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Pre-clinical Pharmacology and Pharmacokinetics in Oral Drug Delivery

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (10 December 2021) | Viewed by 26888

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Special Issue Editors

Dr. Fiona McCartney

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Guest Editor

UCD School of Veterinary Medicine and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
Interests: oral drug delivery; permeation enhancers; intestine; nanoparticles; bioactive compounds; peptides

Dr. John Gleeson

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Guest Editor

Biopharmaceutics - Pharmaceutical Sciences, Merck & Co., Rahway, NJ 07065, USA
Interests: oral drug delivery; intestinal models; IVIVC; permeation enhancers; biopharmaceuticals

Dr. Madele Van Dyk

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Guest Editor

College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, Australia
Interests: precision medicine; precision dosing; targeted therapies; pharmacokinetics; clinical translation; therapeutic drug monitoring
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oral drug delivery, while being the patient-preferred route of delivery, is challenging because of chemical (pH and enzymes) and physical (mucus and epithelia) barriers. A number of strategies have been investigated in order to overcome these barriers, such as modifying drugs to improve stability, the use of permeation enhancers to improve intestinal absorption, and nanoparticles and novel drug delivery systems to improve overall bioavailability. Although current preclinical assessment is heavily dependent on rodent models, there is a need to develop novel in vitro and ex vivo models that better predict human in vivo pharmacokinetics, such as intestinal organoid and microfluidic devices.

This Special Issue will focus on novel approaches to improve the oral bioavailability of drugs as well as strategies to increase the intestinal permeability of drugs. Novel pre-clinical models of the intestine that can improve the in vitro in vivo correlation (IVIVC) are of particular interest in this Special Issue, as are physiologically-based pharmacokinetic (PBPK) models of the intestine or oral drug delivery in preclinical species.

Dr. Fiona McCartney
Dr. John Gleeson
Dr. Madele Van Dyk
Guest Editors

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Keywords

oral drug delivery
oral bioavailability
in vitro in vivo correlation (IVIVC)
physiologically-based pharmacokinetic modelling (PBPK)
intestinal permeability
intestinal absorption
drug transporters
tight junctions

Published Papers (9 papers)

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14 pages, 2431 KiB

Open AccessArticle

Combining Therapeutic Drug Monitoring and Pharmacokinetic Modelling Deconvolutes Physiological and Environmental Sources of Variability in Clozapine Exposure

by Kenneth H. Wills, Stephen J. Behan, Michael J. Nance, Jessica L. Dawson, Thomas M. Polasek, Ashley M. Hopkins, Madelé van Dyk and Andrew Rowland

Pharmaceutics 2022, 14(1), 47; https://doi.org/10.3390/pharmaceutics14010047 - 27 Dec 2021

Cited by 7 | Viewed by 2822

Abstract

Background: Clozapine is a key antipsychotic drug for treatment-resistant schizophrenia but exhibits highly variable pharmacokinetics and a propensity for serious adverse effects. Currently, these challenges are addressed using therapeutic drug monitoring (TDM). This study primarily sought to (i) verify the importance of covariates identified in a prior clozapine population pharmacokinetic (popPK) model in the absence of environmental covariates using physiologically based pharmacokinetic (PBPK) modelling, and then to (ii) evaluate the performance of the popPK model as an adjunct or alternative to TDM-guided dosing in an active TDM population. Methods: A popPK model incorporating age, metabolic activity, sex, smoking status and weight was applied to predict clozapine trough concentrations (C_min) in a PBPK-simulated population and an active TDM population comprising 142 patients dosed to steady state at Flinders Medical Centre in Adelaide, South Australia. Post hoc analyses were performed to deconvolute the impact of physiological and environmental covariates in the TDM population. Results: Analysis of PBPK simulations confirmed age, cytochrome P450 1A2 activity, sex and weight as physiological covariates associated with variability in clozapine C_min (R² = 0.7698; p = 0.0002). Prediction of clozapine C_min using a popPK model based on these covariates accounted for <5% of inter-individual variability in the TDM population. Post hoc analyses confirmed that environmental covariates accounted for a greater proportion of the variability in clozapine C_min in the TDM population. Conclusions: Variability in clozapine exposure was primarily driven by environmental covariates in an active TDM population. Pharmacokinetic modelling can be used as an adjunct to TDM to deconvolute sources of variability in clozapine exposure. Full article

