Cost-effectiveness of a Pharmacogenomic Test for Stratified Isoniazid Dosing in Treatment of Active Tuberculosis

Rens, Neil; Ca, Uyl-de Groot; Goldhaber-Fiebert, Jeremy D.; Croda, Júlio; Andrews, Jason R

doi:10.1093/cid/ciz1212

Cited by 22 publications

(22 citation statements)

References 28 publications

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“…Because patients with TB harboring NAT2 * 5, * 6, and * 7 show much slower N-acetylation than patients homozygous for NAT2 * 4 (Mthiyane et al, 2020), accumulation of INH and hydrazine occurs in SAs, leading to a higher risk of liver injury (An et al, 2018;Brewer et al, 2019). These phenotypes may be the most efficient pharmacogenomics biomarkers for predicting the risk of ATDILI (Azuma et al, 2013;Mushiroda et al, 2016;Wattanapokayakit et al, 2016;Yuliwulandari et al, 2016;Suvichapanich et al, 2019) and may lead to identification of a cost-effective treatment for TB (Rens et al, 2020). Therefore, categorization of patients as RAs, IAs, and SAs may be useful for treatment with NAT2 substrates (Rens et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…These phenotypes may be the most efficient pharmacogenomics biomarkers for predicting the risk of ATDILI (Azuma et al, 2013;Mushiroda et al, 2016;Wattanapokayakit et al, 2016;Yuliwulandari et al, 2016;Suvichapanich et al, 2019) and may lead to identification of a cost-effective treatment for TB (Rens et al, 2020). Therefore, categorization of patients as RAs, IAs, and SAs may be useful for treatment with NAT2 substrates (Rens et al, 2020). Although many studies have reported strong associations of each NAT2 genotype, such as NAT2 * 6A/ * 6A, with the risk of ATDILI (Suvichapanich et al, 2018;Nicoletti et al, 2020;Yuliwulandari et al, 2021), little information is available regarding the associations between NAT2 genotype and the risk of the adverse reactions induced by other NAT2 substrate drugs.…”

Section: Introductionmentioning

confidence: 99%

“…Although many studies have reported strong associations of each NAT2 genotype, such as NAT2 * 6A/ * 6A, with the risk of ATDILI (Suvichapanich et al, 2018;Nicoletti et al, 2020;Yuliwulandari et al, 2021), little information is available regarding the associations between NAT2 genotype and the risk of the adverse reactions induced by other NAT2 substrate drugs. For example, NAT2 phenotypes, such as SA, IA, and RA, have been shown to be associated with hydralazine-induced adverse reactions because hydralazine is primarily metabolized by NAT2 (Spinasse et al, 2014;Rens et al, 2020). Thus, the substrate specificity of N-acetylation with relation to categorization of NAT2 genotypes into phenotypes has also not been reported (Zang et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Functional Characterization of the Effects of N-acetyltransferase 2 Alleles on N-acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity

Fukunaga

Kato²,

Okusaka³

et al. 2021

Front. Genet.

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Variability in the enzymatic activity of N-acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is little information on functional differences in N-acetylation activities according to NAT2 phenotypes, i.e., rapid, intermediate, slow, and ultra-slow acetylators, between different substrate drugs. Here, we estimated NAT2 genotypes in 990 Japanese individuals and compared the frequencies of different genotypes with those of different populations. We then calculated in vitro kinetic parameters of four NAT2 alleles (NAT2∗4, ∗5, ∗6, and ∗7) for N-acetylation of aminoglutethimide, diaminodiphenyl sulfone, hydralazine, isoniazid, phenelzine, procaineamide, sulfamethazine (SMZ), and sulfapyrizine. NAT2∗5, ∗6, and ∗7 exhibited significantly reduced N-acetylation activities with lower Vmax and CLint values of all drugs when compared with NAT2∗4. Hierarchical clustering analysis revealed that 10 NAT2 genotypes were categorized into three or four clusters. According to the results of in vitro metabolic experiments using SMZ as a substrate, the frequencies of ultra-slow acetylators were calculated to be 29.05–54.27% in Europeans, Africans, and South East Asians, whereas Japanese and East Asian populations showed lower frequencies (4.75 and 11.11%, respectively). Our findings will be helpful for prediction of responses to drugs primarily metabolized by NAT2.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional Characterization of the Effects of N-acetyltransferase 2 Alleles on N-acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity

Fukunaga

Kato²,

Okusaka³

et al. 2021

Front. Genet.

