A decade of drug metabolite safety testing: industry and regulatory shared learning

Luffer‐Atlas, Debra; Atrakchi, Aisar

doi:10.1080/17425255.2017.1364362

Cited by 37 publications

(26 citation statements)

References 16 publications

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“…In this study, the in vitro metabolism profiles of CDD were determined using LS9 from different animals to determine the species-dependent characteristics. The LS9 of dog, monkey, and rat was selected in addition to HLS9, on the note that such animals exhibit comparable metabolism profiles to humans, where the major metabolites potentially present in humans can be found in these animals to a similar extent ( Luffer-Atlas and Atrakchi, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

In Vitro Hepatic Metabolism of Curcumin Diethyl Disuccinate by Liver S9 from Different Animal Species

et al. 2020

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Liver S9 (LS9) is a nearly complete collection of all hepatic drug-metabolizing enzymes. It is a low-cost model for predicting drug metabolic activity. This study aimed to identify the suitability of using LS9 of different animal sources in drug metabolism profiling with respect to the possible translation of the in vitro outcomes to clinical studies. The in vitro hepatic metabolism of curcumin diethyl disuccinate (CDD) in LS9 of rats, dogs, monkeys, and humans was evaluated. The identity of CDD metabolites and the metabolism kinetic parameters, including degradation rate constant, in vitro / in vivo intrinsic clearance, and half-life, were determined. CDD was rapidly metabolized into monoethylsuccinyl curcumin and curcumin in LS9 of all tested species mainly by carboxylesterases (CESs), including CES1 and CES2, and butyrylcholinesterase. The in vitro intrinsic clearance of CDD was in the order of human > dog > monkey > rat, whereas that of monoethylsuccinyl curcumin in the order of dog > monkey > human > rat; this parameter was not correlated with their respective in vivo clearance, which followed the order of dog > monkey > rat > human. Therefore, in vitro drug metabolism data inferred from LS9 of nonhuman origin, especially from monkeys and dogs, cannot be used as preclinical data for human trials, as humans have a smaller liver-to-body weight ratio than monkeys, dogs, and rats. The in vivo drug metabolism is dictated by the anatomical factors of the test subject.

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Section: Resultsmentioning

confidence: 99%

In Vitro Hepatic Metabolism of Curcumin Diethyl Disuccinate by Liver S9 from Different Animal Species

et al. 2020

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“…Current regulatory guidance defines disproportionate metabolites that mandate safety evaluation as metabolites that constitute >10% of circulating drug levels in humans and that are either not detected in animals or for which animal exposure is at least 50% lower [ICH M3 (R2), 2010; The US FDA, 2016]. However, certain metabolite classes, such as stable glutathione or N-acetylcysteine conjugates, might be exempt on a case-by-case basis (Luffer-Atlas and Atrakchi, 2017).…”

Section: Applications Beyond Hepatotoxicity Testingmentioning

confidence: 99%

Comprehensive Evaluation of Organotypic and Microphysiological Liver Models for Prediction of Drug-Induced Liver Injury

2019

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Drug-induced liver injury (DILI) is a major concern for the pharmaceutical industry and constitutes one of the most important reasons for the termination of promising drug development projects. Reliable prediction of DILI liability in preclinical stages is difficult, as current experimental model systems do not accurately reflect the molecular phenotype and functionality of the human liver. As a result, multiple drugs that passed preclinical safety evaluations failed due to liver toxicity in clinical trials or postmarketing stages in recent years. To improve the selection of molecules that are taken forward into the clinics, the development of more predictive in vitro systems that enable high-throughput screening of hepatotoxic liabilities and allow for investigative studies into DILI mechanisms has gained growing interest. Specifically, it became increasingly clear that the choice of cell types and culture method both constitute important parameters that affect the predictive power of test systems. In this review, we present current 3D culture paradigms for hepatotoxicity tests and critically evaluate their utility and performance for DILI prediction. In addition, we highlight possibilities of these emerging platforms for mechanistic evaluations of selected drug candidates and present current research directions towards the further improvement of preclinical liver safety tests. We conclude that organotypic and microphysiological liver systems have provided an important step towards more reliable DILI prediction. Furthermore, we expect that the increasing availability of comprehensive benchmarking studies will facilitate model dissemination that might eventually result in their regulatory acceptance.

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“…Despite the recommendations in the guidance and the extensive literature reviews, shortcomings in the understanding of circulating metabolites are still apparent in recent regulatory submissions and have been identified in a number of applications for new marketing authorizations during the past 10 years. The reasons for this are varied but can often be attributed to deficiencies in the knowledge normally gained from the mass balance study and range from the complete absence of a human mass balance study to poorly designed, or incomplete studies, or to unexpected findings in the study confounding the interpretation of the results, e.g., if the radiolabel is found to be in a metabolically labile position.…”

Section: Issues With Plasma Metabolite Identification In Dossiers Formentioning

confidence: 99%

“…A book chapter was also published by the FDA describing regulatory aspects of the mass balance study. It is now nearly 10 years since the ICH M3 (R2) guideline came into force at the end of 2009, and reviews of the decade of use have already been discussed in at least two articles …”

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confidence: 99%

“…It is now nearly 10 years since the ICH M3 (R2) guideline 2 came into force at the end of 2009, and reviews of the decade of use have already been discussed in at least two articles. 12,13 According to the European Medicines Agency (EMA) guideline, 3 the results of a mass balance study should generally be available before starting phase III clinical trials. In general, during the past 10 years, there has been a shift to conduct the human mass balance study earlier in clinical development, 11 i.e., before the demonstration of efficacy.…”

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confidence: 99%

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The Importance of the Human Mass Balance Study in Regulatory Submissions

Coppola¹,

Andersson

Cole³

2019

CPT Pharmacom & Syst Pharma

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The human mass balance study is a key study in the Clinical Pharmacology package of new drug applications. This study, along with the mass balance studies in toxicology species, provides essential information on the exposure of the parent compound and metabolites. Despite current regulatory guidance and previous publications, a lack of this study, or deficiencies in the study, are still seen in regulatory submissions today. This restricts the assessment of the benefit/risk in all populations and on the potential for drug–drug interactions leading to unnecessary precautions in the label. A review of new drug applications identifies a number of examples of inadequate characterization of circulating drug‐related components or of elimination pathways, with questions raised during the regulatory review. In light of this, new insight is given on what is required from the mass balance study and on how to ensure sufficient information is captured.

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A decade of drug metabolite safety testing: industry and regulatory shared learning

Cited by 37 publications

References 16 publications

In Vitro Hepatic Metabolism of Curcumin Diethyl Disuccinate by Liver S9 from Different Animal Species

In Vitro Hepatic Metabolism of Curcumin Diethyl Disuccinate by Liver S9 from Different Animal Species

Comprehensive Evaluation of Organotypic and Microphysiological Liver Models for Prediction of Drug-Induced Liver Injury

The Importance of the Human Mass Balance Study in Regulatory Submissions

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