(This article belongs to the Special Issue Pre-clinical Pharmacology and Pharmacokinetics in Oral Drug Delivery)

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17 pages, 4198 KiB

Open AccessArticle

Effect of a Fiber D-Limonene-Enriched Food Supplement on Intestinal Microbiota and Metabolic Parameters of Mice on a High-Fat Diet

by Maria Chiara Valerii, Silvia Turroni, Carla Ferreri, Michela Zaro, Anna Sansone, Alessandro Dalpiaz, Giada Botti, Luca Ferraro, Renato Spigarelli, Irene Bellocchio, Federica D’Amico and Enzo Spisni

Pharmaceutics 2021, 13(11), 1753; https://doi.org/10.3390/pharmaceutics13111753 - 21 Oct 2021

Cited by 13 | Viewed by 2127

Abstract

Several studies showed that D-Limonene can improve metabolic parameters of obese mice via various mechanisms, including intestinal microbiota modulation. Nevertheless, its effective doses often overcome the acceptable daily intake, rising concerns about toxicity. In this study we administered to C57BL/6 mice for 84 days a food supplement based on D-Limonene, adsorbed on dietary fibers (FLS), not able to reach the bloodstream, to counteract the metabolic effects of a high-fat diet (HFD). Results showed that daily administration of D-Limonene (30 and 60 mg/kg body weight) for 84 days decreased the weight gain of HFD mice. After 84 days we observed a statistically significant difference in weight gain in the group of mice receiving the higher dose of FLS compared to HFD mice (35.24 ± 4.56 g vs. 40.79 ± 3.28 g, p < 0.05). Moreover, FLS at both doses tested was capable of lowering triglyceridemia and also fasting glycemia at the higher dose. Some insights on the relevant fatty acid changes in hepatic tissues were obtained, highlighting the increased polyunsaturated fatty acid (PUFA) levels even at the lowest dose. FLS was also able to positively modulate the gut microbiota and prevent HFD-associated liver steatosis in a dose-dependent manner. These results demonstrate that FLS at these doses can be considered non-toxic and could be an effective tool to counteract diet-induced obesity and ameliorate metabolic profile in mice. Full article

(This article belongs to the Special Issue Pre-clinical Pharmacology and Pharmacokinetics in Oral Drug Delivery)

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12 pages, 2332 KiB

Open AccessArticle

Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue

by Zoe Coombes, Katie Plant, Cristina Freire, Abdul W. Basit, Philip Butler, R. Steven Conlan and Deyarina Gonzalez

Pharmaceutics 2021, 13(10), 1707; https://doi.org/10.3390/pharmaceutics13101707 - 16 Oct 2021

Cited by 3 | Viewed by 2790

Abstract

Following oral administration, the bioavailability of progesterone is low and highly variable. As a result, no clinically relevant, natural progesterone oral formulation is available. After oral delivery, first-pass metabolism initially occurs in the intestines; however, very little information on progesterone metabolism in this organ currently exists. The aim of this study is to investigate the contributions of liver and intestine to progesterone clearance. In the presence of NADPH, a rapid clearance of progesterone was observed in human and rat liver samples (t_1/2 2.7 and 2.72 min, respectively). The rate of progesterone depletion in intestine was statistically similar between rat and human (t_1/2 197.6 min in rat and 157.2 min in human). However, in the absence of NADPH, progesterone was depleted at a significantly lower rate in rat intestine compared to human. The roles of aldo keto reductases (AKR), xanthine oxidase (XAO) and aldehyde oxidase (AOX) in progesterone metabolism were also investigated. The rate of progesterone depletion was found to be significantly reduced by AKR1C, 1D1 and 1B1 in human liver and by AKR1B1 in human intestine. The inhibition of AOX also caused a significant reduction in progesterone degradation in human liver, whereas no change was observed in the presence of an XAO inhibitor. Understanding the kinetics of intestinal as well as liver metabolism is important for the future development of progesterone oral formulations. This novel information can inform decisions on the development of targeted formulations and help predict dosage regimens. Full article

