Dataset Information

Inter-study variability of preclinical in vivo safety studies and translational exposure-QTc relationships--a PKPD meta-analysis.

ABSTRACT:

Background and purpose

Preclinical cardiovascular safety studies (CVS) have been compared between facilities with respect to their sensitivity to detect drug-induced QTc prolongation (?QTc). Little is known about the consistency of quantitative ?QTc predictions that are relevant for translation to humans.

Experimental approach

We derived typical ?QTc predictions at therapeutic exposure (?QTcTHER ) with 95% confidence intervals (95%CI) for 3 Kv 11.1 (hERG) channel blockers (moxifloxacin, dofetilide and sotalol) from a total of 14 CVS with variable designs in the conscious dog. Population pharmacokinetic-pharmacodynamic (PKPD) analysis of each study was followed by a meta-analysis (pooling 2-6 studies including 10-32 dogs per compound) to derive meta-predictions of typical ?QTcTHER . Meta-predictions were used as a reference to evaluate the consistency of study predictions and to relate results to those found in the clinical literature.

Key results

The 95%CIs of study-predicted ?QTcTHER comprised in 13 out of 14 cases the meta-prediction. Overall inter-study variability (mean deviation from meta-prediction at upper level of therapeutic exposure) was 30% (range: 1-69%). Meta-?QTcTHER predictions for moxifloxacin, dofetilide and sotalol overlapped with reported clinical QTc prolongation when expressed as %-prolongation from baseline.

Conclusions and implications

Consistent exposure-?QTc predictions were obtained from single preclinical dog studies of highly variable designs by systematic PKPD analysis, which is suitable for translational purposes. The good preclinical-clinical pharmacodynamic correlations obtained suggest that such an analysis should be more routinely applied to increase the informative and predictive value of results obtained from animal experiments.

SUBMITTER: Gotta V

PROVIDER: S-EPMC4556474 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Publications

Inter-study variability of preclinical in vivo safety studies and translational exposure-QTc relationships--a PKPD meta-analysis.

Gotta V V Cools F F van Ammel K K Gallacher D J DJ Visser S A G SA Sannajust F F Morissette P P Danhof M M van der Graaf P H PH

British journal of pharmacology 20150721 17

<h4>Background and purpose</h4>Preclinical cardiovascular safety studies (CVS) have been compared between facilities with respect to their sensitivity to detect drug-induced QTc prolongation (ΔQTc). Little is known about the consistency of quantitative ΔQTc predictions that are relevant for translation to humans.<h4>Experimental approach</h4>We derived typical ΔQTc predictions at therapeutic exposure (ΔQTcTHER ) with 95% confidence intervals (95%CI) for 3 Kv 11.1 (hERG) channel blockers (moxiflo ...[more]

PMID: 26076100

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Project description:BackgroundSleep is an instrumental behavioral state with evidence supporting its active role in brain function, metabolism, immune function, and cardiovascular systems. Research supports that there are pathways underlying the bidirectional communication between the brain and gastrointestinal system, also known as the "gut-brain axis." Primary research examining sleep and gut microbiome relationships continues to increase. Although current data include both preclinical and clinical research, gut microbiome results are reported through a wide range of metrics (alpha diversity, beta diversity, and bacterial compositional changes), which makes cross-study comparison challenging. Therefore, a synthesis of the research examining sleep and gut microbiome relationships is necessary to understand the state of the science and address gaps in the literature for future research.ObjectiveIn this paper, we outline a scoping review protocol to evaluate and synthesize preclinical and clinical primary research focused on the associations between sleep and the gut microbiome.MethodsThe search strategy was facilitated through a medical research librarian and involved electronic databases including PubMed/MEDLINE, Embase, Scopus, Web of Science, CENTRAL trials database, BIOSIS Citation Index, and the Zoological Record. Gray literature sources including medRxiv and bioRxiv preprint servers were also searched. Studies were screened according to the aims and exclusion and inclusion criteria of the protocol. After screening, data will be extracted and synthesized from the included studies according to predefined sleep and microbiome methodology metrics.ResultsThe search strategy yielded 4622 references that were imported for study screening, and source screening was completed in May 2022 by 2 independent investigators, resulting in a total of 93 sources for data extraction and synthesis. The data synthesis table is expected to be completed by August 2022, and the results will be disseminated through paper submission by December 2022 and presented at conferences related to neuroscience, sleep physiology, bioinformatics, and the microbiome.ConclusionsA scoping review of preclinical and clinical research is needed to synthesize the growing data focused on the relationships between sleep and the gut microbiome. We expect the results of this synthesis will identify gaps in the literature and highlight pathways linking the gut-brain axis and sleep physiology to stimulate future research questions.Trial registrationOpen Science Framework 69TBR; https://osf.io/69tbr.International registered report identifier (irrid)PRR1-10.2196/38605.

Dataset Information

Inter-study variability of preclinical in vivo safety studies and translational exposure-QTc relationships--a PKPD meta-analysis.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Inter-study variability of preclinical in vivo safety studies and translational exposure-QTc relationships--a PKPD meta-analysis.

Similar Datasets

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