CYP2C8, CYP2C9, and CYP2C19 Characterization Using Next-Generation Sequencing and Haplotype Analysis

Gaedigk, Andrea; Boone, Erin C.; Scherer, Steven E.; Lee, Seung‐been; Numanagić, Ibrahim; Sahinalp, S. Cenk; Smith, Joshua D.; McGee, Sean; Radhakrishnan, Aparna; Qin, Xiang; Wang, Wendy Y.; Farrow, Emily; Gonzaludo, Nina; Halpern, Aaron L.; Nickerson, Deborah A.; Miller, Neil; Pratt, Victoria M.; Kalman, Lisa V.

doi:10.1016/j.jmoldx.2021.12.011

Cited by 36 publications

(49 citation statements)

References 38 publications

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“…Subjects were sequenced at the CMH Genomic Medicine Center using ADMEseq, a custom gene panel from Integrated DNA Technologies targeting 289 genes relevant to drug absorption, disposition, metabolism, and excretion, and variants were retrieved as described in detail elsewhere. 21 Variants were manually reviewed. Haplotype (star allele) calls for CYP2C8 and CYP2C9 are according to PharmVar ( https://www.pharmvar.org/ ), 22 , 23 and those for UGT1A1, UGT1A9 and UGT2B7 are according to UGT nomenclature ( https://www.pharmacogenomics.pha.ulaval.ca/ugt‐alleles‐nomenclature/ ).…”

Section: Methodsmentioning

confidence: 99%

Developmental pharmacokinetics of indomethacin in preterm neonates: Severely decreased drug clearance in the first week of life

Krzyzanski

Stockard

Gaedigk

et al. 2022

CPT Pharmacom & Syst Pharma

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Indomethacin is used commonly in preterm neonates for the prevention of intracranial hemorrhage and closure of an abnormally open cardiac vessel. Due to biomedical advances, the infants who receive this drug in the neonatal intensive care unit setting have become younger, smaller, and less mature (more preterm) at the time of treatment. To develop a pharmacokinetics (PK) model to aid future dosing, we designed a prospective cohort study to characterize indomethacin PK in a dynamically changing patient population. A population PK base model was created using NONMEM, and a covariate model was developed in a primary development cohort and subsequently was tested for accuracy in a validation cohort. Postnatal age was a significant covariate for hepatic clearance (CL H ) and renal clearance (CL R ). The typical value of the total clearance (CL, the sum of CL R and CL H ) was 3.09 ml/h and expressed as CL/WT median = 3.96 ml/h/kg, where WT median is the median body weight. The intersubject variability of CL R and CL H were 61% and 207%, respectively. The typical value of the volume of distribution V p = 366 ml (V p /WT median = 470 ml/kg), and its intersubject variability was 38.8%.Half-life was 82.1 h. Compared with more mature and older preterm populations studied previously, indomethacin CL is considerably lower in this contemporary population. Model-informed precision dosing incorporating important covariates other than weight alone offers an opportunity to individualize dosing in a susceptible patient undergoing rapid change. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?With current weight-based dosing, indomethacin exposure is variable, and clinical response is unpredictable in preterm infants.

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Section: Methodsmentioning

confidence: 99%

Developmental pharmacokinetics of indomethacin in preterm neonates: Severely decreased drug clearance in the first week of life

Krzyzanski

Stockard

Gaedigk

et al. 2022

CPT Pharmacom & Syst Pharma

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“…The comparisons were done on a sizeable GeT-RM set of publicly available samples and genes for which genotyping panel validations were available (Pratt et al, 2010(Pratt et al, , 2016aGaedigk et al, 2019). These samples were sequenced with three technologies: (1) PGRNseq v.3 Illumina-based pharmacogene-targeted panel (Gordon et al (2016); 137 samples), (2) Illumina whole-genome sequencing (WGS; 70 samples), and (3) 10X Genomics sequencing (95 samples). In addition to these samples, we also ran Aldy on the set of 45 Coriell samples sequenced by PacBio HiFi pharmacogene-targeted panel (Portik et al, 2021;Kingan et al, 2022) and validated by Scott et al (2021).…”

