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Drug-drug interaction (DDI) data for small molecular drugs approved by the US 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) ≥1.25 for inhibition DDIs or pharmacogenetic studies and ≤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-glycoprotein), with AUCRs of 7.00, 5.07, and 6.25 when coadministered with itraconazole, ketoconazole, and erythromycin, respectively. As precipitants, three drugs were considered strong inhibitors of enzymes (AUCR ≥ 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 ≥5 or ≤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 patients with cancer often receiving polytherapy. 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 US Food and Drug Administration in 2020. It will help to better understand mitigation strategies to manage the DDI risks in the clinic., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Evaluating the potential of new drugs and their metabolites to cause drug-drug interactions (DDIs) is critical for understanding drug safety and efficacy. Although multiple analyses of proprietary metabolite testing data have been published, no systematic analyses of metabolite data collected according to current testing criteria have been conducted. To address this knowledge gap, 120 new molecular entities approved between 2013 and 2018 were reviewed. Comprehensive data on metabolite-to-parent area under the curve ratios (AUC M /AUC P ), inhibitory potency of parent and metabolites, and clinical DDIs were collected. Sixty-four percent of the metabolites quantified in vivo had AUC M /AUC P  ≥ 0.25 and 75% of these metabolites were tested for cytochrome P450 (CYP) inhibition in vitro, resulting in 15 metabolites with potential DDI risk identification. Although 50% of the metabolites with AUC M /AUC P  < 0.25 were also tested in vitro, none of them showed meaningful CYP inhibition potential. The metabolite percentage of plasma total radioactivity cutoff of ≥ 10% did not appear to add value to metabolite testing strategies. No relationship between metabolite versus parent drug polarity and inhibition potency was observed. Comparison of metabolite and parent maximum concentration (C max ) divided by inhibition constant (K i ) values suggested that metabolites can contribute to in vivo DDIs and, hence, quantitative prediction of clinical DDI magnitude may require both parent and metabolite data. This systematic analysis of metabolite data for newly approved drugs supports an AUC M /AUC P cutoff of ≥ 0.25 to warrant metabolite in vitro CYP screening to adequately characterize metabolite inhibitory DDI potential and support quantitative DDI predictions., (© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)

Despite recent advances in recognizing and reducing the risk of drug-drug interactions (DDIs) in developed countries, there are still significant challenges in managing DDIs in low-income countries (LICs) worldwide. In the treatment of major infectious diseases in these regions, multiple factors contribute to ineffective management of DDIs that lead to loss of efficacy or increased risk of adverse events to patients. Some of these difficulties, however, can be overcome. This review aims to evaluate the inherent complexities of DDI management in LICs from pharmacological standpoints and illustrate the unique barriers to effective management of DDIs, such as the challenges of co-infection and treatment settings. A better understanding of comprehensive drug-related properties, population-specific attributes, such as physiological changes associated with infectious diseases, and the use of modeling and simulation techniques are discussed, as they can facilitate the implementation of optimal treatments for infectious diseases at the individual patient level., (© 2019 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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 mechanisms and clinical relevance of these interactions were characterized based on information from new drug application reviews. CYP3A inhibition and induction explained most of the observed drug interactions (new drugs as victims or as perpetrators), and transporters mediated about half of all DDIs, alone or with enzymes. Organic anion transporting polypeptide (OATP)1B1/1B3 played a significant role, mediating more than half of the drug interactions with area under the time-plasma curve (AUC) changes ≥5-fold. As victims, five new drugs were identified as sensitive substrates: abemeciclib, midostaurin, and neratinib for CYP3A and glecaprevir and voxilaprevir for OATP1B1/1B3. As perpetrators, three drugs were considered strong inhibitors: ribociclib for CYP3A, glecaprevir/pibrentasvir for OATP1B1/1B3, and sofosbuvir/velpatasvir/voxilaprevir for OATP1B1/1B3 and breast cancer resistance protein. No strong inducer of enzymes or transporters was identified. DDIs with AUC changes ≥5-fold and almost all DDIs with AUC changes 2- to 5-fold had dose recommendations in their respective drug labels. A small fraction of DDIs with exposure changes <2-fold had a labeling impact, mostly related to drugs with narrow therapeutic indices. As with drugs approved in recent years, all drugs found to be sensitive substrates or strong inhibitors of enzymes or transporters were among oncology or antiviral treatments, suggesting a serious risk of DDIs in these patient populations for whom effective therapy is already complex because of polytherapy., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

