In Vitro Simulation of the Environment in the Upper Gastrointestinal Lumen After Drug Administration in the Fed State Using the TIM-1 System and Comparison With Luminal Data in Adults

Pentafragka, Christina; Tomaszewska, Irena; Bellmann, Susann; Minekus, Mans; Schilderink, Ronald; Vertzoni, Maria; McAllister, Mark

doi:10.1016/j.xphs.2021.10.010

Cited by 4 publications

(10 citation statements)

References 28 publications

(52 reference statements)

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“…These files were created to mimic the TIM-1 conditions under fasted, fed, and achlorhydric conditions (the so-called “proton-pump inhibitor (PPI) effect”). Total bile salt concentrations were incorporated in these physiology files based on the values measured in the experimental TIM-1 under fasted and fed state conditions (Figure B). , The different physiology.cat-files were created in Notepad++ and uploaded in GastroPlus using the mixed multiple dosing module (.mdd-file). Table gives an overview of the different.cat-files for the different TIM-1 conditions.…”

Section: Materials and Methodsmentioning

confidence: 99%

“…Gastric and small intestinal electrolyte solution (GES/SIES) were prepared, as recently described by Pentafragka and colleagues. 17 Briefly, GES was prepared by dissolving 8 g/L sodium chloride, 1.7 g/L potassium chloride, and 0.16 g/L calcium chloride dihydrate in water. A gastric solution containing HPMC 0.4% and bile 0.04% was prepared by dissolving 0.4 g/L bile extract in water, subsequently adding 4.0 g/L HPMC and stirring the solution overnight.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

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Digitalizing the TIM-1 Model Using Computational Approaches─Part Two: Digital TIM-1 Model in GastroPlus

Hens,

Sarcevica,

Tomaszewska

et al. 2023

Mol. Pharmaceutics

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A TIM-1 model is an in vitro gastrointestinal (GI) simulator considering crucial physiological parameters that will affect the in vivo drug release process. The outcome of these experiments can indicate the critical bioavailability attributes (CBAs) that will impact the fraction absorbed in vivo. The model is widely used in the nonclinical stage of drug product development to assess the bioaccessible fraction of drugs for numerous candidate formulations. In this work, we developed a digital TIM-1 model in the GastroPlus platform. In a first step, we performed validation experiments to assess the luminal concentrations and bioaccessible fractions for two marker compounds. The digital TIM-1 was able to adequately reflect the luminal concentrations and bioaccessible fractions of these markers under different prandial conditions, confirming the appropriate integration of mass transfer in the TIM-1 model. In a second set of experiments, a case example with PF-07059013 was performed, where luminal concentrations and bioaccessible fractions were predicted for 200 and 1000 mg doses under fasted and achlorhydric conditions. Experimental and simulated data pointed out that the achlorhydric effect was more pronounced at the 1000 mg dose, showing a solubility-limited dissolution and, consequently, decreased bioaccessible fraction. Toward future applications, the digital TIM-1 model will be thoroughly applied to explore a link between in vitro and in vivo outcomes based on more case examples with model compounds with the access of TIM-1 and plasma data. Ideally, this digital TIM-1 can be directly used in GastroPlus to explore an in vitro−in vivo correlation (IVIVC) between the fraction dissolved (digital TIM-1 settings) and the fraction absorbed (human PBPK settings).

