Research

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18 pages, 2723 KiB

Open AccessArticle

In Vitro–In Vivo Relationship in Mini-Scale—Enabling Formulations of Corallopyronin A

by Tim Becker, Anna K. Krome, Sahel Vahdati, Andrea Schiefer, Kenneth Pfarr, Alexandra Ehrens, Tilman Aden, Miriam Grosse, Rolf Jansen, Silke Alt, Thomas Hesterkamp, Marc Stadler, Marc P. Hübner, Stefan Kehraus, Gabriele M. König, Achim Hoerauf and Karl G. Wagner

Pharmaceutics 2022, 14(8), 1657; https://doi.org/10.3390/pharmaceutics14081657 - 09 Aug 2022

Cited by 4 | Viewed by 2238

Abstract

In vivo studies in mice provide a valuable model to test novel active pharmaceutical ingredients due to their low material need and the fact that mice are frequently used as a species for early efficacy models. However, preclinical in vitro evaluations of formulation [...] Read more.

In vivo studies in mice provide a valuable model to test novel active pharmaceutical ingredients due to their low material need and the fact that mice are frequently used as a species for early efficacy models. However, preclinical in vitro evaluations of formulation principles in mice are still lacking. The development of novel in vitro and in silico models supported the preclinical formulation evaluation for the anti-infective corallopyronin A (CorA). To this end, CorA and solubility-enhanced amorphous solid dispersion formulations, comprising povidone or copovidone, were evaluated regarding biorelevant solubilities and dissolution in mouse-specific media. As an acidic compound, CorA and CorA-ASD formulations showed decreased solubilities in mice when compared with human-specific media. In biorelevant biphasic dissolution experiments CorA-povidone showed a three-fold higher fraction partitioned into the organic phase of the biphasic dissolution, when compared with CorA-copovidone. Bioavailabilities determined by pharmacokinetic studies in BALB/c mice correlated with the biphasic dissolution prediction and resulted in a Level C in vitro–in vivo correlation. In vitro cell experiments excluded intestinal efflux by P-glycoprotein or breast cancer resistance protein. By incorporating in vitro results into a physiologically based pharmacokinetic model, the plasma concentrations of CorA-ASD formulations were predicted and identified dissolution as the limiting factor for bioavailability. Full article

(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs)

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16 pages, 2337 KiB

Open AccessArticle

Fast In Vitro Release and In Vivo Absorption of an Anti-Schizophrenic Drug Paliperidone from Its Soluplus^®/TPGS Mixed Micelles

by Ye Zhou, Chenhui Wang, Wenqian Liu, Meiqing Yang, Bohui Xu and Yong Chen

Pharmaceutics 2022, 14(5), 889; https://doi.org/10.3390/pharmaceutics14050889 - 19 Apr 2022

Cited by 6 | Viewed by 2270

Abstract

The purpose of this study was to develop a drug delivery system for paliperidone (PPD) in order to provide a more effective therapeutic strategy for patients with acute schizophrenia. PPD-loaded Soluplus^®/TPGS mixed micelles (PPD-S/T-MM) were prepared using the thin-film hydration method. [...] Read more.

The purpose of this study was to develop a drug delivery system for paliperidone (PPD) in order to provide a more effective therapeutic strategy for patients with acute schizophrenia. PPD-loaded Soluplus^®/TPGS mixed micelles (PPD-S/T-MM) were prepared using the thin-film hydration method. The critical micelle concentration (CMC) of blank S/T-MM was 4.77 × 10⁻² mg/mL. PPD presented much higher solubility in PPD-S/T-MM formulation than that in pure water. The particle size of blank or drug loaded S/T-MM was around 60 nm. The polydispersity index (PDI) was less than 0.1. PPD-S/T-MM presented a nearly spherical shape under transmission electron microscopy. The encapsulation efficiency (EE%) of PPD-S/T-MM was higher than 94%. Based on the analysis of XRD and DSC, it was proved that PPD was incorporated in the core of the mixed micelles as amorphous dispersion or solid solution. PPD-S/T-MM were stable when they were undergoing dilution with water and the change of environmental pH. Although PPD-S/T-MM showed lower rates to release PPD than those from PPD raw material in acidic solution, they provided faster release rates in neutral conditions than those from PPD raw material who only showed modest dissolution in the same neutral condition. This proves that PPD-S/T-MM can release PPD in a more controlled manner. After oral administration of PPD-S/T-MM (dose of PPD, 6 mg/kg) in rats, the plasma concentration of PPD increased rapidly: T_max was 0.83 ± 0.29 h, and C_max was 844.33 ± 93.73 ng/mL. Oral administration of PPD suspension resulted in longer T_max and lower C_max. The relative oral bioavailability was about 158% for PPD-S/T-MM over PPD suspension. These findings confirm that PPD-S/T-MM can provide faster release in neutral conditions and better oral absorption in rats than those from PPD raw material, which should potentially benefit patients with acute schizophrenia. Full article

