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A comparative evaluation of models to predict human intestinal metabolism from nonclinical data.

ABSTRACT: Extensive gut metabolism is often associated with the risk of low and variable bioavailability. The prediction of the fraction of drug escaping gut wall metabolism as well as transporter-mediated secretion (F_g ) has been challenged by the lack of appropriate preclinical models. The purpose of this study is to compare the performance of models that are widely employed in the pharmaceutical industry today to estimate F_g and, based on the outcome, to provide recommendations for the prediction of human F_g during drug discovery and early drug development. The use of in vitro intrinsic clearance from human liver microsomes (HLM) in three mechanistic models - the ADAM, Q_gut and Competing Rates - was evaluated for drugs whose metabolism is dominated by CYP450s, assuming that the effect of transporters is negligible. The utility of rat as a model for human F_g was also explored. The ADAM, Q_gut and Competing Rates models had comparable prediction success (70%, 74%, 69%, respectively) and bias (AFE = 1.26, 0.74 and 0.81, respectively). However, the ADAM model showed better accuracy compared with the Q_gut and Competing Rates models (RMSE =0.20 vs 0.30 and 0.25, respectively). Rat is not a good model (prediction success =32%, RMSE =0.48 and AFE = 0.44) as it seems systematically to under-predict human F_g . Hence, we would recommend the use of rat to identify the need for F_g assessment, followed by the use of HLM in simple models to predict human F_g . © 2017 Merck KGaA. Biopharmaceutics & Drug Disposition Published by John Wiley & Sons, Ltd.

SUBMITTER: Yau E

PROVIDER: S-EPMC5412686 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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A comparative evaluation of models to predict human intestinal metabolism from nonclinical data.

Yau Estelle E Petersson Carl C Dolgos Hugues H Peters Sheila Annie SA

Biopharmaceutics & drug disposition 20170401 3

Extensive gut metabolism is often associated with the risk of low and variable bioavailability. The prediction of the fraction of drug escaping gut wall metabolism as well as transporter-mediated secretion (F<sub>g</sub> ) has been challenged by the lack of appropriate preclinical models. The purpose of this study is to compare the performance of models that are widely employed in the pharmaceutical industry today to estimate F<sub>g</sub> and, based on the outcome, to provide recommendations fo ...[more]

PMID: 28152562

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Project description:BackgroundHelminthiases are very prevalent worldwide, yet their treatment and control rely on a handful of drugs. Emodepside, a marketed broad-spectrum veterinary anthelminthic with a unique mechanism of action, undergoing development for onchocerciasis is an interesting anthelmintic drug candidate. We tested the in vitro and in vivo activity of emodepside on nematode species that serve as models for human soil-transmitted helminth infection as well as on schistosomes.MethodsIn vitro viability assays were performed over a time course of 72 hours for Trichuris muris, Necator americanus, Ancylostoma ceylanicum, Heligmosomoides polygyrus, Strongyloides ratti, Schistosoma mansoni and Schistosoma haematobium. The drug effect was determined by the survival rate for the larvae and by phenotypical scores for the adult worms. Additionally, mice infected with T. muris and hamsters harboring hookworm infection (N. americanus or A. ceylanicum) were administered orally with emodepside at doses ranging from 1.25 to 75 mg/kg. Expelled worms in the feces were counted until 3 days post-drug intake and worms residing in the intestines were collected and counted after dissection.ResultsAfter 24 hours, emodepside was very active in vitro against both larval and adult stages of the nematodes T. muris, A. ceylanicum, N. americanus, H. polygyrus and S. ratti (IC50 < 4 µM). The good in vitro activity was confirmed in vivo. Hamsters infected with the hookworms were cured when administered orally with 2.5 mg/kg of the drug. Emodepside was also highly active in vivo against T. muris (ED50 = 1.2 mg/kg). Emodepside was moderately active on schistosomula in vitro (IC50 < 8 µM) 24 h post-drug incubation and its activity on adult S. mansoni and S. haematobium was low (IC50: 30-50 µM).ConclusionsEmodepside is highly active against a broad range of nematode species both in vitro and in vivo. The development of emodepside for treating soil-transmitted helminth infections should be pursued.

Project description:BackgroundNonclinical determinants of health are of increasing importance to health care delivery and health policy. Concurrent with growing interest in better addressing patients' nonmedical issues is the exponential growth in availability of data sources that provide insight into these nonclinical determinants of health.ObjectiveThis review aimed to characterize the state of the existing literature on the use of nonclinical health indicators in conjunction with clinical data sources.MethodsWe conducted a rapid review of articles and relevant agency publications published in English. Eligible studies described the effect of, the methods for, or the need for combining nonclinical data with clinical data and were published in the United States between January 2010 and April 2018. Additional reports were obtained by manual searching. Records were screened for inclusion in 2 rounds by 4 trained reviewers with interrater reliability checks. From each article, we abstracted the measures, data sources, and level of measurement (individual or aggregate) for each nonclinical determinant of health reported.ResultsA total of 178 articles were included in the review. The articles collectively reported on 744 different nonclinical determinants of health measures. Measures related to socioeconomic status and material conditions were most prevalent (included in 90% of articles), followed by the closely related domain of social circumstances (included in 25% of articles), reflecting the widespread availability and use of standard demographic measures such as household income, marital status, education, race, and ethnicity in public health surveillance. Measures related to health-related behaviors (eg, smoking, diet, tobacco, and substance abuse), the built environment (eg, transportation, sidewalks, and buildings), natural environment (eg, air quality and pollution), and health services and conditions (eg, provider of care supply, utilization, and disease prevalence) were less common, whereas measures related to public policies were rare. When combining nonclinical and clinical data, a majority of studies associated aggregate, area-level nonclinical measures with individual-level clinical data by matching geographical location.ConclusionsA variety of nonclinical determinants of health measures have been widely but unevenly used in conjunction with clinical data to support population health research.

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A comparative evaluation of models to predict human intestinal metabolism from nonclinical data.

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A comparative evaluation of models to predict human intestinal metabolism from nonclinical data.

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