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This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food and Drug Administration-sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate the progress in the development of a new cardiac safety paradigm, the Comprehensive in Vitro Proarrhythmia Assay (CiPA). The opinions regarding these principles reflect the collective views of those who participated in the discussion of this topic both at and after the breakout session. Although primarily discussed in the context of in silico models, these principles describe the interface between experimental input and model-based interpretation and are intended to be general enough to be applied to other types of nonclinical models for proarrhythmia assessment. This document was developed with the intention of providing a foundation for more consistency and harmonization in developing and validating different models for proarrhythmia risk prediction using the example of the CiPA paradigm.

Abstract MicroRNAs are positive and negative regulators of eukaryotic gene expression that modulate transcript abundance by specific binding to sequence motifs located prevalently in the 3' untranslated regions of target messenger RNAs (mRNA). Interferon-alpha-2a (IFNα) induces a large set of protein coding genes mediating antiproliferative and antiviral responses. Here we use a global microarray-based microRNA detection platform to identify genes that are induced by IFNα in hepatoma- or melanoma-derived human tumor cell lines. Despite the enormous differences in expression levels between these models, we were able to identify microRNAs that are upregulated by IFNα in both lines suggesting the possibility that interferon-regulated microRNAs are involved in the transcriptional repression of mRNA relevant to cytokine responses.

1-phenylcyclopropylamine (1-PCPA) binds covalently to the fungal flavoenzyme monoamine oxidase N in the form of N(super 5)-3-oxo-3-phenylpropyl-FAD. This compound inactivates the enzyme in a reaction similar to that of 1-PCPA and mammalian mitochondrial monoamine oxidase B.

Monoamine oxidase (MAO) A and B are purified to examine the oxidation of 1-methyl-1,2,3,6-tetrahydrosilbazole (MTHS) analogs. Linear kinetic characteristics are revealed by MAO B, while biphasic Lineweaver-Burk plots are observed through MAO A. The alternated enzyme can be reoxidized by different processes which can explain the reasons for nonlinear kinetics. Pure MAO A reveals curvatures in double-reciprocal plots. Trans-MTHS is converted to cis-MTHS by a process of photoinduction to determine the curvature.

A study was conducted on the interaction between flexible analogs of N-methyl-4-phenyl-1,2, 3,6-tetrahydropyridine (MPTP) and of N-methyl-4-phenylpyridinium with highly purified monoamine oxidases (MAO) A and B. The function turnover number was used to evaluate the relative effectiveness of the tetrahydropyridines. Reactivity with MPTP was found to increase with the insertion of a methylene bridge between the phenyl and tetrahydropyridine moieties in MAO B but not in MAO A. On the other hand, the use of an ethylene bridge in MPTP was found to be a better substrate of both forms of MAO.

Abstract Background There is little guidance regarding the risk of exposure of pregnant women/ women of childbearing potential to genotoxic or teratogenic compounds via vaginal dose delivered through seminal fluid during sexual intercourse. Method We summarize current thinking and provide clinical trial considerations for a consistent approach to contraception for males exposed to genotoxic and/or teratogenic compounds or to compounds of unknown teratogenicity, and for collection of pregnancy data from their female partners. Results Where toxicity testing demonstrates genotoxic potential, condom use is required during exposure and for 5 terminal plasma half-lives plus 74 days (one human spermatogenesis cycle) to avoid conception. For non-genotoxic small molecules and immunoglobulins with unknown teratogenic potential or without a no observed adverse effect level (NOAEL) from embryo-fetal development (EFD) studies and no minimal anticipated biological effect level (MABEL), condom use is recommended for males with pregnant partner/female partner of childbearing potential. For teratogenic small molecules with estimated seminal fluid concentration and a margin between projected maternal area under the curve (AUC) and NOAEL AUC from EFD studies of ≥300 (≥100 for immunoglobulins) or in the absence of a NOAEL with a margin between MABEL plasma concentration and maternal Cmax of ≥300 (≥10 for immunoglobulins), condom use is not required. However, condom use is required for margins below the thresholds previously indicated. For small molecules with available seminal fluid concentrations, condom use is required if margins are Pregnancy data should be proactively collected if pregnancy occurs during the condom use period required for males exposed to first-in-class molecules or to molecules with a target/class shown to be teratogenic, embryotoxic or fetotoxic in human or preclinical experiments. Conclusion These recommendations, based on a precaution principle, provide a consistent approach for minimizing the risk of embryo-fetal exposure to potentially harmful drugs during pregnancy of female partners of males in clinical trials. Proactive targeted collection of pregnancy information from female partners should help determine the teratogenic potential of a drug and minimize background noise and ethical/logistical issues.