(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs)

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11 pages, 1745 KiB

Open AccessArticle

Using a State-Bounding Observer to Predict the Guaranteed Limits of Drug Amounts in Rats after Oral Administration Based on an Uncertain Pharmacokinetic Model

by Zuzana Vitková, Martin Dodek, Jarmila Pavlovičová and Anton Vitko

Pharmaceutics 2022, 14(4), 861; https://doi.org/10.3390/pharmaceutics14040861 - 14 Apr 2022

Cited by 2 | Viewed by 1182

Abstract

In the first part of this paper, the problem of using an uncertain pharmacokinetic model is resolved to determine drug concentrations in rats after the oral administration of drug suspensions with and without added tenside. To this end, a generalized pharmacokinetic model determining [...] Read more.

In the first part of this paper, the problem of using an uncertain pharmacokinetic model is resolved to determine drug concentrations in rats after the oral administration of drug suspensions with and without added tenside. To this end, a generalized pharmacokinetic model determining the guaranteed limits of drug concentrations was designed. Based on this, the design of the so-called state-bounding observer is described in the second part. Rather than being driven by the output of the pharmacokinetic model, the observer can be driven exclusively by a concentration collected from a suitable part of the body and predict the possible risk of the drug concentration not remaining within the therapeutic range for a sufficiently long time. Specifically, the observer determines the upper and lower limits of the concentrations in all the compartments, especially those that are inaccessible for the collection of samples. The proposed approaches are demonstrated by examples. Full article

(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs)

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25 pages, 2983 KiB

Open AccessArticle

Population Pharmacokinetic (Pop-PK) Analysis of Torsemide in Healthy Korean Males Considering CYP2C9 and OATP1B1 Genetic Polymorphisms

by Seung-Hyun Jeong, Ji-Hun Jang, Hea-Young Cho and Yong-Bok Lee

Pharmaceutics 2022, 14(4), 771; https://doi.org/10.3390/pharmaceutics14040771 - 01 Apr 2022

Cited by 9 | Viewed by 2052

Abstract

Torsemide is a diuretic drug used for several cardiovascular and chronic diseases. With regard to the clinical application of torsemide, studies on individualized pharmacotherapy and modeling that take variability in pharmacokinetics (PKs) within a population into account have been rarely reported. Thus, the [...] Read more.

Torsemide is a diuretic drug used for several cardiovascular and chronic diseases. With regard to the clinical application of torsemide, studies on individualized pharmacotherapy and modeling that take variability in pharmacokinetics (PKs) within a population into account have been rarely reported. Thus, the objective of this study was to perform population pharmacokinetic (Pop-PK) modeling and to identify effective covariates that could explain the inter-individual variability (IIV) of torsemide PK. Pop-PK modeling for torsemide was performed based on serum concentration data obtained from 112 healthy Korean males and analysis of various genetic and physicochemical parameters. Modeling was performed with nonlinear mixed-effects (NLME) using Phoenix NLME. The finally developed model was fully verified. The model was also reconfirmed using NONMEM software. As a basic model, the PKs of torsemide within the population were well described by a two-compartment model reflecting the lag-time on oral absorption. According to the genetic polymorphisms of OATP1B1 and CYP2C9, significant associations were found in the V/F, CL/F, and CL₂/F of torsemide. These were reflected as effective covariates in the final Pop-PK model of torsemide, resulting in an approximately 5–10% improvement in the model parameter IIV values. Considering that torsemide is a substrate for CYP2C9 and OATP1B1, it was important to search for genetic polymorphisms in CYP2C9 and OATP1B1 as covariates to explain the PK diversity of torsemide between individuals. The differences in CL/F and CL₂/F between the phenotypes of CYP2C9 were approximately 36.5–51%. The difference in V/F between the phenotypes of OATP1B1 was approximately 41–64.6%. These results suggested that the phenotypes of CYP2C9 and OATP1B1 produced significant differences in torsemide PKs. Considering that CYP2C9 and OATP1B1 phenotypes as covariates affected different PK parameters of torsemide, it could be inferred that torsemide’s cell membrane permeation process by OATP1B1 and the metabolic process by CYP2C9 could independently affect each other in vivo without interplay. There was no significant difference in the parameter estimates between modeling software (Phoenix NLME vs. NONMEM). In this study, the torsemide PK variability between individuals was largely explained. In the future, individualized effective drug therapy of torsemide taking individual patient’s genotypes into account might become possible. Full article

