Evaluating the Impact of Physiological Properties of the Gastrointestinal Tract On Drug In Vivo Performance Using Physiologically Based Biopharmaceutics Modeling and Virtual Clinical Trials

Jereb, Rebeka; Opara, Jerneja; Bajc, Aleksander; Petek, Boštjan

doi:10.1016/j.xphs.2021.04.007

Cited by 9 publications

(7 citation statements)

References 69 publications

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“…After ADME screening, 101 active components passed the combined filtering criteria, which were integrated by human intestinal absorption (HIA), human oral bioavailability (OB) limits of 30% (F30%) and Caco-2 cell permeability. For any drug administered orally, HIA is an essential prerequisite for its apparent efficacy ( Jereb et al, 2021 ). OB is the most important pharmacokinetic parameter, indicating the efficiency of drug delivery to the systemic circulation.…”

Section: Resultsmentioning

confidence: 99%

The TCM Preparation Feilike Mixture for the Treatment of Pneumonia: Network Analysis, Pharmacological Assessment and Silico Simulation

et al. 2022

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The Feilike mixture (FLKM) is a valid prescription that is frequently used to assist in the clinical treatment of pneumonia. However, the mechanisms of its effects remain unclear. First, through literature evaluation, it was preliminarily determined that FLKM improved clinical symptoms, regulated immune inflammation response and ameliorated pulmonary function. Then, via database search and literature mining, 759 targets of the 104 active compounds of FLKM were identified. The component-target (CT) network showed that the key active compositions were resveratrol, stigmasterol, beta-sitosterol, sesamin, and quercetin. 115 targets overlapped with pneumonia-related targets. The protein-protein interaction (PPI) network identified TNF, AKT1, IL6, JUN, VEGFA and MAPK3 as hub targets. KEGG analyses found that they were mainly enriched in immune related pathway. Next, in vivo experiment, we observed that FLKM ameliorated pathological injury of lung tissue and reduced neutrophil infiltration in rats with LPS-induced pneumonia. And FLKM decreased the concentration of TNF-α and IL-6 in BALF and downregulated the expression of p38MAPK, AKT and VEGFA in lung tissue. Finally, Molecular docking tests showed tight docking of these predicted targeted proteins with key active compounds. Molecular dynamics simulation was employed to assess stability and flexibility of receptor-ligand. Among them, AKT1- stigmasterol bound more stably, and their binding free energies were −47.91 ± 1.62 kcal/mol. This study revealed core compositions and targets for FLKM treating pneumonia and provided integrated pharmacological evidence to support its clinical efficacy.

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Section: Resultsmentioning

confidence: 99%

The TCM Preparation Feilike Mixture for the Treatment of Pneumonia: Network Analysis, Pharmacological Assessment and Silico Simulation

et al. 2022

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“…The ACAT model consists of nine consecutive compartments (stomach, duodenum, two jejunal compartments, three ileal compartments, cecum, and ascending colon) described by relevant parameters (e.g., pH, volume, length, radius, transit time, etc. ), whereat the system of differential equations is used to calculate the amount of drug dissolved and absorbed from each compartment over time. , Pre-surgery simulations were performed using the default ACAT inputs, except for the percent fluid volumes in the small intestine (23%) and colon (0.5%), which were taken from the literature . The additional ACAT model adjustments for post-bariatric patients included stomach pH value (increased from default pH 1.3 to pH 5.0 for post-LSG patients and pH 7.0 for post-OAGB patients), stomach volume (decreased from default 50 to 10 mL, corresponding to 20% of the pre-surgery gastric volume), and stomach transit time (decreased from default 0.25 to 0.12 h , ).…”

Section: Methodsmentioning

confidence: 99%

“…43,44 Pre-surgery simulations were performed using the default ACAT inputs, except for the percent fluid volumes in the small intestine (23%) and colon (0.5%), which were taken from the literature. 45 The additional ACAT model adjustments for postbariatric patients included stomach pH value (increased from optimized to match the simulated human plasma concentration profile; in accordance with the literature data 64 55 optimized to match the simulated human plasma concentration profile, in accordance with the literature data 62 clearance, CL (L/h/kg) 6 optimized to match the simulated human plasma concentration profile, while keeping the optimized values within the range of the literature-reported data 65,66 0.8 optimized to match the simulated human plasma concentration profile while keeping the optimized values within the range of the literature-reported data 53,67 volume of distribution, V d (L/kg) 4 optimized to match the simulated human plasma concentration profile, while keeping the optimized values within the range of the literature-reported data 65,66 10 optimized to match the simulated human plasma concentration profile while keeping the optimized values within the range of the literature-reported data 53,67 distribution constant, k…”