Section: Resultsmentioning

confidence: 99%

“…There are still some open questions left that need to be answered in future work. Most importantly, the panel-validated calls improved by the star-allele callers through the use of HTS data—often containing novel alleles not previously cataloged in the existing databases—need to be validated in a wet-lab environment for all genes presented, as was done recently for a selection of CYP2C genes (Gaedigk et al ., 2022). More tests are also needed on larger cohorts to accurately evaluate the precision of these tools, Aldy 4 included, on rare fusions.…”

Section: Discussionmentioning

confidence: 99%

“…Aldy 4, Aldy 3, Stargazer and Astrolabe were run on 137 PGRNseq v.3 targeted sequencing (Gordon et al, 2016) samples from the GeT-RM collection. PGRNseq v.3 targets common pharmacogenes and sequences them at high depths (up to 1000× per loci).…”

Section: Pgrnseq V3mentioning

confidence: 99%

“…Some of these tools, such as Aldy and Stargazer, are also able to detect copy number changes and fusions with a high level of accuracy. However, the majority of these tools target only a small set of pharmacogenes (typically CYP2D6 and other cytochrome P450 genes) and are tuned for short-read HTS data generated by the Illumina whole-genome sequencing (WGS), wholeexome sequencing (WES) and (in some cases) targeted sequencing panels such as PGRNseq (Gordon et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Aldy 4: An efficient genotyper and star-allele caller for pharmacogenomics

Hari

Zhou

Gonzaludo

et al. 2022

Preprint

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High-throughput sequencing provides sufficient means for determining genotypes of clinically important pharmacogenes that can be used to tailor medical decisions to individual patients. However, pharmacogene genotyping, also known as star-allele calling, is a challenging problem that requires accurate copy number calling, structural variation discovery, variant calling and phasing within each pharmacogene copy present in the sample. Here we introduce Aldy 4, a fast and efficient tool for genotyping pharmacogenes that utilizes combinatorial optimization for accurate star-allele calling across different sequencing technologies. Aldy 4 adds support for long reads and ships with a novel phasing model and improved copy number and variant calling models. We compare Aldy 4 against the current state-of-the-art star-allele callers on a large and diverse set of samples and genes sequenced by various sequencing technologies, such as whole-genome and targeted Illumina sequencing, barcoded 10X Genomics and PacBio HiFi. We show that Aldy 4 is the most accurate star-allele caller with near-perfect accuracy in all evaluated contexts. We hope that Aldy remains an invaluable tool in the clinical toolbox even with the advent of long-read sequencing technologies. Aldy 4 is available at https://github.com/0xTCG/aldy.

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PharmVar GeneFocus: CYP3A5

Rodríguez‐Antona

Savieo

Lauschke

et al. 2022

Clin Pharma and Therapeutics

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The Pharmacogene Variation Consortium (PharmVar) catalogs star (*) allele nomenclature for the polymorphic human CYP3A5 gene. Genetic variation within the CYP3A5 gene locus impacts the metabolism of several clinically important drugs, including the immunosuppressants tacrolimus, sirolimus, cyclosporine, and the benzodiazepine midazolam. Variable CYP3A5 activity is of clinical importance regarding tacrolimus metabolism. This GeneFocus provides a CYP3A5 gene summary with a focus on aspects regarding standardized nomenclature. In addition, this review also summarizes recent changes and updates, including the retirement of several allelic variants and provides an overview of how PharmVar CYP3A5 star allele nomenclature is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

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CYP2C8, CYP2C9, and CYP2C19 Characterization Using Next-Generation Sequencing and Haplotype Analysis

Cited by 36 publications

References 38 publications

Developmental pharmacokinetics of indomethacin in preterm neonates: Severely decreased drug clearance in the first week of life

Developmental pharmacokinetics of indomethacin in preterm neonates: Severely decreased drug clearance in the first week of life

Aldy 4: An efficient genotyper and star-allele caller for pharmacogenomics

PharmVar GeneFocus: CYP3A5

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