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“…As shown in Figure 4, standard weight-based INH therapy for TB results in over 40% of patients experiencing treatment toxicity and over 30% of patients experiencing treatment failure in populations across the world. Using a robust analysis model of TB treatment costs, Rens and coworkers [89] document that pharmacogenomics-guided therapy is highly cost-effective even with conservative estimates of its impact on INH-induced liver injury and response to therapy.…”

Section: Pharmacogenomic-guided Isoniazid Therapy For Treatment Of Tbmentioning

confidence: 99%

“…Estimated frequency of treatment failure and toxicity of INH treatment for tuberculosis in populations across the world.Adapted from[89].…”

mentioning

confidence: 99%

Arylamine N-acetyltransferase acetylation polymorphisms: paradigm for pharmacogenomic-guided therapy- a focused review

Hein

Millner²

2020

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: The N-acetylation polymorphism has been the subject of comprehensive reviews describing the role of arylamine N-acetyltransferase 2 (NAT2) in the metabolism of numerous aromatic amine and hydrazine drugs. Areas covered: We describe and review data that more clearly defines the effects of NAT2 haplotypes and genotypes on the expression of acetylator phenotype towards selected drugs within human hepatocytes in vitro, within human hepatocyte cultures in situ, and clinical measures such as bioavailability, plasma metabolic ratios of parent to N-acetyl metabolite, elimination rate constants and plasma half-life, and/or clearance determinations in human subjects. We review several drugs (isoniazid, hydralazine, sulfamethazine, amifampridine, procainamide, sulfasalazine, amonafide and metamizole) for which NAT2 phenotype-guided therapy may be important. The value of pharmacogenomics-guided isoniazid therapy for the prevention and treatment of tuberculosis is presented as a paradigm for NAT2 phenotype-dependent dosing strategies. Expert opinion: Studies in human subjects and cryopreserved human hepatocytes show evidence for rapid, intermediate and slow acetylator phenotypes, with further data suggesting genetic heterogeneity within the slow acetylator phenotype. Incorporation of more robust NAT2 genotype/phenotypes relationships, including genetic heterogeneity within the slow acetylator phenotype, should lead to further advancements in both health outcomes and cost benefit for prevention and treatment of tuberculosis.

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Influence of N-acetyltransferase 2 (NAT2) genotype/single nucleotide polymorphisms on clearance of isoniazid in tuberculosis patients: a systematic review of population pharmacokinetic models

Thomas

Raju

Chaithra

et al. 2022

Eur J Clin Pharmacol

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Purpose Significant pharmacokinetic variabilities have been reported for isoniazid across various populations. We aimed to summarize population pharmacokinetic studies of isoniazid in tuberculosis (TB) patients with a specific focus on the influence of N-acetyltransferase 2 (NAT2) genotype/single-nucleotide polymorphism (SNP) on clearance of isoniazid. Methods A systematic search was conducted in PubMed and Embase for articles published in the English language from inception till February 2022 to identify population pharmacokinetic (PopPK) studies of isoniazid. Studies were included if patient population had TB and received isoniazid therapy, non-linear mixed effects modelling, and parametric approach was used for building isoniazid PopPK model and NAT2 genotype/SNP was tested as a covariate for model development. Results A total of 12 articles were identified from PubMed, Embase, and hand searching of articles. Isoniazid disposition was described using a two-compartment model with first-order absorption and linear elimination in most of the studies. Significant covariates influencing the pharmacokinetics of isoniazid were NAT2 genotype, body weight, lean body weight, body mass index, fat-free mass, efavirenz, formulation, CD4 cell count, and gender. Majority of studies conducted in adult TB population have reported a twofold or threefold increase in isoniazid clearance for NAT2 rapid acetylators compared to slow acetylators. Conclusion The variability in disposition of isoniazid can be majorly attributed to NAT2 genotype. This results in a trimodal clearance pattern with a multi-fold increase in clearance of NAT2 rapid acetylators compared to slow acetylators. Further studies exploring the generalizability/adaptability of developed PopPK models in different clinical settings are required.

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Cost-effectiveness of a Pharmacogenomic Test for Stratified Isoniazid Dosing in Treatment of Active Tuberculosis

Cited by 22 publications

References 28 publications

Functional Characterization of the Effects of N-acetyltransferase 2 Alleles on N-acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity

Functional Characterization of the Effects of N-acetyltransferase 2 Alleles on N-acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity

Arylamine N-acetyltransferase acetylation polymorphisms: paradigm for pharmacogenomic-guided therapy- a focused review

Influence of N-acetyltransferase 2 (NAT2) genotype/single nucleotide polymorphisms on clearance of isoniazid in tuberculosis patients: a systematic review of population pharmacokinetic models

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