A Mechanistic Physiologically-Based Biopharmaceutics Modeling (PBBM) Approach to Assess the In Vivo Performance of an Orally Administered Drug Product: From IVIVC to IVIVP

Bermejo, Marival; Hens, Bart; Dickens, Joseph; Mudie, Deanna M.; Paixão, Paulo; Tsume, Yasuhiro; Shedden, Kerby; Amidon, Gordon L.

doi:10.3390/pharmaceutics12010074

Cited by 53 publications

(32 citation statements)

References 47 publications

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“…In vitro experiments tailored to account for fluid volume changes can give valuable information on the gastrointestinal behaviour of oral drug products that are frequently co-administered with PPIs or in populations where GI fluid volume may be impacted [ 4 ]. In addition, PBPK models can allow evaluating the sensitivity of drug absorption to relevant changes in gastrointestinal fluid volume [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir

et al. 2020

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Proton-pump inhibitors (PPIs), frequently prescribed to lower gastric acid secretion, often exert an effect on the absorption of co-medicated drug products. A previous study showed decreased plasma levels of the lipophilic drug ritonavir after co-administration with the PPI Nexium (40 mg esomeprazole), even though duodenal concentrations were not affected. The present study explored if a PPI-induced decrease in gastrointestinal (GI) fluid volume might contribute to the reduced absorption of ritonavir. In an exploratory cross-over study, five volunteers were given a Norvir tablet (100 mg ritonavir) orally, once without PPI pre-treatment and once after a three-day pre-treatment with the PPI esomeprazole. Blood samples were collected for eight hours to assess ritonavir absorption and magnetic resonance imaging (MRI) was used to determine the gastric and duodenal fluid volumes during the first three hours after administration of the tablet. The results confirmed that PPI intake reduced ritonavir plasma concentrations by 40%. The gastric residual volume and gastric fluid volume decreased by 41% and 44% respectively, while the duodenal fluid volume was reduced by 33%. These data suggest that the PPI esomeprazole lowers the available fluid volume for dissolution, which may limit the amount of ritonavir that can be absorbed. Although additional factors may play a role, the effect of PPI intake on the GI fluid volume should be considered when simulating the absorption of poorly soluble drugs like ritonavir in real-life conditions.

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Section: Discussionmentioning

confidence: 99%

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir

et al. 2020

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“…In other cases, IVIVC tools were used to assess the impact of in vitro variability on in vivo BE criteria, to predict formulation differences in dissolution testing, and to compare convolution and deconvolution methods for the development of IVIVC [ 40 , 66 , 67 ]. Quite recently an in-silico modeling approach (the “Mechanistic Physiologically-Based Biopharmaceutics Modeling”) was used to predict the in vivo concentrations of ibuprofen through the use of a mechanistic oral absorption model built in the Phoenix WinNonlin ® software and coupled with the GastroPlus ® simulator [ 68 ]. Similarly, aiming at predicting the possibility of bioequivalence for fluconazole capsules, Duque et al, utilized dissolution profiles in order to simulate plasma levels and then evaluate their bioequivalence, using Population Simulator TM in GastroPlus ® [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

An In Vitro–In Vivo Simulation Approach for the Prediction of Bioequivalence

Vlachou

Karalis

2021

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The aim of this study was to develop a new in vitro–in vivo simulation (IVIVS) approach in order to predict the outcome of a bioequivalence study. The predictability of the IVIVS procedure was evaluated through its application in the development process of a new generic product of amlodipine/irbesartan/hydrochlorothiazide. The developed IVIVS methodology is composed of three parts: (a) mathematical description of in vitro dissolution profiles, (b) mathematical description of in vivo kinetics, and (c) development of joint in vitro–in vivo simulations. The entire programming was done in MATLAB® and all created scripts were validated through other software. The IVIVS approach can be implemented for any number of subjects, clinical design, variability and can be repeated for thousands of times using Monte Carlo techniques. The probability of success of each scenario is recorded and finally, an overall assessment is made in order to select the most suitable batch. Alternatively, if the IVIVS shows reduced probability of BE success, the R&D department is advised to reformulate the product. In this study, the IVIVS approach predicted successfully the BE outcome of the three drugs. During the development of generics, the IVIVS approach can save time and expenses.

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“…Data from MRI studies will play a pivotal role in the validation of predictive in vitro and in silico tools as frequently used by formulation scientists in pharmaceutical drug development. For example, MRI data from a previous study were implemented in a physiologically-based pharmacokinetic (PBPK) simulation tool to adequately reflect the residual fluid volumes in the different compartments of the GI tract [ 48 , 49 ]. The acquired data from this study can be further used to revise GI motility and transit times in these platforms to make predictions with better accuracy and precision.…”

Section: Discussionmentioning

confidence: 99%

Measurement of fasted state gastric antral motility before and after a standard bioavailability and bioequivalence 240 mL drink of water: Validation of MRI method against concomitant perfused manometry in healthy participants

et al. 2020

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Objective The gastrointestinal environment in which drug products need to disintegrate before the drug can dissolve and be absorbed has not been studied in detail due to limitations, especially invasiveness of existing techniques. Minimal in vivo data is available on undisturbed gastrointestinal motility to improve relevance of predictive dissolution models and in silico tools such as physiologically-based pharmacokinetic models. Recent advances in magnetic resonance imaging methods could provide novel data and insights that can be used as a reference to validate and, if necessary, optimize these models. The conventional method for measuring gastrointestinal motility is via a manometric technique involving intubation. Nevertheless, it is feasible to measure gastrointestinal motility with magnetic resonance imaging. The aim of this study was is to develop and validate a magnetic resonance imaging method using the most recent semi-automated analysis method against concomitant perfused manometry method. Material and methods Eighteen healthy fasted participants were recruited for this study. The participants were intubated with a water-perfused manometry catheter. Subsequently, stomach motility was assessed by cine-MRI acquired at intervals, of 3.5min sets, at coronal oblique planes through the abdomen and by simultaneous water perfused manometry, before and after administration of a standard bioavailability / bioequivalence 8 ounces (~240mL) drink of water. The magnetic resonance imaging motility images were analysed using Spatio-Temporal Motility analysis STMM techniques. The area under the curve of the gastric motility contractions was calculated for each set and compared between techniques. The study visit was then repeated one week later. Results Data from 15 participants was analysed. There was a good correlation between the MRI antral motility plots area under the curve and corresponding perfused manometry motility area under the curve (r = 0.860) during both antral contractions and quiescence. Conclusion Non-invasive dynamic magnetic resonance imaging of gastric antral motility coupled with recently developed, semi-automated magnetic resonance imaging data processing techniques correlated well with simultaneous, ‘gold standard’ water perfused manometry. This will be particularly helpful for research purposes related to oral absorption where the absorption of a drug is highly depending on the underlying gastrointestinal processes such as gastric emptying, gastrointestinal motility and availability of residual fluid volumes. Clinical trial This trial was registered at ClinicalTrials.gov as NCT03191045.

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A Mechanistic Physiologically-Based Biopharmaceutics Modeling (PBBM) Approach to Assess the In Vivo Performance of an Orally Administered Drug Product: From IVIVC to IVIVP

Cited by 53 publications

References 47 publications

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir

An In Vitro–In Vivo Simulation Approach for the Prediction of Bioequivalence

Measurement of fasted state gastric antral motility before and after a standard bioavailability and bioequivalence 240 mL drink of water: Validation of MRI method against concomitant perfused manometry in healthy participants

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