<i>NAT2</i>
            Polymorphisms and their Influence on the Pharmacology and Toxicity of Isoniazid in TB Patients

Werely, Cedric J.; Donald, Peter R.; Helden, Paul D. van

doi:10.2217/17410541.4.2.123

Cited by 8 publications

(4 citation statements)

References 70 publications

(75 reference statements)

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“…INH undergoes N-acetyltransferase 2 (NAT2) mediated conversion to acetyl-INH in the liver. Due to widespread genetic polymorphisms in NAT2 and a demonstrated correlation between polymorphism and INH concentration–time profile [21], INH profiles were characterized for slow, intermediate, and fast acetylators with 11 out of the 15 subjects phenotyped as fast acetylators, i.e., high metabolizers. Further discussion, therefore, focuses on fast acetylators and their increased risk of treatment failure.…”

Section: Resultsmentioning

confidence: 99%

Tuberculosis drugs’ distribution and emergence of resistance in patient’s lung lesions: A mechanistic model and tool for regimen and dose optimization

et al. 2019

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Background The sites of mycobacterial infection in the lungs of tuberculosis (TB) patients have complex structures and poor vascularization, which obstructs drug distribution to these hard-to-reach and hard-to-treat disease sites, further leading to suboptimal drug concentrations, resulting in compromised TB treatment response and resistance development. Quantifying lesion-specific drug uptake and pharmacokinetics (PKs) in TB patients is necessary to optimize treatment regimens at all infection sites, to identify patients at risk, to improve existing regimens, and to advance development of novel regimens. Using drug-level data in plasma and from 9 distinct pulmonary lesion types (vascular, avascular, and mixed) obtained from 15 hard-to-treat TB patients who failed TB treatments and therefore underwent lung resection surgery, we quantified the distribution and the penetration of 7 major TB drugs at these sites, and we provide novel tools for treatment optimization. Methods and findings A total of 329 plasma- and 1,362 tissue-specific drug concentrations from 9 distinct lung lesion types were obtained according to optimal PK sampling schema from 15 patients (10 men, 5 women, aged 23 to 58) undergoing lung resection surgery (clinical study NCT00816426 performed in South Korea between 9 June 2010 and 24 June 2014). Seven major TB drugs (rifampin [RIF], isoniazid [INH], linezolid [LZD], moxifloxacin [MFX], clofazimine [CFZ], pyrazinamide [PZA], and kanamycin [KAN]) were quantified. We developed and evaluated a site-of-action mechanistic PK model using nonlinear mixed effects methodology. We quantified population- and patient-specific lesion/plasma ratios (RPLs), dynamics, and variability of drug uptake into each lesion for each drug. CFZ and MFX had higher drug exposures in lesions compared to plasma (median RPL 2.37, range across lesions 1.26–22.03); RIF, PZA, and LZD showed moderate yet suboptimal lesion penetration (median RPL 0.61, range 0.21–2.4), while INH and KAN showed poor tissue penetration (median RPL 0.4, range 0.03–0.73). Stochastic PK/pharmacodynamic (PD) simulations were carried out to evaluate current regimen combinations and dosing guidelines in distinct patient strata. Patients receiving standard doses of RIF and INH, who are of the lower range of exposure distribution, spent substantial periods (>12 h/d) below effective concentrations in hard-to-treat lesions, such as caseous lesions and cavities. Standard doses of INH (300 mg) and KAN (1,000 mg) did not reach therapeutic thresholds in most lesions for a majority of the population. Drugs and doses that did reach target exposure in most subjects include 400 mg MFX and 100 mg CFZ. Patients with cavitary lesions, irrespective of drug choice, have an increased likelihood of subtherapeutic concentrations, leading to a higher risk of resistance acquisition while on treatment. A limitation of this study was the small sample size of 15 patients, performed in a unique study population of TB patients who failed...

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Section: Resultsmentioning

confidence: 99%

Tuberculosis drugs’ distribution and emergence of resistance in patient’s lung lesions: A mechanistic model and tool for regimen and dose optimization

et al. 2019

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“…Different genetic mutations may play a role in determining how a patient will respond to the commonly used TB medication isoniazid (Werely et al 2007 ). Acetylation status of individuals plays an important contributory role in the tuberculosis pandemic.…”

Section: Personalized Management Of Tuberculosismentioning

confidence: 99%

Textbook of Personalized Medicine

Jain¹

2015

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“…The authors consequently assumed that the significant differences in NAT genotypes could contribute to the distinctive cancer morbidity and mortality pattern seen in the African populations in South Africa. Furthermore, in a review paper on NAT2 polymorphisms and their effect on isoniazid treatment in TB patients, the role that slow acetylation alleles could play in patient compliance, isoniazid-toxicity and the emergence of drug-resistant strains of mycobateria, is emphasized [ 14 ].…”

Section: Genetic Variation In Pharmacogenetically Relevant Genes (Phamentioning

confidence: 99%

Pharmacogenomic Research in South Africa: Lessons Learned and Future Opportunities in the Rainbow Nation

Warnich¹,

Drögemöller²,

Pepper³

et al. 2011

CPPM

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South Africa, like many other developing countries, stands to benefit from novel diagnostics and drugs developed by pharmacogenomics guidance due to high prevalence of disease burden in the region. This includes both communicable (e.g., HIV/AIDS and tuberculosis) and non-communicable (e.g., diabetes and cardiovascular) diseases. For example, although only 0.7% of the world’s population lives in South Africa, the country carries 17% of the global HIV/AIDS burden and 5% of the global tuberculosis burden. Nobel Peace Prize Laureate Archbishop Emeritus Desmond Tutu has coined the term Rainbow Nation, referring to a land of wealth in its many diverse peoples and cultures. It is now timely and necessary to reflect on how best to approach new genomics biotechnologies in a manner that carefully considers the public health needs and extant disease burden in the region. The aim of this paper is to document and review the advances in pharmacogenomics in South Africa and importantly, to evaluate the direction that future research should take. Previous research has shown that the populations in South Africa exhibit unique allele frequencies and novel genetic variation in pharmacogenetically relevant genes, often differing from other African and global populations. The high level of genetic diversity, low linkage disequilibrium and the presence of rare variants in these populations question the feasibility of the use of current commercially available genotyping platforms, and may partially account for genotype-phenotype discordance observed in past studies. However, the employment of high throughput technologies for genomic research, within the context of large clinical trials, combined with interdisciplinary studies and appropriate regulatory guidelines, should aid in acceleration of pharmacogenomic discoveries in high priority therapeutic areas in South Africa. Finally, we suggest that projects such as the H3Africa Initiative, the SAHGP and PGENI should play an integral role in the coordination of genomic research in South Africa, but also other African countries, by providing infrastructure and capital to local researchers, as well as providing aid in addressing the computational and statistical bottlenecks encountered at present.

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NAT2 Polymorphisms and their Influence on the Pharmacology and Toxicity of Isoniazid in TB Patients

Cited by 8 publications

References 70 publications

Tuberculosis drugs’ distribution and emergence of resistance in patient’s lung lesions: A mechanistic model and tool for regimen and dose optimization

Tuberculosis drugs’ distribution and emergence of resistance in patient’s lung lesions: A mechanistic model and tool for regimen and dose optimization

Textbook of Personalized Medicine

Pharmacogenomic Research in South Africa: Lessons Learned and Future Opportunities in the Rainbow Nation

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