Recent developments in<i>in vitro</i>and<i>in vivo</i>models for improved translation of preclinical pharmacokinetics and pharmacodynamics data

Yadav, Jaydeep; Hassani, Mehdi El; Sodhi, Jasleen K.; Lauschke, Volker M.; Hartman, Jessica H.; Russell, Lauren

doi:10.1080/03602532.2021.1922435

Cited by 22 publications

(17 citation statements)

References 261 publications

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“…In the case of bupropion (CYP2B6 activity), abiotic degradation of the compound was observed, especially in the HL-ICOs. Determining the real in vitro dose facilitates reliable extrapolation of in vitro data towards in silico models [ 18 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

“…Over the years, the development of non-animal alternatives evolved to generate human-based toxicity data as well as to replace, reduce and refine animal use (3Rs) in safety evaluations [ 16 , 17 ]. To perform reliable human-based toxicity screens or mechanistic studies into DILI pathways, hepatic human in vitro models need to express morphological and functional features, such as drug metabolism, similar to an in vivo situation [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

et al. 2023

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Emerging advances in the field of in vitro toxicity testing attempt to meet the need for reliable human-based safety assessment in drug development. Intrahepatic cholangiocyte organoids (ICOs) are described as a donor-derived in vitro model for disease modelling and regenerative medicine. Here, we explored the potential of hepatocyte-like ICOs (HL-ICOs) in in vitro toxicity testing by exploring the expression and activity of genes involved in drug metabolism, a key determinant in drug-induced toxicity, and the exposure of HL-ICOs to well-known hepatotoxicants. The current state of drug metabolism in HL-ICOs showed levels comparable to those of PHHs and HepaRGs for CYP3A4; however, other enzymes, such as CYP2B6 and CYP2D6, were expressed at lower levels. Additionally, EC50 values were determined in HL-ICOs for acetaminophen (24.0–26.8 mM), diclofenac (475.5–>500 µM), perhexiline (9.7–>31.5 µM), troglitazone (23.1–90.8 µM), and valproic acid (>10 mM). Exposure to the hepatotoxicants showed EC50s in HL-ICOs comparable to those in PHHs and HepaRGs; however, for acetaminophen exposure, HL-ICOs were less sensitive. Further elucidation of enzyme and transporter activity in drug metabolism in HL-ICOs and exposure to a more extensive compound set are needed to accurately define the potential of HL-ICOs in in vitro toxicity testing.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

et al. 2023

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“…This would allow comparison and potential extrapolation of experimental outcomes from different models [55]. Established biomarkers could facilitate in these comparisons [54,56,57]. For bone regeneration, commonly assessed biomarkers include e.g., alkaline phosphatase, RUNX2, bone morphogenetic protein 2 and 7, osteopontin, osteocalcin, collagen type I, and vascular markers VEGF and CD31 [58].…”

Section: Discussionmentioning

confidence: 99%

Evaluating material-driven regeneration in a tissue engineered human in vitro bone defect model

Wildt

Cramer

Silva

et al. 2023

Bone

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“…This would allow comparison and potential extrapolation of experimental outcomes from different models [51]. Established biomarkers could facilitate in these comparisons [50,52,53]. For bone regeneration, commonly assessed biomarkers include e.g ., alkaline phosphatase, RUNX2, bone morphogenetic protein 2 and 7, osteopontin, osteocalcin, collagen type I, and vascular markers VEGF and CD31 [54].…”

Section: Discussionmentioning

confidence: 99%

Evaluating material-driven regeneration in a tissue engineered humanin vitrobone defect model

Wildt

Cramer

Silva

et al. 2022

Preprint

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Advanced in vitro human bone defect models can contribute to the evaluation of materials for in situ bone regeneration, addressing both translational and ethical concerns regarding animal models. In this study, we attempted to develop such a model to study material-driven regeneration, using a tissue engineering approach. By co-culturing human umbilical vein endothelial cells (HUVECs) with human bone marrow-derived mesenchymal stromal cells (hBMSCs) on silk fibroin scaffolds with in vitro critically sized defects, the growth of vascular-like networks and three-dimensional bone-like tissue was facilitated. After a model build-up phase of 28 days, materials were artificially implanted and HUVEC and hBMSC migration, cell-material interactions, and osteoinduction were evaluated 14 days after implantation. The materials physiologically relevant for bone regeneration included a platelet gel as blood clot mimic, cartilage spheres as soft callus mimics, and a fibrin gel as control. Although the in vitro model was limited in the evaluation of immune responses, hallmarks of physiological bone regeneration were observed in vitro. These included the endothelial cell chemotaxis induced by the blood clot mimic and the mineralization of the soft callus mimic. Therefore, the present in vitro model could contribute to an improved pre-clinical evaluation of biomaterials while reducing the need for animal experiments.

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Recent developments inin vitroandin vivomodels for improved translation of preclinical pharmacokinetics and pharmacodynamics data

Cited by 22 publications

References 261 publications

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

Evaluating material-driven regeneration in a tissue engineered human in vitro bone defect model

Evaluating material-driven regeneration in a tissue engineered humanin vitrobone defect model

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