(This article belongs to the Special Issue Pre-clinical Pharmacology and Pharmacokinetics in Oral Drug Delivery)

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20 pages, 3563 KiB

Open AccessArticle

Improved Bioavailability of Ebastine through Development of Transfersomal Oral Films

by Nayyer Islam, Muhammad Irfan, Ameer Fawad Zahoor, Muhammad Shahid Iqbal, Haroon Khalid Syed, Ikram Ullah Khan, Akhtar Rasul, Salah-Ud-Din Khan, Alaa M. Alqahtani, Muzzamil Ikram, Muhammad Abdul Qayyum, Ahmed Khames, Sana Inam and Mohammed A. S. Abourehab

Pharmaceutics 2021, 13(8), 1315; https://doi.org/10.3390/pharmaceutics13081315 - 23 Aug 2021

Cited by 14 | Viewed by 3256

Abstract

The main objective of this research work was the development and evaluation of transfersomes integrated oral films for the bioavailability enhancement of Ebastine (EBT) to treat allergic rhinitis. The flexible transfersomes, consisting of drug (EBT), lipid (Phosphatidylcholine) and edge activator (EA) Polyoxyethylene sorbitan monooleate or Sorbitan monolaurate, were prepared with the conventional thin film hydration method. The developed transfersomes were further integrated into oral films using the solvent casting method. Transfersomes were evaluated for their size distribution, surface charge, entrapment efficiency (EE%) and relative deformability, whereas the formulated oral films were characterized for weight, thickness, pH, folding endurance, tensile strength, % of elongation, degree of crystallinity, water content, content uniformity, in vitro drug release and ex vivo permeation, as well as in vivo pharmacokinetic and pharmacodynamics profile. The mean hydrodynamic diameter of transfersomes was detected to be 75.87 ± 0.55 nm with an average PDI and zeta potential of 0.089 ± 0.01 and 33.5 ± 0.39 mV, respectively. The highest deformability of transfersomes of 18.52 mg/s was observed in the VS-3 formulation. The average entrapment efficiency of the transfersomes was about 95.15 ± 1.4%. Transfersomal oral films were found smooth with an average weight, thickness and tensile strength of 174.72 ± 2.3 mg, 0.313 ± 0.03 mm and 36.4 ± 1.1 MPa, respectively. The folding endurance, pH and elongation were found 132 ± 1, 6.8 ± 0.2 and 10.03 ± 0.4%, respectively. The ex vivo permeability of EBT from formulation ETF-5 was found to be approximately 2.86 folds higher than the pure drug and 1.81 folds higher than plain film (i.e., without loaded transfersomes). The relative oral bioavailability of ETF-5 was 2.95- and 1.7-fold higher than that of EBT-suspension and plain film, respectively. In addition, ETF-5 suppressed the wheal and flare completely within 24 h. Based on the physicochemical considerations, as well as in vitro and in vivo characterizations, it is concluded that the highly flexible transfersomal oral films (TOFs) effectively improved the bioavailability and antihistamine activity of EBT. Full article

(This article belongs to the Special Issue Pre-clinical Pharmacology and Pharmacokinetics in Oral Drug Delivery)

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15 pages, 80147 KiB

Open AccessArticle

Intestinal Transcytosis of a Protein Cargo and Nanoparticles Mediated by a Non-Toxic Form of Pseudomonas aeruginosa Exotoxin A

by Ruiying Li, Floriane Laurent, Alistair Taverner, Julia Mackay, Paul A. De Bank and Randall J. Mrsny

Pharmaceutics 2021, 13(8), 1171; https://doi.org/10.3390/pharmaceutics13081171 - 29 Jul 2021

