The future of drug safety testing: expanding the view and narrowing the focus.

CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several key drug substrates, results in some important issues relating to drug safety and efficacy. CYP2C9 substrate selectivity is detailed and, based on crystal structures for the enzyme, we describe how CYP2C9 catalyzes these reactions. Factors relevant to clinical response to CYP2C9 substrates including inhibition, induction and genetic polymorphism are discussed in detail. In particular, we consider the issue of ethnic variation in pattern and frequency of genetic polymorphisms and clinical implications. Warfarin is the most well studied CYP2C9 substrate; recent work on use of dosing algorithms that include CYP2C9 genotype to improve patient safety during initiation of warfarin dosing are reviewed and prospects for their clinical implementation considered. Finally, we discuss a novel approach to cataloging the functional capabilities of rare 'variants of uncertain significance', which are increasingly detected as more exome and genome sequencing of diverse populations is conducted.

/pdf/pharmacogenomics-of-cyp2c9-functional-and-clinical-3kqt34j8ve.pdf

Pharmacogenomics of CYP2C9: Functional and Clinical Considerations.

Background Warfarin is a highly effective anticoagulant however its effectiveness relies on maintaining INR in therapeutic range. Finding the correct dose is difficult due to large inter-individual variability. Two genes, CYP2C9 and VKORC1, have been associated with this variability, leading to genotype-guided dosing tables in warfarin labeling. Nonetheless, it remains unclear how genotypic information should be used in practice. Navigating the literature to determine how genotype will influence warfarin response in a particular patient is difficult, due to significant variation in patient ethnicity, outcomes investigated, study design, and methodological rigor. Our systematic review was conducted to enable fair and accurate interpretation of which variants affect which outcomes, in which patients, and to what extent. Methodology/principal findings A comprehensive search strategy was applied and 117 studies included. Primary outcomes were stable dose, time to stable dose and bleeding events. Methodological quality was assessed using criteria of Jorgensen and Williamson and data synthesized in meta-analyses using advanced methods. Pooled effect estimates were significant in most ethnic groups for CYP2C9*3 and stable dose (mutant types requiring between 1.1(0.7-1.5) and 2.3 (1.6-3.0)mg/day). Effect estimates were also significant for VKORC1 and stable dose for most ethnicities, although direction differed between asians and non-asians (mutant types requiring between 0.8(0.4-1.3) and 1.5(1.1-1.8)mg/day more in asians and between 1.5(0.7-2.2) and 3.1(2.7-3.6)mg/day less in non-asians). Several studies were excluded due to inadequate data reporting. Assessing study quality highlighted significant variability in methodological rigor. Notably, there was significant evidence of selective reporting, of outcomes and analysis approaches. Conclusions/significance Genetic associations with warfarin response vary between ethnicities. In order to achieve unbiased estimates in different populations, a high level of methodological rigor must be maintained and studies should report sufficient data to enable inclusion in meta-analyses. We propose minimum reporting requirements, suggest methodological guidelines and provide recommendations for reducing the risk of selective reporting.

/pdf/influence-of-cyp2c9-and-vkorc1-on-patient-response-to-3tn6g76brt.pdf

Influence of CYP2C9 and VKORC1 on patient response to warfarin: a systematic review and meta-analysis.

Introduction: It is known that warfarin treatment is problematic, due to its narrow therapeutic range and to the great interindividual variability. Numerous papers have shown the important contribution of CYP2C9 and VKORC1 genetic variants to this variability. Recently, a new SNP within the CYP4F2 gene was found associated with warfarin dose in the USA. Aims: The aim of our work was to replicate this study in the Italian population and to assess the new CYP4F2 variant relative contribution in explaining warfarin dose variability with respect to CYP2C9 and VKORC1 genetic variants together with age and weight. Materials & methods: CYP4F2 rs2108622 genotyping was performed by allelic discrimination assay by TaqMan® technology. Analysis of variance and multiple linear regression analyses were carried out to examine the contribution of genetic and nongenetic factors. Results: Our TT patients require 5.49 mg/day versus 2.93 mg/day of our CC patients. Analysis of variance indicates that about 7% of mean weekly w...

CYP4F2 genetic variant (rs2108622) significantly contributes to warfarin dosing variability in the Italian population.

Genetic and clinical factors relating to warfarin dosing

Objectives: Polymorphism in the genes for cytochrome (CYP)2C9 and the vitamin K epoxide reductase complex subunit 1 (VKORC1) affect the pharmacokinetics and pharmacodynamics of warfarin. We developed and validated a warfarin-dosing algorithm for a multi-ethnic population that predicts the best dose for stable anticoagulation, and compared its performance against other regression equations. Methods: We determined the allele and haplotype frequencies of genes for CYP2C9 and VKORC1 on 167 Caucasian, African–American, Asian and Hispanic patients on warfarin. On a subset where complete data were available (n = 92), we developed a dosing equation that predicts the actual dose needed to maintain target anticoagulation using demographic variables and genotypes. This regression was validated against an independent group of subjects. We also applied our data to five other published warfarin-dosing equations. Results: The allele frequency for CYP2C9*2 and *3 and the A allele for VKORC1 3673 was similar to previously...

