Gastric emptying and intestinal appearance of nonabsorbable drugs phenol red and paromomycin in human subjects: A multi-compartment stomach approach

Paixão, Paulo; Bermejo, Marival; Hens, Bart; Tsume, Yasuhiro; Dickens, Joseph; Shedden, Kerby; Salehi, Niloufar; Koenigsknecht, Mark J.; Baker, Jason; Hasler, William L.; Lionberger, Robert; Fan, Jianghong; Wysocki, Jeffrey; Wen, Bo; Lee, Allen; Frances, Ann; Amidon, Gregory E.; Yu, Alex; Benninghoff, Gail; Löbenberg, Raimar; Talattof, Arjang; Sun, Duxin; Amidon, Gordon L.

doi:10.1016/j.ejpb.2018.05.033

Cited by 27 publications

(15 citation statements)

References 41 publications

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“…Default settings of the software for luminal blood flow, fluid volume, bile salt content, segmental pH, metabolic activity and small intestinal residence time were used. The mean gastric emptying time (GET) in the fasted state was set to 0.25 h (matching the builtin 'segregated transit time' model value instead of the default value of 0.4 h used in the 'global' transit time model), as suggested by human clinical data and several authors Hens et al, 2014;Paixão et al, 2018;Psachoulias et al, 2011). All relevant input parameters for the development of the PBPK models and simulations are summarized in…”

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confidence: 99%

Establishing virtual bioequivalence and clinically relevant specifications using in vitro biorelevant dissolution testing and physiologically-based population pharmacokinetic modeling. case example: Naproxen

Loisios-Konstantinidis

Cristofoletti

Fotaki

et al. 2020

European Journal of Pharmaceutical Sciences

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Background: Physiologically-based population pharmacokinetic modeling (popPBPK) coupled with in vitro biopharmaceutics tools such as biorelevant dissolution testing can serve as a powerful tool to establish virtual bioequivalence and set clinically relevant specifications. One of several applications of popPBPK modeling is in the emerging field of virtual bioequivalence (VBE), where it can be used to streamline drug development by implementing model-informed formulation design and to inform regulatory decision-making e.g., with respect to evaluating the possibility of extending BCS-based biowaivers beyond BCS Class I and III compounds in certain cases. Methods: In this study, Naproxen, a BCS class II weak acid was chosen as the model compound. In vitro biorelevant solubility and dissolution experiments were performed and the resulting data were used as an input to the PBPK model, following a stepwise workflow for the confirmation of the biopharmaceutical parameters. The naproxen PBPK model was developed by implementing a middleout approach and verified against clinical data obtained from the literature. Once confidence in the performance of the model was achieved, several in vivo dissolution scenarios, based on model-based analysis of the in vitro data, were used to simulate clinical trials in healthy adults. Inter-occasion variability (IOV) was also added to critical physiological parameters and mechanistically propagated through the simulations. The various trials were simulated on a "worst/best case" dissolution scenario and average bioequivalence was assessed according to Cmax, AUC and tmax. Results: VBE results demonstrated that naproxen products with in vitro dissolution reaching 85% dissolved within 90 minutes would lie comfortably within the bioequivalence limits for Cmax and AUC. Based on the establishment of VBE, a dissolution "safe space" was designed and a clinically relevant specification for naproxen products was proposed. The interplay between formulation-related and drug-specific PK parameters (e.g., t1/2) to predict the in vivo performance was also investigated. Conclusion: Over a wide range of values, the in vitro dissolution rate is not critical for the clinical performance of naproxen products and therefore naproxen could be eligible for BCS-based biowaivers 3 based on in vitro dissolution under intestinal conditions. This approach may also be applicable to other poorly soluble acidic compounds with long half-lives, providing an opportunity to streamline drug development and regulatory decision-making without putting the patient at a risk.

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confidence: 99%

Establishing virtual bioequivalence and clinically relevant specifications using in vitro biorelevant dissolution testing and physiologically-based population pharmacokinetic modeling. case example: Naproxen

Loisios-Konstantinidis

Cristofoletti

Fotaki

et al. 2020

European Journal of Pharmaceutical Sciences

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“…It was observed that a large fraction of the phenol red solution rapidly emptied depending on the strong phase III contractions of the migrating motor complex. 28,29 Posaconazole 40 mg Suspension (pH 1.6)…”

Section: Resultsmentioning

confidence: 99%

Application of a Dynamic Fluid and pH Model to Simulate Intraluminal and Systemic Concentrations of a Weak Base in GastroPlus™

Hens

Bolger

2019

Journal of Pharmaceutical Sciences

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The application of preclinical in vitro and in silico models can help formulation scientists to predict the in vivo performance of a drug in an early stage of oral drug product development. An important aspect is that these models should include equations that represent mechanisms that are biorelevant and are sensitive to changes in parameter values. Human gastrointestinal physiology involves many processes that change as a function of time. In this work, a dynamic fluid and pH model was applied in GastroPlus ™ to simulate intraluminal and systemic concentrations of the weak base posaconazole in a biorelevant manner. Simulated results were compared with observed data, extracted from a previously reported human in vivo gastrointestinal aspiration study. Three different formulations were explored (i.e., 1 solution [20 mg dose strength] and 2 suspensions [both 40 mg dose strength]). Simulated results were compared and in line with the observed results for different intraluminal (e.g., precipitated fraction) and systemic parameters (e.g., plasma C max). The optimization of the advanced compartmental and absorption transit model related to fluid dynamics and dynamic pH in this work creates perspectives to validate this model with other reference data derived from aspiration/magnetic resonance imaging studies.

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“…The manometry traces from the gastric ports were segmented to synchronise with each 3.5 min MRI acquisition. The output was the AUC in mmHg × second [35].…”

Section: Plos Onementioning

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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Gastric emptying and intestinal appearance of nonabsorbable drugs phenol red and paromomycin in human subjects: A multi-compartment stomach approach

Cited by 27 publications

References 41 publications

Establishing virtual bioequivalence and clinically relevant specifications using in vitro biorelevant dissolution testing and physiologically-based population pharmacokinetic modeling. case example: Naproxen

Establishing virtual bioequivalence and clinically relevant specifications using in vitro biorelevant dissolution testing and physiologically-based population pharmacokinetic modeling. case example: Naproxen

Application of a Dynamic Fluid and pH Model to Simulate Intraluminal and Systemic Concentrations of a Weak Base in GastroPlus™

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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