Cited by 5 | Viewed by 2295

Abstract

The low permeability of nanoparticles (NPs) across the intestinal epithelium remains a major challenge for their application of delivering macromolecular therapeutic agents via the oral route. Previous studies have demonstrated the epithelial transcytosis capacity of a non-toxic version of Pseudomonas aeruginosa exotoxin A (ntPE). Here, we show that ntPE can be used to deliver the protein cargo green fluorescent protein (GFP) or human growth hormone (hGH), as genetic fusions, across intact rat jejunum in a model where the material is administered by direct intra-luminal injection (ILI) in vivo in a transcytosis process that required less than 15 min. Next, ntPE chemically coupled onto biodegradable alginate/chitosan condensate nanoparticles (AC NPs-ntPE) were shown to transport similarly to ntPE-GFP and ntPE-hGH across rat jejunum. Finally, AC NPs-ntPE loaded with GFP as a model cargo were demonstrated to undergo a similar transcytosis process that resulted in GFP being colocalized with CD11c⁺ cells in the lamina propria after 30 min. Control NP preparations, not decorated with ntPE, were not observed within polarized epithelial cells or within the cells of the lamina propria. These studies demonstrate the capacity of ntPE to facilitate the transcytosis of a covalently associated protein cargo as well as a biodegradable NP that can undergo transcytosis across the intestinal epithelium to deliver a noncovalently associated protein cargo. In sum, these studies support the potential applications of ntPE to facilitate the oral delivery of macromolecular therapeutics under conditions of covalent or non-covalent association. Full article

(This article belongs to the Special Issue Pre-clinical Pharmacology and Pharmacokinetics in Oral Drug Delivery)

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14 pages, 1390 KiB

Open AccessArticle

A Bidirectional Permeability Assay for beyond Rule of 5 Compounds

by Yunhai Cui, Cyril Desevaux, Ines Truebenbach, Peter Sieger, Klaus Klinder, Alan Long and Achim Sauer

Pharmaceutics 2021, 13(8), 1146; https://doi.org/10.3390/pharmaceutics13081146 - 27 Jul 2021

Cited by 9 | Viewed by 4488

Abstract

Bidirectional permeability measurement with cellular models grown on Transwell inserts is widely used in pharmaceutical research since it not only provides information about the passive permeability of a drug, but also about transport proteins involved in the active transport of drug substances across physiological barriers. With the increasing number of investigative drugs coming from chemical space beyond Lipinski’s Rule of 5, it becomes more and more challenging to provide meaningful data with the standard permeability assay. This is exemplified here by the difficulties we encountered with the cyclic depsipeptides emodepside and its close analogs with molecular weight beyond 1000 daltons and cLogP beyond 5. The aim of this study is to identify potential reasons for these challenges and modify the permeability assays accordingly. With the modified assay, intrinsic permeability and in vitro efflux of depsipeptides could be measured reliably. The improved correlation to in vivo bioavailability and tissue distribution data indicated the usefulness of the modified permeability assay for the in vitro screening of compounds beyond the Rule of 5. Full article

(This article belongs to the Special Issue Pre-clinical Pharmacology and Pharmacokinetics in Oral Drug Delivery)

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12 pages, 1143 KiB

Open AccessArticle

Rapid and Sensitive Quantification of Intracellular Glycyl-Sarcosine for Semi-High-Throughput Screening for Inhibitors of PEPT-1

by Teresa von Linde, Gzona Bajraktari-Sylejmani, Walter E. Haefeli, Jürgen Burhenne, Johanna Weiss and Max Sauter

Pharmaceutics 2021, 13(7), 1019; https://doi.org/10.3390/pharmaceutics13071019 - 03 Jul 2021