A total of 103 drugs (including 14 combination drugs) were approved by the U.S. Food and Drug Administration from 2013 to 2016. Pharmacokinetic-based drug interaction profiles were analyzed using the University of Washington Drug Interaction Database, and the clinical relevance of these observations was characterized based on information from new drug application reviews. CYP3A was involved in approximately two-thirds of all drug-drug interactions (DDIs). Transporters (alone or with enzymes) participated in about half of all interactions, but most of these were weak-to-moderate interactions. When considered as victims, eight new molecular entities (NMEs; cobimetinib, ibrutinib, isavuconazole, ivabradine, naloxegol, paritaprevir, simeprevir, and venetoclax) were identified as sensitive substrates of CYP3A, two NMEs (pirfenidone and tasimelteon) were sensitive substrates of CYP1A2, one NME (dasabuvir) was a sensitive substrate of CYP2C8, one NME (eliglustat) was a sensitive substrate of CYP2D6, and one NME (grazoprevir) was a sensitive substrate of OATP1B1/3 (with changes in exposure greater than 5-fold when coadministered with a strong inhibitor). Approximately 75% of identified CYP3A substrates were also substrates of P-glycoprotein. As perpetrators, most clinical DDIs involved weak-to-moderate inhibition or induction. Only idelalisib showed strong inhibition of CYP3A, and lumacaftor behaved as a strong CYP3A inducer. Among drugs with large changes in exposure (≥5-fold), whether as victim or perpetrator, the most-represented therapeutic classes were antivirals and oncology drugs, suggesting a significant risk of clinical DDIs in these patient populations., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

In recent years, an increasing number of clinical drug-drug interactions (DDIs) have been attributed to inhibition of intestinal organic anion-transporting polypeptides (OATPs); however, only a few of these DDI results were reflected in drug labels. This review aims to provide a thorough analysis of intestinal OATP-mediated pharmacokinetic-based DDIs, using both in vitro and clinical investigations, highlighting the main mechanistic findings and discussing their clinical relevance. On the basis of pharmacogenetic and clinical DDI results, a total of 12 drugs were identified as possible clinical substrates of OATP2B1 and OATP1A2. Among them, 3 drugs, namely atenolol, celiprolol, and fexofenadine, have emerged as the most sensitive substrates to evaluate clinical OATP-mediated intestinal DDIs when interactions with P-glycoprotein by the test compound can be ruled out. With regard to perpetrators, 8 dietary or natural products and 1 investigational drug, ronacaleret (now terminated), showed clinical intestinal inhibition attributable to OATPs, producing ≥20% decreases in area under the plasma concentration-time curve of the co-administered drug. Common juices, such as apple juice, grapefruit juice, and orange juice, are considered potent inhibitors of intestinal OATP2B1 and OATP1A2 (decreasing exposure of the co-administered substrate by ∼85%) and may be adequate prototype inhibitors to investigate intestinal DDIs mediated by OATPs., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

As a follow up to previous reviews, the aim of the present analysis was to systematically examine all drug metabolism, transport, pharmacokinetics (PK), and drug-drug interaction (DDI) data available in the 33 new drug applications (NDAs) approved by the Food and Drug Administration (FDA) in 2015, using the University of Washington Drug Interaction Database, and to highlight the significant findings. In vitro, a majority of the new molecular entities (NMEs) were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. In vivo, 95 clinical DDI studies displayed positive PK interactions, with an area under the curve (AUC) ratio ≥ 1.25 for inhibition or ≤ 0.8 for induction. When NMEs were considered as victim drugs, 21 NMEs had at least one positive clinical DDI, with three NMEs shown to be sensitive substrates of CYP3A (AUC ratio ≥ 5 when coadministered with strong inhibitors): cobimetinib, isavuconazole (the active metabolite of prodrug isavuconazonium sulfate), and ivabradine. As perpetrators, nine NMEs showed positive inhibition and three NMEs showed positive induction, with some of these interactions involving both enzymes and transporters. The most significant changes for inhibition and induction were observed with rolapitant, a moderate inhibitor of CYP2D6 and lumacaftor, a strong inducer of CYP3A. Physiologically based pharmacokinetics simulations and pharmacogenetics studies were used for six and eight NMEs, respectively, to inform dosing recommendations. The effects of hepatic or renal impairment on the drugs' PK were also evaluated to support drug administration in these specific populations., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Modeling and simulation of drug disposition has emerged as an important tool in drug development, clinical study design and regulatory review, and the number of physiologically based pharmacokinetic (PBPK) modeling related publications and regulatory submissions have risen dramatically in recent years. However, the extent of use of PBPK modeling by researchers, and the public availability of models has not been systematically evaluated. This review evaluates PBPK-related publications to 1) identify the common applications of PBPK modeling; 2) determine ways in which models are developed; 3) establish how model quality is assessed; and 4) provide a list of publically available PBPK models for sensitive P450 and transporter substrates as well as selective inhibitors and inducers. PubMed searches were conducted using the terms "PBPK" and "physiologically based pharmacokinetic model" to collect published models. Only papers on PBPK modeling of pharmaceutical agents in humans published in English between 2008 and May 2015 were reviewed. A total of 366 PBPK-related articles met the search criteria, with the number of articles published per year rising steadily. Published models were most commonly used for drug-drug interaction predictions (28%), followed by interindividual variability and general clinical pharmacokinetic predictions (23%), formulation or absorption modeling (12%), and predicting age-related changes in pharmacokinetics and disposition (10%). In total, 106 models of sensitive substrates, inhibitors, and inducers were identified. An in-depth analysis of the model development and verification revealed a lack of consistency in model development and quality assessment practices, demonstrating a need for development of best-practice guidelines., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