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Section: Materials and Methodsmentioning

confidence: 99%

Section: ■ Materials and Methodsmentioning

confidence: 99%

Digitalizing the TIM-1 Model Using Computational Approaches─Part Two: Digital TIM-1 Model in GastroPlus

Hens,

Sarcevica,

Tomaszewska

et al. 2023

Mol. Pharmaceutics

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Section: Introductionmentioning

confidence: 99%

“…The physiological parameters can be adjusted to fasted, fed, and PPI conditions, as these settings are computer-controlled. Therefore, in the fed state, the gastric emptying rate can be decreased and secretions can be adjusted to reflect increased levels of bile and digestive enzymes observed after food ingestion …”

Section: Introductionmentioning

confidence: 99%

“…Therefore, in the fed state, the gastric emptying rate can be decreased and secretions can be adjusted to reflect increased levels of bile and digestive enzymes observed after food ingestion. 21 The application of physiologically based pharmacokinetic (PBPK) models can help the formulation scientist to further explore the impact of any formulation, physiology, or population parameter on the systemic exposure of the drug. 22−24 Sensitivity analyses can be performed to judge which parameters play a pivotal role in the absorption process.…”

Section: ■ Introductionmentioning

confidence: 99%

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Effect of Food and a Proton-Pump Inhibitor on the Absorption of Encorafenib: An In Vivo–In Vitro–In Silico Approach

et al. 2023

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Encorafenib is a kinase inhibitor indicated for the treatment of patients with BRAF mutant melanoma and BRAF mutant metastatic colorectal cancer. To understand the effect of food and coadministration with a proton-pump inhibitor (PPI), in vitro, in vivo, and in silico data were generated to optimize the clinical dose, evaluate safety, and better understand the oral absorption process under these conditions. Study 1 evaluated the effect of food on the plasma pharmacokinetics, safety, and tolerability after a single oral dose of encorafenib 100 mg. Study 2 evaluated the same end points with coadministration of encorafenib and rabeprazole (PPI perpetrator). The in vitro gastrointestinal TIM-1 model was used to investigate the release of encorafenib and the amount available for absorption under different testing conditions (fasted, fed, and with the use of a PPI). The fasted, fed, and PPI states were predicted for the encorafenib commercial capsule in GastroPlus 9.8. In study 1, both AUC inf and AUC last decreased by 4% with the administration of a high-fat meal. The C max was 36% lower than with fasted conditions. All 3 exposure parameters in study 2 (AUC inf , AUC last , and C max ) had mean changes of <10% when encorafenib was coadministered with a PPI. Using the in vitro gastrointestinal simulator TIM-1, the model demonstrated a similar release of drug, as the bioaccessible fraction, in the 3 conditions was equal (≥80%), predicting no PPI or food effect for this drug formulation. The modeling in GastroPlus 9.8 demonstrated complete absorption of encorafenib when formulated as an amorphous solid dispersion. To obtain these results, it was crucial to integrate the amorphous solubility of the drug that shows a 20-fold higher solubility at pH 6.8 compared with crystalline solubility. The increased amorphous solubility is likely the reason no PPI effect was observed compared with fasted state conditions. The prolongation in gastric emptying in the fed state resulted in delayed plasma T max for encorafenib. No dose adjustment is necessary when encorafenib is administered in the fed state or when coadministered with a PPI. Both the TIM-1 and physiologically based pharmacokinetic model results were consistent with the observed clinical data, suggesting that these will be valuable tools for future work.

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In vitro release and bioaccessibility of oral solid preparations in a dynamic gastrointestinal system simulating fasted and fed states: A case study of metformin hydrochloride tablets

Yang,

Hu,

et al. 2024

International Journal of Pharmaceutics

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In Vitro Simulation of the Environment in the Upper Gastrointestinal Lumen After Drug Administration in the Fed State Using the TIM-1 System and Comparison With Luminal Data in Adults

Cited by 4 publications

References 28 publications

Digitalizing the TIM-1 Model Using Computational Approaches─Part Two: Digital TIM-1 Model in GastroPlus

Digitalizing the TIM-1 Model Using Computational Approaches─Part Two: Digital TIM-1 Model in GastroPlus

Effect of Food and a Proton-Pump Inhibitor on the Absorption of Encorafenib: An In Vivo–In Vitro–In Silico Approach

In vitro release and bioaccessibility of oral solid preparations in a dynamic gastrointestinal system simulating fasted and fed states: A case study of metformin hydrochloride tablets

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