(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs)

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13 pages, 1249 KiB

Open AccessArticle

Safety and Pharmacokinetic Assessment of Oral Proglumide in Those with Hepatic Impairment

by Christine C. Hsu, Sunil Bansal, Hong Cao, Coleman I. Smith, Aiwu Ruth He, Martha D. Gay, Yaoxiang Li, Amrita Cheema and Jill P. Smith

Pharmaceutics 2022, 14(3), 627; https://doi.org/10.3390/pharmaceutics14030627 - 12 Mar 2022

Cited by 1 | Viewed by 1916

Abstract

Proglumide is an orally administered cholecystokinin receptor antagonist that was found to improve nonalcoholic steatohepatitis, reverse liver fibrosis, and decrease incidence of hepatocellular carcinoma (HCC) in animal models. The current investigation aimed to test the pharmacokinetics and safety of proglumide in subjects with [...] Read more.

Proglumide is an orally administered cholecystokinin receptor antagonist that was found to improve nonalcoholic steatohepatitis, reverse liver fibrosis, and decrease incidence of hepatocellular carcinoma (HCC) in animal models. The current investigation aimed to test the pharmacokinetics and safety of proglumide in subjects with hepatic impairment compared with healthy controls. In this translational study, subjects with confirmed cirrhosis, Child-Pugh stage A or B, or healthy controls were recruited for a single-dosing study. Baseline urine and blood samples were obtained before administration of proglumide and also collected after ingestion up to 24 h. Drug concentrations measured by mass spectroscopy revealed peak plasma concentrations (Cmax) of 7847, 9721, and 10,635 ng/mL at about 1 h (Tmax) for healthy controls, subjects with Child-Pugh A, and B cirrhosis, respectively. The serum elimination half time was 3 h. Maximum urine drug concentration (Cmax = ~411 µg/mL) was observed at 3 h, and urinary drug concentration declined at 5 h. There were no adverse events reported, and follow-up liver panels in cirrhosis subjects were unchanged or improved. This investigation demonstrated that proglumide is safe and has similar pharmacokinetic properties in subjects with cirrhosis as in healthy controls; therefore, it will be safe to test the efficacy of proglumide as a therapeutic agent in those subjects with cirrhosis or HCC. Full article

(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs)

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14 pages, 3901 KiB

Open AccessArticle

Oral Formulation Based on Irbesartan Nanocrystals Improve Drug Solubility, Absorbability, and Efficacy

by Noriaki Nagai, Fumihiko Ogata, Ayari Ike, Yurisa Shimomae, Hanano Osako, Yosuke Nakazawa, Naoki Yamamoto and Naohito Kawasaki

Pharmaceutics 2022, 14(2), 387; https://doi.org/10.3390/pharmaceutics14020387 - 10 Feb 2022

Cited by 3 | Viewed by 2034

Abstract

We previously reported that the bioavailability (BA) of irbesartan (IRB), a BSC class II drug, was improved by preparing nanocrystalline suspensions. However, nanocrystalline suspensions have chemical and physical instabilities and must be converted into tablets through drying approaches in order to overcome such [...] Read more.

