Organ Impairment—Drug–Drug Interaction Database: A Tool for Evaluating the Impact of Renal or Hepatic Impairment and Pharmacologic Inhibition on the Systemic Exposure of Drugs

Yeung, CY; Yoshida, Kenta; Kusama, Makiko; Zhang, H; Ragueneau‐Majlessi, Isabelle; Argon, Sophie; Li, L; Chang, Peng; Le, CD; Zhao, Ping; Zhang, L; Sugiyama, Yuichi; Huang, Suli

doi:10.1002/psp4.55

Cited by 18 publications

(22 citation statements)

References 4 publications

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“…A fraction of a delafloxacin dose is conjugated by the liver into glucuronidated metabolites for excretion by the kidneys, and this process is facilitated through the liver . However, unlike hepatic metabolism through the cytochrome P450 system, phase 2 conjugation by the liver is rarely impacted by hepatic disease until there is severe damage . Therefore, one might predict that hepatic disease would not be a major factor in the disposition of delafloxacin and its glucuronide metabolites.…”

Section: Discussionmentioning

confidence: 99%

“…13 However, unlike hepatic metabolism through the cytochrome P450 system, phase 2 conjugation by the liver is rarely impacted by hepatic disease until there is severe damage. 14,15 Therefore, one might predict that hepatic disease would not be a major factor in the disposition of delafloxacin and its glucuronide metabolites. However, because a large percentage of delafloxacin is cleared by the kidneys (ß65%), whether as intact molecule or the conjugated metabolites, we also could have a confounding variable in subjects with varying degrees of renal function.…”

Section: Discussionmentioning

confidence: 99%

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Clinical Pharmacology of Delafloxacin in Patients With Hepatic Impairment

Hoover¹,

Marbury

Preston

et al. 2016

The Journal of Clinical Pharma

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Delafloxacin is a novel anionic fluoroquinolone with robust activity against Gram‐positive, Gram‐negative, atypical, and anaerobic bacteria, including methicillin‐resistant S aureus. Delafloxacin is currently being studied for the treatment of acute bacterial skin and skin structure infections and community‐acquired pneumonia. This was a phase 1, open‐label pharmacokinetic and safety study of a single intravenous dose of 300 mg delafloxacin in subjects with mild, moderate, and severe hepatic impairment (Child‐Pugh class A, B, and C, respectively) compared with matched healthy controls. The effects of hepatic impairment were assessed by ANOVA of log‐transformed values for AUC0‐∞, Cmax, and systemic clearance, with hepatic group as a fixed effect. Mean AUC0‐∞ and Cmax in each impairment group were not significantly different from those of the pooled healthy subjects (P > 0.05). The 90% confidence interval (CI) of the percentage ratios of least‐squares means of AUC0‐∞ did not indicate significant differences between the impairment groups and pooled healthy controls: Child‐Pugh class A (mild) 114.4 (CI: 95.6, 137.0), Child‐Pugh class B (moderate) 114.8 (CI: 95.9, 137.4), and Child‐Pugh class C (severe) 115.1 (CI: 96.1, 137.8). A single IV infusion of delafloxacin was generally well tolerated in all treatment groups. The exposure and clearance of delafloxacin in subjects with mild, moderate, or severe hepatic impairment did not significantly differ from those of pooled, matched healthy subjects. Based on these pharmacokinetic data, dose adjustment of delafloxacin in the presence of hepatic impairment is not needed.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical Pharmacology of Delafloxacin in Patients With Hepatic Impairment

Hoover¹,

Marbury

Preston

et al. 2016

The Journal of Clinical Pharma

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“…To date, the relationship between CKD and various elimination pathways has been examined for only a limited number of drugs. 7,8,14,15 We have recently developed an extensive database that allows for characterization of some of the interrelationships between impaired liver and kidney function and drug-drug interactions (DDIs) on pharmacokinetics, 16 but the database was not exhaustive with respect to CKD effects on nonrenally eliminated drugs. In the current study we compiled the available data to examine relationships between CKD and pharmacokinetics of model drugs for two elimination pathways, CYP2D6 and CYP3A4/5.…”

Section: What This Study Adds To Our Knowledge?mentioning

confidence: 99%

Systematic and quantitative assessment of the effect of chronic kidney disease on CYP2D6 and CYP3A4/5

