<i>In vitro</i> and <i>in vivo</i> methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

Lu, Chuang; Di, Li

doi:10.1002/bdd.2212

Cited by 58 publications

(49 citation statements)

References 198 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Prediction on the basis of in vitro studies is now an integral part of early drug development (Lu and Di 2020 ) as well as of the medicines agency guidelines (EMA, FDA, and MHLW/PMDA). Computational models such as physiologically based pharmacokinetic models are now being used for quantitative prediction of in vivo interactions from in vitro experiments (Kato 2020 ; Min and Bae 2017 ), and these models are used extensively by drug developers before and during clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Inhibition and induction of CYP enzymes in humans: an update

et al. 2020

View full text Add to dashboard Cite

The cytochrome P450 (CYP) enzyme family is the most important enzyme system catalyzing the phase 1 metabolism of pharmaceuticals and other xenobiotics such as herbal remedies and toxic compounds in the environment. The inhibition and induction of CYPs are major mechanisms causing pharmacokinetic drug–drug interactions. This review presents a comprehensive update on the inhibitors and inducers of the specific CYP enzymes in humans. The focus is on the more recent human in vitro and in vivo findings since the publication of our previous review on this topic in 2008. In addition to the general presentation of inhibitory drugs and inducers of human CYP enzymes by drugs, herbal remedies, and toxic compounds, an in-depth view on tyrosine-kinase inhibitors and antiretroviral HIV medications as victims and perpetrators of drug–drug interactions is provided as examples of the current trends in the field. Also, a concise overview of the mechanisms of CYP induction is presented to aid the understanding of the induction phenomena.

show abstract

Section: Introductionmentioning

confidence: 99%

Inhibition and induction of CYP enzymes in humans: an update

et al. 2020

View full text Add to dashboard Cite

show abstract

“…147,148 In contrast, myocardial metabolism is mostly for energetic cellular requirements, although the possibility of drug transformation and clearance in the heart has been identified. [149][150][151] At the mechanistic level, the expression and activity of enzymes and transporters tightly regulate drug clearance, 152 and the use of iPSC-differentiated cells for such studies must ensure the stability of the expression and activity of enzymes and transporters. 153 Related to the stability of cellular function, culturing hepatic cells in 3D platforms and under fluidic flow has been shown to stabilize transport and metabolism.…”

Section: Toxicitymentioning

confidence: 99%

Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects

Dame

Ribeiro

2020

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

Hepatic and cardiac drug adverse effects are among the leading causes of attrition in drug development programs, in part due to predictive failures of current animal or in vitro models. Hepatocytes and cardiomyocytes differentiated from human induced pluripotent stem cells (iPSCs) hold promise for predicting clinical drug effects, given their human-specific properties and their ability to harbor genetically determined characteristics that underlie inter-individual variations in drug response. Currently, the fetal-like properties and heterogeneity of hepatocytes and cardiomyocytes differentiated from iPSCs make them physiologically different from their counterparts isolated from primary tissues and limit their use for predicting clinical drug effects. To address this hurdle, there have been ongoing advances in differentiation and maturation protocols to improve the quality and use of iPSC-differentiated lineages. Among these are in vitro hepatic and cardiac cellular microsystems that can further enhance the physiology of cultured cells, can be used to better predict drug adverse effects, and investigate drug metabolism, pharmacokinetics, and pharmacodynamics to facilitate successful drug development. In this article, we discuss how cellular microsystems can establish microenvironments for these applications and propose how they could be used for potentially controlling the differentiation of hepatocytes or cardiomyocytes. The physiological relevance of cells is enhanced in cellular microsystems by simulating properties of tissue microenvironments, such as structural dimensionality, media flow, microfluidic control of media composition, and co-cultures with interacting cell types. Recent studies demonstrated that these properties also affect iPSC differentiations and we further elaborate on how they could control differentiation efficiency in microengineered devices. In summary, we describe recent advances in the field of cellular microsystems that can control the differentiation and maturation of hepatocytes and cardiomyocytes for drug evaluation. We also propose how future research with iPSCs within engineered microenvironments could enable their differentiation for scalable evaluations of drug effects. Impact statement Cardiac and hepatic adverse drug effects are among the leading causes of attrition in preclinical and clinical drug development programs as well as marketing withdrawals. The insufficiency of animal testing models has led to considerable interest in the employment of cardiac and hepatic models using human-induced pluripotent stem cells (iPSCs) for drug toxicity testing. However, current batches of iPSC-derived cardiomyocytes and hepatocytes are variable and not matured as adult primary tissues, which limit their prediction of drug effects. This article discusses how the use of microfluidics can create microenvironments to better control differentiation protocols and increase the physiological relevance of iPSC-derived cardiomyocytes and hepatocytes. Development and standardization of technologies will enable evaluation of the potential value of cellular microsystems to improve the in vitro models used in drug development programs. Future steps in this field include controlled connections of organ systems to better recreate clinical metabolism and pharmacokinetics.

show abstract

“…Drug influx transporters, efflux transporters and metabolic enzymes such as cytochrome P450 enzymes (CYP450s) and UDP-glucuronosyltransferases (UGTs) are widely expressed in the liver, intestine or kidney. They coordinately work to control the disposition of the drug in vivo, called as “interplay of transporters and enzymes” [ 1 , 2 , 3 , 4 ]. CYP3A4, the main CYP450s, accounts for 30–40% of hepatic CYP450s and mediates 60–70% of drug metabolism [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Prediction of Cyclosporin-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Model Characterizing Interplay of Drug Transporters and Enzymes

Yang

Zhang

et al. 2020

IJMS

View full text Add to dashboard Cite

Uptake transporter organic anion transporting polypeptides (OATPs), efflux transporters (P-gp, BCRP and MRP2) and cytochrome P450 enzymes (CYP450s) are widely expressed in the liver, intestine or kidney. They coordinately work to control drug disposition, termed as “interplay of transporters and enzymes”. Cyclosporine A (CsA) is an inhibitor of OATPs, P-gp, MRP2, BCRP and CYP3As. Drug–drug interaction (DDI) of CsA with victim drugs occurs via disordering interplay of transporters and enzymes. We aimed to establish a whole-body physiologically-based pharmacokinetic (PBPK) model which predicts disposition of CsA and nine victim drugs including atorvastatin, cerivastatin, pravastatin, rosuvastatin, fluvastatin, simvastatin, lovastatin, repaglinide and bosentan, as well as drug–drug interactions (DDIs) of CsA with nine victim drugs to investigate the integrated effect of enzymes and transporters in liver, intestinal and kidney on drug disposition. Predictions were compared with observations. Most of the predictions were within 0.5–2.0 folds of observations. Atorvastatin was represented to investigate individual contributions of transporters and CYP3As to atorvastatin disposition and their integrated effect. The contributions to atorvastatin disposition were hepatic OATPs >> hepatic CYP3A > intestinal CYP3As ≈ efflux transporters (P-gp/BCRP/MRP2). The results got the conclusion that the developed PBPK model characterizing the interplay of enzymes and transporters was successfully applied to predict the pharmacokinetics of 10 OATP substrates and DDIs of CsA with 9 victim drugs.

show abstract

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

Cited by 58 publications

References 198 publications

Inhibition and induction of CYP enzymes in humans: an update

Inhibition and induction of CYP enzymes in humans: an update

Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects

Prediction of Cyclosporin-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Model Characterizing Interplay of Drug Transporters and Enzymes

Contact Info

Product

Resources

About