Section: Ex Vivo Solubilitymentioning

confidence: 99%

Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery

et al. 2022

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Gastrointestinal anatomical/physiological changes after bariatric surgery influence variables affecting the fate of drugs after ingestion, and medication management of these patients requires a thorough and complex mechanistic analysis. The aim of this research was to study whether loratadine/desloratadine antiallergic treatment of bariatric patients is at risk of being ineffective due to impaired solubility/dissolution. The pH-dependent solubility of loratadine/desloratadine was studied in vitro, as well as ex vivo, in gastric content aspirated from patients before versus after bariatric surgery. Then, a biorelevant dissolution method was developed to simulate the gastric conditions after sleeve gastrectomy (SG) or one-anastomosis gastric bypass (OAGB), accounting for key variables (intragastric volume, pH, and contractility), and the dissolution of loratadine/desloratadine was studied pre- versus post-surgery. Dissolution was also studied after tablet crushing or syrup ingestion, as these actions are recommended after bariatric surgery. Finally, these experimental data were implemented in a newly developed physiologically based pharmacokinetic (PBPK) model to simulate loratadine/desloratadine PK profiles pre- versus post-surgery. For both drugs, pH-dependent solubility was demonstrated, with decreased solubility at higher pH; over the pH range 1–7, loratadine solubility decreased ∼2000-fold, and desloratadine decreased ∼120-fold. Ex vivo solubility in aspirated human gastric fluid pre- versus post-surgery was in good agreement with these in vitro results and revealed that while desloratadine solubility still allows complete dissolution post-surgery, loratadine solubility post-surgery is much lower than the threshold required for the complete dissolution of the drug dose. Indeed, severely hampered loratadine dissolution was revealed, dropping from 100% pre-surgery to only 3 and 1% post-SG and post-OAGB, respectively. Tablet crushing did not increase loratadine dissolution in any post-bariatric condition, nor did loratadine syrup in post-OAGB (pH 7) media, while in post-laparoscopic SG conditions (pH 5), the syrup provided partial improvement of up to 40% dissolution. Desloratadine exhibited quick and complete dissolution across all pre-/post-surgery conditions. PBPK simulations revealed pronounced impaired absorption of loratadine post-surgery, with 84–88% decreased C max, 28–36% decreased F a, and 24–31% decreased overall bioavailability, depending on the type of bariatric procedure. Desloratadine absorption remained unchanged post-surgery. We propose that desloratadine should be preferred over loratadine in bariatric patients, and as loratadine is an over-the-counter medication, antiallergic therapy after bariatric surgery requires special attention by patients and clinicians alike. This mechanistic approach that reveals potential post-surgery complexity, and at the same time provides adequate substitutions, may contribute to better pharmacotherapy and overall patient care after bariatric surgery.

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“…In approaches to PK studies, the study conducted by Jereb et al (2021) evaluated delayed-release tablet pantoprazole compared to dolutegravir and its impact on the patient's gastrointestinal tract after a meal and in the fasted state. This study used virtual models, with pantoprazole performing better than dolutegravir in terms of bioavailability.…”

Section: Gastroplus™mentioning

confidence: 99%

Application of in silico methods in clinical research and development of drugs and their formulation: A scoping review

Colli¹,

Cabral²,

Matos³

et al. 2022

J App Pharm Sc

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The drug regularization process involves many steps that are complex and time-consuming. The demand for new drugs has prompted researchers and regulatory authorities to search for predictive methods that can streamline the development process. Current studies point to innovative computational techniques in a drug's study phases. This study aims to carry out a scoping review of research involving the application of computational methods and in silico studies in the clinical research and development of new drugs. A scoping review was conducted according to the eferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Online databases from 2001 to 2021 in English were used and the trial registration was 10.17605/OSF.IO/USXCM. The development of protocols and the application of a computational method for researching new drugs and their formulation, published in a peer-reviewed journal, were included. The data extraction and analysis were performed by two independent reviewers. In this study, 312 articles were retrieved, of which 6 were duplicates. After the title was read, only 101 remained for analysis. After the abstracts were read, 34 papers were considered for the scoping review. The use of in silico methodologies has been expanding in terms of research into the development of new drugs and the improvement of existing products.

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Evaluating the Impact of Physiological Properties of the Gastrointestinal Tract On Drug In Vivo Performance Using Physiologically Based Biopharmaceutics Modeling and Virtual Clinical Trials

Cited by 9 publications

References 69 publications

The TCM Preparation Feilike Mixture for the Treatment of Pneumonia: Network Analysis, Pharmacological Assessment and Silico Simulation

The TCM Preparation Feilike Mixture for the Treatment of Pneumonia: Network Analysis, Pharmacological Assessment and Silico Simulation

Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery

Application of in silico methods in clinical research and development of drugs and their formulation: A scoping review

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