Yoshida

Sun

Zhang

et al. 2016

Clin Pharma and Therapeutics

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Recent reviews suggest that chronic kidney disease (CKD) can affect the pharmacokinetics of nonrenally eliminated drugs, but the impact of CKD on individual elimination pathways has not been systematically evaluated. In this study we developed a comprehensive dataset of the effect of CKD on the pharmacokinetics of CYP2D6‐ and CYP3A4/5‐metabolized drugs. Drugs for evaluation were selected based on clinical drug–drug interaction (CYP3A4/5 and CYP2D6) and pharmacogenetic (CYP2D6) studies. Information from dedicated CKD studies was available for 13 and 18 of the CYP2D6 and CYP3A4/5 model drugs, respectively. Analysis of these data suggested that CYP2D6‐mediated clearance is generally decreased in parallel with the severity of CKD. There was no apparent relationship between the severity of CKD and CYP3A4/5‐mediated clearance. The observed elimination‐route dependency in CKD effects between CYP2D6 and CYP3A4/5 may inform the need to conduct clinical CKD studies with nonrenally eliminated drugs for optimal use of drugs in patients with CKD.

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“…FDA recommends that sponsors conduct organ impairment studies if HI and/or RI might affect a drug and/or its active metabolites' PK, or if the drug might be used in these respective populations (Yeung et al, 2015). For the purpose of this review, the AUC and C max ratios (impaired/control) were considered as a standard outcome measurement of the effect of various degrees of organ impairment on the NMEs, using values observed in patients with HI or RI versus those observed in control healthy populations.…”

Section: Downloaded Frommentioning

confidence: 99%

Key Findings from Preclinical and Clinical Drug Interaction Studies Presented in New Drug and Biological License Applications Approved by the Food and Drug Administration in 2014

Ritchie

Zhu

et al. 2015

Drug Metabolism and Disposition

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Regulatory approval documents contain valuable information, often not published, to assess the drug-drug interaction (DDI) profile of newly marketed drugs. This analysis aimed to systematically review all drug metabolism, transport, pharmacokinetics, and DDI data available in the new drug applications and biologic license applications approved by the U.S. Food and Drug Administration in 2014, using the University of Washington Drug Interaction Database, and to highlight the significant findings. Among the 30 new drug applications and 11 biologic license applications reviewed, 35 new molecular entities (NMEs) were well characterized with regard to drug metabolism, transport, and/or organ impairment 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. In vivo, when NMEs were considered as victim drugs, 16 NMEs had at least one in vivo DDI study with a clinically significant change in exposure (area under the time-plasma concentration curve or C max ratio ‡2 or £0.5), with 6 NMEs shown to be sensitive substrates of cytochrome P450 enzymes (area under the time-plasma concentration curve ratio ‡5 when coadministered with potent inhibitors): paritaprevir and naloxegol (CYP3A), eliglustat (CYP2D6), dasabuvir (CYP2C8), and tasimelteon and pirfenidone (CYP1A2). As perpetrators, seven NMEs showed clinically significant inhibition involving both enzymes and transporters, although no clinically significant induction was observed. Physiologically based pharmacokinetic modeling and pharmacogenetics studies were used for six and four NMEs, respectively, to optimize dosing recommendations in special populations and/or multiple impairment situations. In addition, the pharmacokinetic evaluations in patients with hepatic or renal impairment provided useful quantitative information to support drug administration in these fragile populations. IntroductionThe evaluation of pharmacokinetic drug-drug interactions (DDIs) during the development of a new molecular entity (NME) is based on a systematic and mechanistic approach that includes the assessment of both the possible effect of the NME on other drugs (NME as a perpetrator or precipitant) as well as the effect of other drugs on the NME (NME as a victim or object) (Zhang et al., 2009b). The results of extensive in vitro and clinical evaluations using probe substrates and inhibitors of drug metabolizing enzymes (DMEs) and transporters are used to predict broader interactions with other drugs, herbs, and/or food products that may be administered concomitantly (Zhang et al., 2009a, b;Lee et al., 2010;Tweedie et al., 2013). This knowledge is critical to support personalized dosing recommendations and to inform health care providers of the potential risk for drug interactions through drug labeling . The U.S. Food and Drug Administration (FDA) makes the entire new drug application (NDA) and biologic license application (BLA) approval packages, including s...

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Organ Impairment—Drug–Drug Interaction Database: A Tool for Evaluating the Impact of Renal or Hepatic Impairment and Pharmacologic Inhibition on the Systemic Exposure of Drugs

Cited by 18 publications

References 4 publications

Clinical Pharmacology of Delafloxacin in Patients With Hepatic Impairment

Clinical Pharmacology of Delafloxacin in Patients With Hepatic Impairment

Systematic and quantitative assessment of the effect of chronic kidney disease on CYP2D6 and CYP3A4/5

Key Findings from Preclinical and Clinical Drug Interaction Studies Presented in New Drug and Biological License Applications Approved by the Food and Drug Administration in 2014

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