The aim of the present work was to perform a systematic review of drug metabolism, transport, pharmacokinetics, and DDI data available in the NDAs approved by the FDA in 2013, using the University of Washington Drug Interaction Database, and to highlight significant findings. Among 27 NMEs approved, 22 (81%) were well characterized with regard to drug metabolism, transport, or organ impairment, in accordance with the FDA drug interaction guidance (2012) and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. However, in vivo, only half (n = 11) showed clinically relevant drug interactions, with most related to the NMEs as victim drugs and CYP3A being the most affected enzyme. As perpetrators, the overall effects for NMEs were much less pronounced, compared with when they served as victims. In addition, the pharmacokinetic evaluation in patients with hepatic or renal impairment provided useful information for further understanding of the drugs' disposition., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding XueBiJing, a five-herb medicine, to antibiotic-based sepsis care. Although adding XueBiJing further reduced 28-day mortality via modulating the host response, pharmacokinetic herb–drug interaction is a widely recognized issue that needs to be studied. Building on our earlier systematic chemical and human pharmacokinetic investigations of XueBiJing, we evaluated the degree of pharmacokinetic compatibility for XueBiJing/antibiotic combination based on mechanistic evidence of interaction risk. Considering both XueBiJing‒antibiotic and antibiotic‒XueBiJing interaction potential, we integrated informatics-based approach with experimental approach and developed a compound pair-based method for data processing. To reflect clinical reality, we selected for study XueBiJing compounds bioavailable for drug interactions and 45 antibiotics commonly used in sepsis care in China. Based on the data of interacting with drug metabolizing enzymes and transporters, no XueBiJing compound could pair, as perpetrator, with the antibiotics. Although some antibiotics could, due to their inhibition of uridine 5′-diphosphoglucuronosyltransferase 2B15, organic anion transporters 1/2 and/or organic anion-transporting polypeptide 1B3, pair with senkyunolide I, tanshinol and salvianolic acid B, the potential interactions (resulting in increased exposure) are likely desirable due to these XueBiJing compounds' low baseline exposure levels. Inhibition of aldehyde dehydrogenase by 7 antibiotics probably results in undesirable reduction of exposure to protocatechuic acid from XueBiJing. Collectively, XueBiJing/antibiotic combination exhibited a high degree of pharmacokinetic compatibility at clinically relevant doses. The methodology developed can be applied to investigate other drug combinations. Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding XueBiJing, an intravenous five-herb injection, to antibiotic-based sepsis care. XueBiJing/antibiotic combination exhibited a high degree of pharmacokinetic compatibility at clinically relevant doses; this supports their concurrent use in sepsis care. Image 1 [ABSTRACT FROM AUTHOR]

Organic anion transporting polypeptides (OATPs) 1B1 and 1B3 facilitate the uptake of drugs and endogenous compounds into the liver. In recent years, the impact of these transporters on drug–drug interactions (DDIs) has become a focus of research, and the evaluation of their role in drug disposition is recommended by regulatory agencies worldwide.1–3 Although sensitive substrates of OATP1B1/1B3 have been identified in the literature and probe drugs have been proposed by regulatory agencies, there is no general consensus on the ideal in vivo substrate for clinical DDI studies as analysis may be confounded by contribution from other metabolic and/or transport pathways.1–3 A thorough analysis of the available in vitro and in vivo data regarding OATP1B1/1B3 substrates was performed using the in vitro, clinical, and pharmacogenetic modules in the University of Washington Drug Interaction Database. A total of 34 compounds were identified and further investigated as possible clinical substrates using a novel indexing system. By analyzing the compounds for in vivo characteristics, including sensitivity to inhibition by known OATP1B1/1B3 inhibitors, selectivity for OATP1B1/1B3 compared with other transport and metabolic pathways, and safety profiles, a total of six compounds were identified as potential clinical markers of OATP1B1/1B3 activity. [ABSTRACT FROM AUTHOR]