatin), MRP2 (etoposide, olmesartan) and mixed (methotrexate, mitoxantrone) substrates were determined in wild-type C2BBe1 and KO cells. For digoxin and paclitaxel, the ER decreased to less than 2 in the cell lines lacking P-gp expression. The ER decreased to less than 3 for prazosin and less than 2 for rosuvastatin in the cell lines lacking BCRP expression. For etoposide and olmesartan, the ER decreased to less than 2 in the cell lines lacking MRP2 expression. The ER of methotrexate and mitoxantrone decreased in single- and double-KO cells without BCRP and MRP2 expression. These results show that KO cell lines have the potential to better interpret complex drug-transporter interactions without depending upon multi-targeted inhibitors or overlapping substrates. For drugs that are substrates of multiple transporters, the single- and double-KO cells may be used to assess their affinities for the different transporters.Graphical

Breast Cancer Resistance Protein: Structure, Localization, Functions, Significance for Rational Pharmacotherapy

INTRODUCTION: Currently, investigation of efflux transport systems of an organism is an important scientific and practical task permitting to more deeply investigate the pharmacokinetics of medical drugs and to optimize pharmacotherapy of a number of diseases. The super family of ABC transporters plays a significant role in transport of biobiotics, the processes of absorption, distribution and excretion of medical drugs from an organism, in realization of undesired drug-drug interactions and development of pharmacoresistance. An important representative of this super family is breast cancer resistance protein (BCRP). AIM: Systematization of the data on BCRP structure, localization, functions, substrates and modulators of its activity. This literature review presents modern data on the molecular and spatial structure of BCRP, its localization in the cell, in organs and tissues. The data from studies of the functions of BCRP in an organism, of its role in the development of undesired drug-drug interactions at different stages of pharmacokinetics are summarized. An up-to-date list of medicinal drugs that are substrates and inhibitors of BCRP is given. Modern approaches to testing medical drugs for belonging to BCRP substrates or modulators of its activity are disclosed. CONCLUSION: The significance of BCRP consists in the existence of a wide range of drugs that are its substrates or modulators of its activity. Upon that, of increasing significance is the investigation both of new and long-known medicinal substances for their belonging to substrates, inducers or inhibitors of breast cancer resistance protein, in order to increase the effectiveness of pharmacotherapy and reduce the risk of undesired drug interactions. Search for non-drug substrates and modulators of BCRP activity permits to obtain new markers for conducting effective studies of safe pharmacokinetics both in vitro and in vivo.

Bioavailability of dronedarone tablets administered with or without food in healthy participants

Study objectiveThere is inadequate awareness of the effect of food on the bioavailability of dronedarone. We report results from two phase 1 studies assessing the effect of food on dronedarone's bioavailability. Design, setting and participantsStudy 1; single-center, open-label, randomized study in healthy adults (males and females). Study 2; single-center, open-label, randomized study in healthy males. InterventionsStudy 1; a single 400-mg oral dose of dronedarone (marketed formulation) in fed (high-fat [47.4 g] meal) and fasted states. Study 2; a single 800-mg oral dose of dronedarone (two 400-mg tablets) after fat-rich (37.3 g) and low-fat (5.3 g) meals, and after fasting. Main outcome measuresPharmacokinetic parameters including maximum plasma concentration (Cmax) and area under the curve from time 0 to last measurable time (AUClast) were assessed for dronedarone and its active N-debutyl metabolite. ResultsTwenty-six participants were included in Study 1 and nine in Study 2. In Study 1, administration of 400 mg dronedarone with a high-fat meal vs. fasted state resulted in 2.8-fold and 2.0-fold increases in Cmax and AUClast, respectively. In Study 2, administration of 800 mg dronedarone with a fat-rich or low-fat meal vs. fasted state resulted in 4.6-fold and 3.2-fold increases in Cmax, respectively, and 3.1-fold and 2.3-fold increases, respectively, in AUClast. Results for the N-debutyl metabolite were similar to dronedarone. No adverse events were considered related to dronedarone. ConclusionWith food, the bioavailability of dronedarone is markedly increased. In clinical practice, dronedarone should be administered with a complete meal to maximize drug absorption.