A Rapid Pharmacogenomic Assay to Detect Polymorphisms and Guide Isoniazid Dosing for Tuberculosis Treatment.
Rationale: Standardized dosing of antitubercular drugs contributes to a substantial incidence of toxicities, inadequate treatment response, and relapse, in part due to variable drug concentrations achieved. SNPs in the NAT2 (N-acetyltransferase-2) gene explain the majority of interindividual pharmac...
| Publicado en: | American Journal of Respiratory & Critical Care Medicine Vol. 204; no. 11; pp. 1317 - 1327 |
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| Autores principales: | , , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
Oxford University Press / USA
12/1/2021
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=154004548&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 154004548 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 1073449X 1FG jtl: American Journal of Respiratory & Critical Care Medicine issn: 1073449X maglogo: N pubinfo: dt: 12/1/2021 vid: 204 iid: 11 pid: 622 pub: Oxford University Press / USA artinfo: ui: 154004548 154004548 NLM34375564 154004548 10.1164/rccm.202103-0564OC NLM34375564 154004548 ppf: 1317 ppct: 10 formats: tig: atl: A Rapid Pharmacogenomic Assay to Detect Polymorphisms and Guide Isoniazid Dosing for Tuberculosis Treatment. aug: au: Verma, Renu Patil, Sunita Nan Zhang Moreira, Flora M. F. Vitorio, Marize T. Santos, Andrea da S. Wallace, Ellen Gnanashanmugam, Devasena Persing, David H. Savic, Rada M. Croda, Julio Andrews, Jason R. Zhang, Nan affil: Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California sug: subj: Tuberculosis, Pulmonary Antitubercular Agents Pharmacokinetics Transferases Isoniazid Pharmacokinetics Polymorphism, Genetic Polymerase Chain Reaction Algorithms Prospective Studies Genotype Tuberculosis, Pulmonary Metabolism Isoniazid Administration and Dosage Human Tuberculosis, Pulmonary Drug Therapy Predictive Value of Tests Pharmacogenetics Antitubercular Agents Administration and Dosage Comparative Studies Multicenter Studies Evaluation Research Validation Studies ab: Rationale: Standardized dosing of antitubercular drugs contributes to a substantial incidence of toxicities, inadequate treatment response, and relapse, in part due to variable drug concentrations achieved. SNPs in the NAT2 (N-acetyltransferase-2) gene explain the majority of interindividual pharmacokinetic variability of isoniazid (INH). However, an obstacle to implementing pharmacogenomic-guided dosing is the lack of a point-of-care assay. Objectives: To develop and test a NAT2 classification algorithm, validate its performance in predicting isoniazid clearance, and develop a prototype pharmacogenomic assay. Methods: We trained random forest models to predict NAT2 acetylation genotype from unphased SNP data using a global collection of 8,561 phased genomes. We enrolled 48 patients with pulmonary tuberculosis, performed sparse pharmacokinetic sampling, and tested the acetylator prediction algorithm accuracy against estimated INH clearance. We then developed a cartridge-based multiplex quantitative PCR assay on the GeneXpert platform and assessed its analytical sensitivity on whole blood samples from healthy individuals. Measurements and Main Results: With a 5-SNP model trained on two-thirds of the data (n = 5,738), out-of-sample acetylation genotype prediction accuracy on the remaining third (n = 2,823) was 100%. Among the 48 patients with tuberculosis, predicted acetylator types were 27 (56.2%) slow, 16 (33.3%) intermediate, and 5 (10.4%) rapid. INH clearance rates were lowest in predicted slow acetylators (median 14.5 L/h), moderate in intermediate acetylators (median 40.3 L/h), and highest in fast acetylators (median 53.0 L/h). The cartridge-based assay accurately detected all allele patterns directly from 25 μl of whole blood. Conclusions: An automated pharmacogenomic assay on a platform widely used globally for tuberculosis diagnosis could enable personalized dosing of INH. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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