Corrigendum to ’Development of a mechanistic biokinetic model for hepatic bile acid handling to predict possible cholestatic effects of drugs’ [European Journal of Pharmaceutical Sciences 115 (2018) 175-184] (S0928098718300071) (10.1016/j.ejps.2018.01.007))

The authors regret the molar unit is incorrectly displayed on the x-axis in Fig. 4A and 4C and on the y-axis in Fig. 4B, 4D and Fig. 5. The correct versions of the figures are displayed below together with the unchanged legends. The authors would like to apologise for any inconvenience caused. DOI of original article: 10.1016/j.ejps.2018.01.00

The application of organ-on-chip models for the prediction of human pharmacokinetic profiles during drug development

Organ-on-chip (OoC) technology has led to in vitro models with many new possibilities compared to conventional in vitro and in vivo models. In this review, the potential of OoC models to improve the prediction of human oral bioavailability and intrinsic clearance is discussed, with a focus on the functionality of the models and the application in current drug development practice. Multi-OoC models demonstrating the application for pharmacokinetic (PK) studies are summarized and existing challenges are identified. Physiological parameters for a minimal viable platform of a multi-OoC model to study PK are provided, together with PK specific read-outs and recommendations for relevant reference compounds to validate the model. Finally, the translation to in vivo PK profiles is discussed, which will be required to routinely apply OoC models during drug development

Proteomics of human liver membrane transporters: a focus on fetuses and newborn infants

Background: Hepatic membrane transporters are involved in the transport of many endogenous and exogenous compounds, including drugs. We aimed to study the relation of age with absolute transporter protein expression in a cohort of 62 mainly fetus and newborn samples. Methods: Protein expressions of BCRP, BSEP, GLUT1, MCT1, MDR1, MRP1, MRP2, MRP3, NTCP, OCT1, OATP1B1, OATP1B3, OATP2B1 and ATP1A1 were quantified with LC-MS/MS in isolated crude membrane fractions of snap-frozen post-mortem fetal and pediatric, and surgical adult liver samples. mRNA expression was quantified using RNA sequencing, and genetic variants with TaqMan assays. We explored relationships between protein expression and age (gestational age [GA], postnatal age [PNA], and postmenstrual age); between protein and mRNA expression; and between protein expression and genotype. Results: We analyzed 36 fetal (median GA 23.4 weeks [range 15.3–41.3]), 12 premature newborn (GA 30.2 weeks [24.9–36.7], PNA 1.0 weeks [0.14–11.4]), 10 term newborn (GA 40.0 weeks [39.7–41.3], PNA 3.9 weeks [0.3–18.1]), 4 pediatric (PNA 4.1 years [1.1–7.4]) and 8 adult liver samples. A relationship with age was found for BCRP, BSEP, GLUT1, MDR1, MRP1, MRP2, MRP3, NTCP, OATP1B1 and OCT1, with the strongest relationship for postmenstrual age. For most transporters mRNA and protein expression were not correlated. No genotype-protein expression relationship was detected. Discussion and conclusion: Various developmental patterns of protein expression of hepatic transporters emerged in fetuses and newborns up to four months of age. Postmenstrual age was the most robust factor predicting transporter expression in this cohort. Our data fill an important gap in current pediatric transporter ontogeny knowledge

The potential of multi-organ-on-chip models for assessment of drug disposition as alternative to animal testing

The development of new medicines suffers from attrition, especially in the development pipeline. Eight out of nine drug candidates entering the clinical testing phase fail, mostly due to poor safety and efficacy. The low predictive value of animal models, used in earlier phases of drug development, for effects in humans poses a major problem. In particular, drug disposition can markedly differentiate in experimental animals versus humans. Meanwhile, classic in vitro methods can be used but these models lack the complexity to mimic holistic physiological processes occurring in the human body, especially organ–organ interactions. Therefore, better predictive methods to investigate drug disposition in the preclinical phase are needed, for which recent developments in multiorgan-on-chip methods are very promising. To be able to capture human physiology as good as possible, multiorgan-on-chips should feature 1) human cells endogenously expressing main transporters and metabolizing enzymes; 2) organ models relevant for exposure route; 3) individual organs-on-chip connected in a physiologically relevant manner; 4) a tight cellular barrier between the compartments; 5) organ models properly polarized in 3D; 6) allow for sampling in all major compartments; 7) constructed from materials that do not absorb or adsorb the compound of interest; 8) cells should grow in absence of fetal calf serum and Matrigel; 9) validated with a panel of compounds with known characteristics in humans; 10) an integrated computer model translating concentrations to the human situation. Here, an overview of available systems is presented and the difficult route towards a fully validated system is discussed

The potential of multi-organ-on-chip models for assessment of drug disposition as alternative to animal testing