We previously reported that the bioavailability (BA) of irbesartan (IRB), a BSC class II drug, was improved by preparing nanocrystalline suspensions. However, nanocrystalline suspensions have chemical and physical instabilities and must be converted into tablets through drying approaches in order to overcome such instabilities. In this study, we attempted to design a molded tablet based on nanocrystalline IRB suspensions (IRB-NP tablet) and investigated the effects of this IRB-NP tablet on blood pressure (BP) in a stroke-prone spontaneously hypertensive (SHR-SP) rat. The IRB-NP tablet (with a hardness of 42.6 N) was developed by combining various additives (methylcellulose, 2-hydroxypropyl-β-cyclodextrin HPβCD, D-mannitol, polyvinylpyrrolidone, and gum arabic) followed by bead-milling and freeze-drying treatments. The mean particle size in the redispersions of the IRB-NP tablet was approximately 118 nm. The solubility and intestinal absorption of IRB in the IRB-NP tablet were significantly enhanced in comparison with the microcrystalline IRB tablet (IRB-MP tablet), and both solubility and clathrin-dependent endocytosis helped improve the low BA of the IRB. In addition, the BP-reducing effect of the IRB-NP tablet was significantly higher than that of the IRB-MP tablet. These results provide useful information for the preservation of nanocrystalline suspensions of BCS class II drugs, such as IRB. Full article

(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs)

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12 pages, 1647 KiB

Open AccessArticle

The Influence of Fed State Lipolysis Inhibition on the Intraluminal Behaviour and Absorption of Fenofibrate from a Lipid-Based Formulation

by Marlies Braeckmans, Joachim Brouwers, Danny Riethorst, Cécile Servais, Jan Tack and Patrick Augustijns

Pharmaceutics 2022, 14(1), 119; https://doi.org/10.3390/pharmaceutics14010119 - 04 Jan 2022

Cited by 2 | Viewed by 1856

Abstract

The bioavailability of lipophilic drugs may or may not be increased when administered with food due to increased solubilisation in fed state gastrointestinal (GI) fluids. The in vivo interplay between drug solubilisation, lipid phase digestion and drug absorption is complex and remains poorly [...] Read more.

The bioavailability of lipophilic drugs may or may not be increased when administered with food due to increased solubilisation in fed state gastrointestinal (GI) fluids. The in vivo interplay between drug solubilisation, lipid phase digestion and drug absorption is complex and remains poorly understood. This study aimed to investigate the role of fed state GI lipolysis on the intraluminal behaviour and absorption of fenofibrate, formulated as the lipid-based formulation Fenogal. Therefore, a crossover study was performed in healthy volunteers using orlistat as lipase inhibitor. Fenofibrate concentrations were determined in the proximal jejunum and linked to simultaneously assessed systemic fenofibric acid concentrations. Inhibition of lipolysis by orlistat resulted in a faster onset of absorption in 4 out of 6 volunteers, reflected by a decrease in systemic T_max between 20 and 140 min. In addition, the increase of undigested lipids present in the small intestine upon orlistat co-administration sustained drug solubilisation for a longer period, resulting in higher fenofibrate concentrations in the jejunum and improved absorption in 5 out of 6 volunteers (median AUC_0–8h 8377 vs. 5832 μM.min). Sustaining drug solubilisation in the lipid phase may thus contribute to the absorption of lipophilic drugs. More research into the different mechanisms underlying lipophilic drug absorption from fed state media at different levels of digestion is warranted. Full article

(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs)

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Review

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28 pages, 4086 KiB

Open AccessReview

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

by Nagarjun Rangaraj, Sunitha Sampathi, Vijayabhaskarreddy Junnuthula, Praveen Kolimi, Preethi Mandati, Sagar Narala, Dinesh Nyavanandi and Sathish Dyawanapelly

Pharmaceutics 2022, 14(9), 1807; https://doi.org/10.3390/pharmaceutics14091807 - 27 Aug 2022

Cited by 5 | Viewed by 4200

Abstract

Among various drug administration routes, oral drug delivery is preferred and is considered patient-friendly; hence, most of the marketed drugs are available as conventional tablets or capsules. In such cases, the administration of drugs with or without food has tremendous importance on the [...] Read more.

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

(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs)

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