Dosing algorithm for warfarin using CYP2C9 and VKORC1 genotyping from a multi-ethnic population: comparison with other equations.

. During a solar eclipse the solar irradiance reaching the
top of the atmosphere (TOA) is reduced in the Moon shadow. The solar irradiance is
commonly measured by Earth observation satellites before the start of the
solar eclipse and is not corrected for this reduction, which results in a
decrease in the computed TOA reflectances. Consequently, air quality products
that are derived from TOA reflectance spectra, such as the ultraviolet (UV)
absorbing aerosol index (AAI), are distorted or undefined in the shadow of the
Moon. The availability of air quality satellite data in the penumbral and
antumbral shadow during solar eclipses, however, is of particular interest to
users studying the atmospheric response to solar eclipses. Given the time and
location of a point on the Earth's surface, we explain how to compute the
obscuration during a solar eclipse, taking into account wavelength-dependent
solar limb darkening. With the calculated obscuration fractions, we restore
the TOA reflectances and the AAI in the penumbral shadow during the annular
solar eclipses on 26 December 2019 and 21 June 2020 measured by the
TROPOMI/S5P instrument. We compare the calculated obscuration to the estimated
obscuration using an uneclipsed orbit. In the corrected products, the
signature of the Moon shadow disappeared, but only if wavelength-dependent
solar limb darkening is taken into account. We find that the Moon shadow
anomaly in the uncorrected AAI is caused by a reduction of the measured
reflectance at 380  nm , rather than a colour change of the measured
light. We restore common AAI features such as the sunglint and desert dust,
and we confirm the restored AAI feature on 21 June 2020 at the Taklamakan
Desert by measurements of the GOME-2C satellite instrument on the same day but
outside the Moon shadow. No indication of local absorbing aerosol changes
caused by the eclipses was found. We conclude that the correction method of
this paper can be used to detect real AAI rising phenomena during a solar
eclipse and has the potential to restore any other product that is derived
from TOA reflectance spectra. This would resolve the solar eclipse anomalies
in satellite air quality measurements in the penumbra and antumbra and would
allow for studying the effect of the eclipse obscuration on the composition of
the Earth's atmosphere from space.

/pdf/restoring-the-top-of-atmosphere-reflectance-during-solar-56c8ax22qg.pdf

Restoring the top-of-atmosphere reflectance during solar eclipses: a proof of concept with the UV absorbing aerosol index measured by TROPOMI

During a solar eclipse the solar irradiance reaching the top-of-atmosphere (TOA) is reduced in the Moon shadow. The solar irradiance is commonly measured by Earth observation satellites before the start of the solar eclipse and is not corrected for this reduction, which results in a decrease of the computed TOA reflectances. Consequently, air quality products that are derived from TOA reflectance spectra, such as the ultraviolet (UV) Absorbing Aerosol Index (AAI), are distorted or undefined in the shadow of the Moon. The availability of air quality satellite data in the penumbral and antumbral shadow during solar eclipses, however, is of particular interest to users studying the atmospheric response to solar eclipses. Given the time and location of a point on the Earth's surface, we explain how to compute the obscuration during a solar eclipse taking into account wavelength-dependent solar limb darkening. With the calculated obscuration fractions, we restore the TOA reflectances and the AAI in the penumbral shadow during the annular solar eclipses on 26 December 2019 and 21 June 2020 measured by the TROPOMI/S5P instrument. In the corrected products, the signature of the Moon shadow disappeared, but only if wavelength-dependent solar limb darkening is taken into account. We conclude that the correction method of this paper can be used to detect real AAI rising phenomena during a solar eclipse and has the potential to restore any other product that is derived from TOA reflectance spectra. This would resolve the solar eclipse anomalies in satellite air quality measurements and would allow for studying the effect of the eclipse obscuration on the composition of the Earth's atmosphere from space.

/pdf/restoring-the-top-of-atmosphere-reflectance-during-solar-3q9dv7kvn9.pdf

Restoring the top-of-atmosphere reflectance during solar eclipses: a proof of concept with the UV Absorbing Aerosol Index measured by TROPOMI

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Dosing algorithm for warfarin using CYP2C9 and VKORC1 genotyping from a multi-ethnic population: comparison with other equations.

Restoring the top-of-atmosphere reflectance during solar eclipses: a proof of concept with the UV absorbing aerosol index measured by TROPOMI

Restoring the top-of-atmosphere reflectance during solar eclipses: a proof of concept with the UV Absorbing Aerosol Index measured by TROPOMI