Tag: transporter

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Risk of pharmacokinetic drug-drug interactions with novel drugs approved by the US FDA in 2022: a detailed review of DDI data from NDA documentation.

Presented at the 25th North American ISSX Meeting, September 2023
Jingjing Yu, Yan Wang, and Isabelle Ragueneau-Majlessi

2023 ISSX Poster Presentation – 2022 NDA Reviews

Abstract

Understanding the ADME processes involved in pharmacokinetic-based drug-drug interactions (DDIs) is critical to facilitate an optimal management of DDIs in the clinic. In the present work, drug metabolism and transport in vitro and in vivo data for small molecular drugs approved by the U.S. Food and Drug Administration in 2022 (N=22) were analyzed using the Certara Drug Interaction Database. The mechanism(s) and clinical relevance of these interactions were characterized based on information available in the new drug application (NDA) reviews.

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Enzyme- and Transporter-Mediated Clinical Drug Interactions with Drugs by the U.S. Food and Drug Administration in 2021: What Can be Learned from New Drug applications Reviews?

Presented at the ISSX/MDO Meeting, September 2022
Jingjing Yu, Yan Wang, and Isabelle Ragueneau-Majlessi

2022 ISSX Poster Presentation – 2021 NDA Reviews

Abstract

 The mechanistic evaluation of enzyme- and transporter-based drug-drug interactions (DDIs) during drug development is critical to support management strategies in the clinic.

The objectives of the study were to review pharmacokinetic-based clinical DDI data available in the new drug application (NDA) reviews for drugs approved by the FDA in 2021, and to understand the main mechanisms that mediate interactions resulting in label recommendations. 

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Pharmacokinetic Drug-Drug Interactions With Drugs Approved by the U.S. Food and Drug Administration in 2020: Mechanistic Understanding and Clinical Recommendations

Drug Metab Dispos. 2021 Oct7; 47(2); 135-144

Abstract

Pharmacokinetic-based drug-drug interaction (DDI) data for drugs approved by the U.S. Food and Drug Administration in 2017 (N = 34) were analyzed using the University of Washington Drug Interaction Database. The mechaniDrug-drug interaction (DDI) data for small molecular drugs approved by the U.S. Food and Drug Administration in 2020 (N = 40) were analyzed using the University of Washington Drug Interaction Database. The mechanism(s) and clinical relevance of these interactions were characterized based on information available in the new drug application reviews. About 180 positive clinical studies, defined as mean area under the curve ratios (AUCRs) {greater than or equal to} 1.25 for inhibition DDIs or pharmacogenetic studies and {less than or equal to} 0.8 for induction DDIs, were then fully analyzed. Oncology was the most represented therapeutic area, including 30% of 2020 approvals. As victim drugs, inhibition and induction of CYP3A explained most of all observed clinical interactions. Three sensitive substrates were identified: avapritinib (CYP3A), lonafarnib (CYP3A), and relugolix (P-gp), with AUCRs of 7.00, 5.07, and 6.25 when co-administered with itraconazole, ketoconazole, and erythromycin, respectively. As precipitants, three drugs were considered strong inhibitors of enzymes (AUCR {greater than or equal to} 5): cedazuridine for cytidine deaminase, and lonafarnib and tucatinib for CYP3A. No drug showed strong inhibition of transporters. No strong inducer of enzymes or transporters was identified. As expected, all DDIs with AUCRs {greater than or equal to} 5 or {less than or equal to} 0.2 and almost all those with AUCRs of 2-5 and 0.2-0.5 triggered dosing recommendations in the drug label. Overall, all 2020 drugs found to be either sensitive substrates or strong inhibitors of enzymes or transporters were oncology treatments, underscoring the need for effective DDI management strategies in cancer patients often receiving poly-therapy. Significance Statement This minireview provides a thorough and specific overview of the most significant pharmacokinetic-based DDI data observed (or expected) with small molecular drugs approved by the U.S. Food and Drug Administration in 2020. It will help to better understand mitigation strategies to manage the DDI risks in the clinic.

