The utility of in vitro trials that use Caco-2 cell systems as a replacement for animal intestinal permeability and human bioequivalence measurements in drug development

Estudante, Margarida; Mello-Sampayo, Cristina de; Şahin, Selma; Morais, José; Benet, Leslie Z.

doi:10.19277/bbr.12.1.110

“…To this end, Scopus was used to identify papers or databases that contain relatively large datasets of Caco-2 Papp values or Fup values. The final selection of Caco-2 Papp data were obtained from Estudante et al (2015), Gertz et al (2010), Hallifax et al (2012), Hou et al (2004, Larregieu & Benet (2014), Lee et al (2017), Li et al (2007), and Neuhoff et al (2003). In case of Fup, the R httk database (EPA) and data from Ye et al (2016), Wang et al (2014), Srivastava et al (2021), Jones et al (2021), Ferguson et al (2019, Chen et al (2019), and Deshmukh and Harsch ( 2011) were selected.…”

Section: Data Collectionmentioning

confidence: 99%

Impact of in vitro experimental variation in kinetic parameters on physiologically based kinetic (PBK) model simulations

Punt

¹

2022

ALTEX

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In vitro toxicokinetic data are critical in meeting an increased regulatory need to improve chemical safety evaluations towards a better understanding of internal human chemical exposure and toxicity. In vitro intrinsic hepatic clearance (CLint), the fraction unbound in plasma (Fup), and the intestinal apparent permeability (Papp) are important parameters as input in a physiologically based kinetic (PBK) model to make first estimates of internal exposure after oral dosing. In the present study we explored the experimental variation in the values for these parameters as reported in the literature. Furthermore, the impact that this experimental variation has on PBK model predictions of maximum plasma concentration (Cmax) and the area under the concentration time curve (AUC0-24h) was determined. As a result of the experimental variation in CLint, Papp, and Fup, the predicted variation in Cmax for individual compounds ranged between 1.4-to 28-fold and the predicted variation in AUC0-24h ranged between 1.4-and 23-fold. These results indicate that there are still some important steps to take to achieve robust data that can be used in regulatory applications. To gain regulatory acceptance of in vitro kinetic data and PBK models based on in vitro input data, the boundaries in experimental conditions as well as the applicability domain and the use of different in vitro kinetic models need to be described in guidance documents.

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“…To this end, Scopus was used to identify papers or databases that contain relatively large datasets of Caco-2 Papp values or Fup values. The final selection of Caco-2 Papp data were obtained from Estudante et al (2015), Gertz et al (2010), Hallifax et al (2012), Hou et al (2004, Larregieu & Benet (2014), Lee et al (2017), Li et al (2007), and Neuhoff et al (2003). In case of Fup, the R httk database (EPA) and data from Ye et al (2016), Wang et al (2014), Srivastava et al (2021), Jones et al (2021), Ferguson et al (2019, Chen et al (2019), and Deshmukh and Harsch ( 2011) were selected.…”

Section: Data Collectionmentioning

confidence: 99%

Impact of in vitro experimental variation in kinetic parameters on physiologically based kinetic (PBK) model simulations_suppl1

Punt

¹

2022

ALTEX

0

View full text Add to dashboard Cite

In vitro toxicokinetic data are critical in meeting an increased regulatory need to improve chemical safety evaluations towards a better understanding of internal human chemical exposure and toxicity. In vitro intrinsic hepatic clearance (CLint), the fraction unbound in plasma (Fup), and the intestinal apparent permeability (Papp) are important parameters as input in a physiologically based kinetic (PBK) model to make first estimates of internal exposure after oral dosing. In the present study we explored the experimental variation in the values for these parameters as reported in the literature. Furthermore, the impact that this experimental variation has on PBK model predictions of maximum plasma concentration (Cmax) and the area under the concentration time curve (AUC0-24h) was determined. As a result of the experimental variation in CLint, Papp, and Fup, the predicted variation in Cmax for individual compounds ranged between 1.4-to 28-fold and the predicted variation in AUC0-24h ranged between 1.4-and 23-fold. These results indicate that there are still some important steps to take to achieve robust data that can be used in regulatory applications. To gain regulatory acceptance of in vitro kinetic data and PBK models based on in vitro input data, the boundaries in experimental conditions as well as the applicability domain and the use of different in vitro kinetic models need to be described in guidance documents.

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Anti-mycobacterial activity of labdane and halimane diterpenes obtained from Plectranthus ornatus Codd

Andrade

¹

,

Romagnoli

²

,

Almeida

³

et al. 2018

BBR

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Natural products are a unique source of lead compounds for medicinal chemistry. Several diterpenes isolated from Plectranthus spp. have been reported to have interesting tuberculostatic activity and P. ornatus Codd. has been used in some regions of Brazil as an anti-infective. Previously, diterpenes with halimane and labdane skeletons were isolated in large quantities from P. ornatus Codd. We assessed the anti-mycobacterial activity of these compounds, performing a preliminar assay with the non-virulent strain Mycobacterium smegmatis. The cytotoxicity of the diterpenes with halimane and labdane skeletons was tested with the lactate dehydrogenase assay, where no considerable cytotoxic effects were found up to 25 µg.mL-1. Subsequently, the microdilution method was used to determine the minimum inhibitory concentration (MIC) against M. smegmatis. The MIC that inhibited the growth of the non-virulent mycobacteria by ≥99% was 100 µg.mL-1 for the diterpene with halimane skeleton, whereas for the diterpene with a labdane skeleton was >100 µg.mL-1. To the best of our knowledge, this is the first report on diterpenes with halimane and labdane skeletons isolated from P. ornatus in macrophages cytotoxicity, and in a preliminar assay for anti-mycobacterial activity. Further studies are suggested on M. tuberculosis, particularly for the diterpenes with halimane skeleton.

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The utility of in vitro trials that use Caco-2 cell systems as a replacement for animal intestinal permeability and human bioequivalence measurements in drug development

Cited by 3 publications

References 10 publications

Impact of in vitro experimental variation in kinetic parameters on physiologically based kinetic (PBK) model simulations

Impact of in vitro experimental variation in kinetic parameters on physiologically based kinetic (PBK) model simulations

Impact of in vitro experimental variation in kinetic parameters on physiologically based kinetic (PBK) model simulations_suppl1

Anti-mycobacterial activity of labdane and halimane diterpenes obtained from Plectranthus ornatus Codd

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