Cited by 3 | Viewed by 2964

Abstract

The peptide transporter PEPT-1 (SLC15A1) plays a major role in nutritional supply with amino acids by mediating the intestinal influx of dipeptides and tripeptides generated during food digestion. Its role in the uptake of small bioactive peptides and various therapeutics makes it an important target for the investigation of the systemic absorption of small peptide-like active compounds and prodrug strategies of poorly absorbed therapeutics. The dipeptide glycyl-sarcosine (Gly-Sar), which comprises an N-methylated peptide bond that increases stability against enzymatic degradation, is widely utilized for studying PEPT-1-mediated transport. To support experiments on PEPT-1 inhibitor screening to identify potential substrates, we developed a highly sensitive Gly-Sar quantification assay for Caco-2 cell lysates with a dynamic range of 0.1 to 1000 ng/mL (lower limit of quantification 0.68 nM) in 50 µL of cell lysate. The assay was validated following the applicable recommendations for bioanalytic method validation of the FDA and EMA. Sample preparation and quantification were established in 96-well cell culture plates that were also used for the cellular uptake studies, resulting in a rapid and robust screening assay for PEPT-1 inhibitors. This sample preparation principle, combined with the high sensitivity of the UPLC-MS/MS quantification, is suitable for screening assays for PEPT-1 inhibitors and substrates in high-throughput formats and holds the potential for automation. Applicability was demonstrated by IC₅₀ determinations of the known PEPT-1 inhibitor losartan, the known substrates glycyl-proline (Gly-Pro), and valaciclovir, the prodrug of aciclovir, which itself is no substrate of PEPT-1 and consequently showed no inhibition in our assay. Full article

(This article belongs to the Special Issue Pre-clinical Pharmacology and Pharmacokinetics in Oral Drug Delivery)

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16 pages, 1851 KiB

Open AccessArticle

Effect of Curcumin Nanoemulsions Stabilized with MAG and DAG-MCFAs in a Fructose-Induced Hepatic Steatosis Rat Model

by Beatriz Agame-Lagunes, Peter Grube-Pagola, Rebeca García-Varela, Alfonso Alexander-Aguilera and Hugo S. García

Pharmaceutics 2021, 13(4), 509; https://doi.org/10.3390/pharmaceutics13040509 - 08 Apr 2021

Cited by 6 | Viewed by 2474

Abstract

Current changes in diet, characterized by an increase in the intake of sweetened beverages, are heavily related to metabolic disorders such as non-alcoholic fatty liver. This condition can produce simple steatosis and, in worse cases, potentially result in steatohepatitis, fibrosis, and cirrhosis, comparable to the damage caused by the consumption of more or less 20–30 g of alcohol per day. The main objective of this research was to evaluate the effect of curcumin (Curcuma longa) nanoemulsions, using mono- and diacylglycerides medium chain fatty acids as stabilizers in an in vivo hepatic steatosis rat model. Pathology was induced by providing 30% fructose intake in the drinking water. Globule sizes under 200 nm that were stable for 4 weeks were obtained; curcumin encapsulated in the nanoemulsion was >70%. The results revealed an improvement regarding body and liver weight in the animals treated with curcumin nanoemulsions. A decrease in total cholesterol, LDL, AST/ALT, and HDL in serum was observed; however, no apparent improvement regarding serum glucose or triacylglycerides values was noted. Histological analysis showed a significant decrease in the extent of steatosis, inflammation, and brown adipose tissue in the treated animals. Full article

(This article belongs to the Special Issue Pre-clinical Pharmacology and Pharmacokinetics in Oral Drug Delivery)

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6 pages, 509 KiB

Open AccessCommentary

Re-Assessing PK/PD Issues for Oral Protein and Peptide Delivery

by Randall J. Mrsny and Tahir A. Mahmood

Pharmaceutics 2021, 13(7), 1006; https://doi.org/10.3390/pharmaceutics13071006 - 02 Jul 2021

Cited by 2 | Viewed by 2146

Abstract

Due to a lack of safe and effective oral delivery strategies for most protein and peptide therapeutics, pharmaceutical drug developers have focused on parenteral routes to administer these agents. Recent advances in delivery technologies have now shown clinical validation for a few of these biopharmaceuticals following oral administration. While these initial opportunities have provided more than just a glimmer of hope within the industry, there are important aspects of oral biopharmaceutical delivery that do not completely align with pharmacokinetic (PK) parameters and pharmacodynamics (PD) outcomes that have been learned from parenteral administrations. This commentary examines some of these issues with the goal of presenting a rationale for re-assessing methods, models, and success criteria to better measure oral protein or peptide delivery outcomes related to PK/PD events. Full article

(This article belongs to the Special Issue Pre-clinical Pharmacology and Pharmacokinetics in Oral Drug Delivery)

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