The development of new medicines suffers from attrition, especially in the development pipeline. Eight out of nine drug candidates entering the clinical testing phase fail, mostly due to poor safety and efficacy. The low predictive value of animal models, used in earlier phases of drug development, for effects in humans poses a major problem. In particular, drug disposition can markedly differentiate in experimental animals versus humans. Meanwhile, classic in vitro methods can be used but these models lack the complexity to mimic holistic physiological processes occurring in the human body, especially organ–organ interactions. Therefore, better predictive methods to investigate drug disposition in the preclinical phase are needed, for which recent developments in multiorgan-on-chip methods are very promising. To be able to capture human physiology as good as possible, multiorgan-on-chips should feature 1) human cells endogenously expressing main transporters and metabolizing enzymes; 2) organ models relevant for exposure route; 3) individual organs-on-chip connected in a physiologically relevant manner; 4) a tight cellular barrier between the compartments; 5) organ models properly polarized in 3D; 6) allow for sampling in all major compartments; 7) constructed from materials that do not absorb or adsorb the compound of interest; 8) cells should grow in absence of fetal calf serum and Matrigel; 9) validated with a panel of compounds with known characteristics in humans; 10) an integrated computer model translating concentrations to the human situation. Here, an overview of available systems is presented and the difficult route towards a fully validated system is discussed

The potential of multi-organ-on-chip models for assessment of drug disposition as alternative to animal testing

The development of new medicines suffers from attrition, especially in the development pipeline. Eight out of nine drug candidates entering the clinical testing phase fail, mostly due to poor safety and efficacy. The low predictive value of animal models, used in earlier phases of drug development, for effects in humans poses a major problem. In particular, drug disposition can markedly differentiate in experimental animals versus humans. Meanwhile, classic in vitro methods can be used but these models lack the complexity to mimic holistic physiological processes occurring in the human body, especially organ–organ interactions. Therefore, better predictive methods to investigate drug disposition in the preclinical phase are needed, for which recent developments in multiorgan-on-chip methods are very promising. To be able to capture human physiology as good as possible, multiorgan-on-chips should feature 1) human cells endogenously expressing main transporters and metabolizing enzymes; 2) organ models relevant for exposure route; 3) individual organs-on-chip connected in a physiologically relevant manner; 4) a tight cellular barrier between the compartments; 5) organ models properly polarized in 3D; 6) allow for sampling in all major compartments; 7) constructed from materials that do not absorb or adsorb the compound of interest; 8) cells should grow in absence of fetal calf serum and Matrigel; 9) validated with a panel of compounds with known characteristics in humans; 10) an integrated computer model translating concentrations to the human situation. Here, an overview of available systems is presented and the difficult route towards a fully validated system is discussed

The consequence of regional gradients of P-gp and CYP3A4 for drug-drug interactions by P-gp inhibitors and the P-gp/CYP3A4 interplay in the human intestine ex vivo

Intestinal P-gp and CYP3A4 work coordinately to reduce the intracellular concentration of drugs, and drug-drug interactions (DDIs) based on this interplay are of clinical importance and require pre-clinical investigation. Using precision-cut intestinal slices (PCIS) of human jejunum, ileum and colon, we investigated the P-gp/CYP3A4 interplay and related DDIs with P-gp inhibitors at the different regions of the human intestine with quinidine (Qi), dual substrate of P-gp and CYP3A4, as probe. All the P-gp inhibitors increased the intracellular concentrations of Qi by 2.1-2.6 fold in jejunum, 2.6-3.8 fold in ileum but only 1.2-1.3 fold in colon, in line with the different P-gp expression in these intestinal regions. The selective P-gp inhibitors (CP100356 and PSC833) enhanced 3-hydroxy-quinidine (3OH-Qi) in jejunum and ileum, while dual inhibitors of P-gp and CYP3A4 (verapamil and ketoconazole) decreased the 3OH-Qi production, despite of the increased intracellular Qi concentration, due to inhibition of CYP3A4. The outcome of DDIs based on P-gp/CYP3A4 interplay, shown as remarkable changes in the intracellular concentration of both the parent drug and the metabolite, varied among the intestinal regions, probably due to the different expression of P-gp and CYP3A4, and were different from those found in rat PCIS, which may have important implications for the disposition and toxicity of drugs and their metabolites

The progress of intestinal epithelial models from cell lines to gut-on-chip

Over the past years, several preclinical in vitro and ex vivo models have been developed that helped to understand some of the critical aspects of intestinal functions in health and disease such as inflammatory bowel disease (IBD). However, the translation to the human in vivo situation remains problematic. The main reason for this is that these approaches fail to fully reflect the multifactorial and complex in vivo environment (e.g., including microbiota, nutrition, and immune response) in the gut system. Although conventional models such as cell lines, Ussing chamber, and the everted sac are still used, increasingly more sophisticated intestinal models have been developed over the past years including organoids, InTESTine™ and microfluidic gut-on-chip. In this review, we gathered the most recent insights on the setup, advantages, limitations, and future perspectives of most frequently used in vitro and ex vivo models to study intestinal physiology and functions in health and disease