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Systematic Review of Drug Disposition Characteristics of Drugs Most Affected by Hepatic Impairment

Presented virtually at 24th North American ISSX Meeting, September 2021
Jessica Sontheimer, Zoé Borgel, Jingjing Yu, William Copalu, Catherine K. Yeung, Eva Berglund, and Isabelle Ragueneau-Majlessi

2021 ISSX Poster Presentation – Drug Disposition Characteristics and Hepatic Impairment

Abstract

The aim of the study was to systematically review the disposition parameters of drugs most affected by hepatic impairment(HI) and investigate whether there are elimination characteristics (such as enzyme or transporter involvement in drug elimination) that predisposed for a large effect of HI on drug exposure.

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Mechanisms and clinical significance of pharmacokinetic-based drug-drug interactions with drugs approved by the U.S. Food and Drug Administration in 2020

Presented virtually at the 24th North American ISSX Meeting, September 2021
Jingjing Yu, Yan Wang, and Isabelle Ragueneau-Majlessi

2021 ISSX Poster Presentation – 2020 NDA Clinical DDI Review

Abstract

The aim of the present work was to review pharmacokinetic drug-drug interaction (DDI) data available in New Drug Applications (NDAs) for drugs approved by the US Food and Drug Administration in 2020 and analyze the mechanisms mediating interactions in order to facilitate an optimal management of DDIs in the clinic.

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Excipient knowledgebase: Development of a comprehensive tool for understanding the disposition and interaction potential of common excipients

CPT Pharmacometrics Syst Pharmacol. 2021 Aug;10(8):953-961

Abstract

Although the use of excipients is widespread, a thorough understanding of the drug interaction potential of these compounds remains a frequent topic of current research. Not only can excipients alter the disposition of coformulated drugs, but it is likely that these effects on co-administered drugs can reach to clinical significance leading to potential adverse effects or loss of efficacy. These risks can be evaluated through use of in silico methods of mechanistic modeling, including approaches, such as population pharmacokinetic (PK) and physiologically-based PK modeling, which require a comprehensive understanding of the compounds to ensure accurate predictions. We established a knowledgebase of the available compound (or substance) and interaction-specific parameters with the goal of providing a single source of physiochemical, in vitro, and clinical PK and interaction data of commonly used excipients. To illustrate the utility of this knowledgebase, a model for cremophor EL was developed and used to hypothesize the potential for CYP3A- and P-gp-based interactions as a proof of concept.

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Systemic Evaluation of Drug-Drug Interaction Labeling Language and Clinical Recommendations: Digoxin as an Example of Narrow Therapeutics Index P-Glycoprotein Substrate

Presented virtually at ASCPT Annual Meeting, March 2021
Lindsay M. Henderson, Claire Steinbronn, Jingjing Yu, Cathy Yeung, and Isabelle Ragueneau-Majlessi

2021 ASCPT Poster Presentation – DDI labeling language and clinical recommendations, digoxin as an example

Abstract

This study’s objective was to evaluate the consistency in DDI labeling language of recently marketed drugs (2012-2020) when found to alter the exposure of coadministered digoxin, a clinical P-glycoprotein (P-gp) substrate and narrow therapeutic index (NTI) medication.

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Mechanisms and clinical relevance of pharmacokinetic-based clinical drug-drug interactions for drugs recently approved by the US Food and Drug Administration

Identification and Quantification of Drugs, Metabolites, Drug Metabolizing Enzymes, and Transporters – Concepts, Methods, and Translational Sciences. Second Edition 2020, Chapter 11, 339-358.

