Raymond Evers
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View article: Deconvoluting the in vitro to in vivo drug clearance gap: questioning the predictive performance of traditional hepatic clearance models
Deconvoluting the in vitro to in vivo drug clearance gap: questioning the predictive performance of traditional hepatic clearance models Open
In vitro to in vivo extrapolation (IVIVE) methods for hepatic clearance (CLH) prediction often underpredict, partly due to reliance on mathematical liver disposition models such as the well-stirred model (WSM) or parallel tube model (PTM).…
View article: Canine Mdr1 Knockout MDCK Cells Reliably Estimate Human Small Intestinal Permeability (<i>P</i><sub>eff</sub>) and Fraction Absorbed (<i>f</i><sub>a</sub>)
Canine Mdr1 Knockout MDCK Cells Reliably Estimate Human Small Intestinal Permeability (<i>P</i><sub>eff</sub>) and Fraction Absorbed (<i>f</i><sub>a</sub>) Open
Human intestinal permeability is a key determinant of the oral fraction absorbed (fa) of active pharmaceutical ingredients (APIs). This study evaluated the ability of an in-house canine Mdr1 (cMdr1) knockout (KO) Madin-Darby Canine Kidney …
View article: Toward improved clearance predictions and distribution profiles employing the isolated perfused rat liver model: Experimental optimization
Toward improved clearance predictions and distribution profiles employing the isolated perfused rat liver model: Experimental optimization Open
To reduce the drug attrition due to failure in clinical trials, an early accurate hepatic clearance (CLH) prediction for small molecule drugs is critical. However, the routinely used in vitro to in vivo extrapolation (IVIVE) methods to pre…
View article: Human organotypic colon in vitro microtissue: unveiling a new window into colonic drug disposition
Human organotypic colon in vitro microtissue: unveiling a new window into colonic drug disposition Open
The purpose of this study was to evaluate EpiColon, a novel human organotypic 3D colon microtissue prototype, developed to assess colonic drug disposition, with a particular focus on permeability ranking, and compare its performance to Cac…
View article: Toward improved predictions of pharmacokinetics of transported drugs in hepatic impairment: Insights from the extended clearance model
Toward improved predictions of pharmacokinetics of transported drugs in hepatic impairment: Insights from the extended clearance model Open
Hepatic impairment (HI) moderately (<5‐fold) affects the systemic exposure (i.e., area under the plasma concentration–time curve [AUC]) of drugs that are substrates of the hepatic sinusoidal organic anion transporting polypeptide (OATP) tr…
View article: Predicting changes in the pharmacokinetics of CYP3A‐metabolized drugs in hepatic impairment and insights into factors driving these changes
Predicting changes in the pharmacokinetics of CYP3A‐metabolized drugs in hepatic impairment and insights into factors driving these changes Open
Physiologically based pharmacokinetic models, populated with drug‐metabolizing enzyme and transporter (DMET) abundance, can be used to predict the impact of hepatic impairment (HI) on the pharmacokinetics (PK) of drugs. To increase confide…
View article: Physiologically‐based pharmacokinetic modeling for primary metabolites of <scp>CYP3A</scp> and P‐glycoprotein inhibitors in drug–drug interactions: Should we assume the free drug hypothesis?
Physiologically‐based pharmacokinetic modeling for primary metabolites of <span>CYP3A</span> and P‐glycoprotein inhibitors in drug–drug interactions: Should we assume the free drug hypothesis? Open
Metabolites of perpetrators may contribute to drug–drug interactions (DDIs) mediated by inhibition/induction of drug-metabolizing enzymes and transporters. Using physiologically-based pharmacokinetic (PBPK) modeling, we provide our perspec…
View article: The next frontier in ADME science: Predicting transporter-based drug disposition, tissue concentrations and drug-drug interactions in humans
The next frontier in ADME science: Predicting transporter-based drug disposition, tissue concentrations and drug-drug interactions in humans Open
This is the accepted manuscript version of the work published in its final form as Storelli, F., Yin, M., Kumar, A. R., Ladumor, M. K., Evers, R., Chothe, P. P., Enogieru, O. J., Liang, X., Lai, Y., & Unadkat, J. D. (2022). The next fronti…
View article: Regulation of Drug Transport Proteins—From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium
Regulation of Drug Transport Proteins—From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium Open
Membrane transport proteins are involved in the absorption, disposition, efficacy, and/or toxicity of many drugs. Numerous mechanisms (e.g., nuclear receptors, epigenetic gene regulation, microRNAs, alternative splicing, post‐translational…
View article: Assessment of Pharmacokinetic Interaction Between Gefapixant (MK‐7264), a P2X3 Receptor Antagonist, and the OATP1B1 Drug Transporter Substrate Pitavastatin
Assessment of Pharmacokinetic Interaction Between Gefapixant (MK‐7264), a P2X3 Receptor Antagonist, and the OATP1B1 Drug Transporter Substrate Pitavastatin Open
Gefapixant (MK‐7264, AF‐219), a first‐in‐class P2X3 antagonist, is being developed as oral treatment for refractory or unexplained chronic cough. Based on in vitro data, gefapixant exerts inhibitory activity on the organic anion transporte…
View article: Physiologically‐based pharmacokinetic modeling to evaluate in vitro‐to‐in vivo extrapolation for intestinal P‐glycoprotein inhibition
Physiologically‐based pharmacokinetic modeling to evaluate in vitro‐to‐in vivo extrapolation for intestinal P‐glycoprotein inhibition Open
As one of the key components in model‐informed drug discovery and development, physiologically‐based pharmacokinetic (PBPK) modeling linked with in vitro‐to‐in vivo extrapolation (IVIVE) is widely applied to quantitatively predict drug–dru…
View article: Application of a Rat Liver Drug Bioactivation Transcriptional Response Assay Early in Drug Development That Informs Chemically Reactive Metabolite Formation and Potential for Drug-induced Liver Injury
Application of a Rat Liver Drug Bioactivation Transcriptional Response Assay Early in Drug Development That Informs Chemically Reactive Metabolite Formation and Potential for Drug-induced Liver Injury Open
Drug-induced liver injury is a major reason for drug candidate attrition from development, denied commercialization, market withdrawal, and restricted prescribing of pharmaceuticals. The metabolic bioactivation of drugs to chemically react…
View article: Disease‐Associated Changes in Drug Transporters May Impact the Pharmacokinetics and/or Toxicity of Drugs: A White Paper From the International Transporter Consortium
Disease‐Associated Changes in Drug Transporters May Impact the Pharmacokinetics and/or Toxicity of Drugs: A White Paper From the International Transporter Consortium Open
Drug transporters are critically important for the absorption, distribution, metabolism, and excretion (ADME) of many drugs and endogenous compounds. Therefore, disruption of these pathways by inhibition, induction, genetic polymorphisms, …