Abstract

New drug application reviews contain critical drug interaction study results with newly approved drugs tested both as victims and as perpetrators of drug-drug interactions (DDIs). Pharmacokinetic-based DDI data for drugs approved by the US Food and Drug Administration in 2013–2017 (N = 137) were analyzed using the University of Washington Drug Interaction Database. For the largest metabolism- and transporter-based drug interactions, defined as a change in exposure ≥ 5-fold in victim drugs, the mechanisms and clinical relevance were characterized. Consistent with the major role of CYP3A in drug disposition, CYP3A inhibition and induction explained a majority of the observed interactions (new drugs as victims or as perpetrators). However, transporter-mediated interactions were also prevalent, with OATP1B1/1B3 playing a significant role. As victims, 17 and 4 new molecular entities (NMEs) were identified to be sensitive substrates of enzymes and transporters, respectively. When considered as perpetrators, three drugs showed strong inhibition of CYP3A, one was a strong CYP3A inducer, and two showed strong inhibition of transporters (OATP1B1/1B3 and/or BCRP). All DDIs with AUC changes ≥ 5-fold had labeling recommendations in their respective drug labels, contraindicating or limiting the coadministration with known substrates or perpetrators of the enzyme/transporter involved. The majority of sensitive substrates or strong inhibitors were oncology and antiviral treatments, suggesting a significant risk of DDIs in these patient populations for whom therapeutic management is already complex due to poly-therapy. Pharmacogenetic studies and physiologically based pharmacokinetic models were commonly used to assess the drug interaction potential in specific populations and clinical scenarios. Finally, absorption-based DDIs were evaluated in approximately 30% of drug applications, and 14 NMEs had label recommendations based on the results.

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Inhibitors of Organic Anion-Transporting Polypeptides 1B1 and 1B3: Clinical Relevance and Regulatory Perspective

J Clin Pharmacol. 2020 Aug; 60(8); 1087-1098.
Published online 2020 Mar 20

Abstract

Organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 are the primary hepatic transporters responsible for uptake of drugs into the liver and, as such, an area of growing research focus. Currently, evaluation of these transporters as potential mediators of drug-drug interactions (DDIs) is recommended by regulatory agencies worldwide during the drug development process. Despite the growing focus on OATP1B1/1B3 as mediators of DDIs, only 2 drugs are recommended as index inhibitors for use in clinical studies, single-dose rifampin and cyclosporine, each with limitations for the utility of the resulting data. In this study a thorough analysis of the available in vitro and clinical data was conducted to identify drugs that are clinically relevant inhibitors of OATP1B1/1B3 and, from those, to select any novel index inhibitors. A total of 13 drugs and 16 combination products were identified as clinical inhibitors of OATP1B1/1B3, showing significant changes in exposure for sensitive substrates of the transporters, with strong supporting in vitro evidence. Although none of the identified inhibitors qualified as index inhibitors, this study confirmed the utility of cyclosporine and single-dose rifampin as index inhibitors to evaluate the effect of broad, multiple-pathway inhibition and more selective OATP1B1/1B3 inhibition, respectively.

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In Vitro-to-In Vivo Extrapolation of Transporter Inhibition Data for Drugs Approved by the US Food and Drug Administration in 2018

Clin Transl Sci.
Published online 2020 Jan 25

Abstract

A systematic analysis of the inhibition transporter data available in New Drug Applications of drugs approved by the US Food and Drug Administration (FDA) in 2018 (N = 42) was performed. In vitro‐to‐in vivo predictions using basic models were available for the nine transporters currently recommended for evaluation. Overall, 29 parents and 16 metabolites showed in vitro inhibition of at least one transporter, with the largest number of drugs found to be inhibitors of P‐gp followed by BCRP. The most represented therapeutic areas were oncology drugs and anti‐infective agents, each comprising 31%. Among drugs with prediction values greater than the FDA recommended cutoffs and further evaluated in vivo, 56% showed positive clinical interactions (area under the concentration‐time curve ratio (AUCRs) ≥ 1.25). Although all the observed or simulated inhibitions were weak (AUCRs < 2), seven of the nine interactions (involving five drugs) resulted in labeling recommendations. Interestingly, more than half of the drugs with predictions greater than the cutoffs had no further evaluations, highlighting that current basic models represent a useful, simple first step to evaluate the clinical relevance of in vitro findings, but that multiple other factors are considered when deciding the need for clinical studies. Four drugs had prediction values less than the cutoffs but had clinical evaluations or physiologically‐based pharmacokinetic simulations available. Consistent with the predictions, all of them were confirmed not to inhibit these transporters in vivo (AUCRs of 0.94–1.09). Overall, based on the clinical evaluations available, drugs approved in 2018 were found to have a relatively limited impact on drug transporters, with all victim AUCRs < 2.