PharmGKB summary

Klein, Daniel; Boukouvala, Sotiria; McDonagh, Ellen M.; Shuldiner, Scott R.; Laurieri, Nicola; Thorn, Caroline F.; Altman, Russ B.; Klein, Teri E.

doi:10.1097/fpc.0000000000000232

Cited by 50 publications

(21 citation statements)

References 97 publications

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“…However, 40 mg/kg/day of isoniazid was needed to achieve the stricter EC 99 target for the CSF exposure in patients with slow acetylator status, while even higher doses were needed to reach the CSF target in patients with fast acetylator status. Nevertheless, a higher dose of isoniazid than currently recommended (8 to 12 mg/kg/day) may not be advisable due to risk of hepatotoxicity and peripheral neuropathy ( 27 ). Simulated exposures at steady state and the corresponding PTA for each isoniazid dose are presented in Fig.…”

Section: Resultsmentioning

confidence: 99%

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Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis

Panjasawatwong

Wattanakul

Hoglund

et al. 2020

Antimicrob Agents Chemother

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Optimal dosing of children with tuberculous meningitis (TBM) remains uncertain and are currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampicin, pyrazinamide and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. One-hundred Vietnamese children with TBM were treated with an 8-month anti-tuberculosis regimen. Nonlinear mixed-effects modeling was used to evaluate the pharmacokinetic properties of the four drugs, and to simulate different dosing strategies. The pharmacokinetic properties of rifampicin and pyrazinamide in plasma were described successfully by one-compartment disposition models, while isoniazid and ethambutol in plasma were described by two-compartment disposition models. All drug models included allometric scaling of body weight and enzyme maturation during the first years of life. CSF penetration of rifampicin was relatively poor and increased with increasing protein levels in CSF, a marker of CSF inflammation. Isoniazid and pyrazinamide showed good CSF penetration. Currently recommended doses of isoniazid and pyrazinamide, but not ethambutol and rifampicin, were sufficient to achieve target exposures. Ethambutol dose cannot be increased because of ocular toxicity. Simulation results suggested that rifampicin dosing at 50 mg/kg/day would be required to achieve the target exposure. Moreover, low rifampicin plasma exposure was associated with an increased risk of neurological disability. Therefore, higher doses of rifampicin could be considered, but further studies are needed to establish the safety and efficacy of increased dosing.

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Section: Resultsmentioning

confidence: 99%

“…Isoniazid is primarily metabolized to acetyl isoniazid (AcINH) by NAT2 ( 27 ). Genetic polymorphisms in NAT2, which result in fast, intermediate, and slow acetylators, have been shown to impact isoniazid plasma concentrations ( 29 , 30 ).…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis

Panjasawatwong

Wattanakul

Hoglund

et al. 2020

Antimicrob Agents Chemother

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“…Enzim CYP2E1 mengubah monoasetil hidrazin dan asetil hidrazin menjadi senyawa pemicu hepatotoksik [29]- [31].…”

Section: Pembahasanunclassified

Resiko Hepatotoksik Populasi Indonesia Akibat Polimorfisme Enzim NAT2 dan CYP2E1 dalam Metabolisme Isoniazid

Santoso

Chabibah

Pribadi

2021

UJAS

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Artikel ini menyajikan data profil resiko kejadian hepatotoksik akibat polimorfisme NAT2 dan CYP2E1 dalam metabolisme isoniazid pada populasi Indonesia di antara berbagai populasi sejumlah negara. Penelitian berlangsung melalui telaah pustaka yang diperoleh dari google schoolar. Pencarian pustaka menggunakan tiga varian kata kunci; (1) “pharmacogenomic dan tuberculosis dan INH dan NAT2 dan CYP2E1 dan polymorphism”, (2) “isoniazid dan hepatotoxicity dan polymorphism dan N-acetyltransferase”, (3) “isoniazid dan hepatotoxicity dan polymorphism dan CYP2E1”. Analisis resiko hepatotoksik berdasarkan nilai odd ratio (confidence interval) menggunakan software Stata MP edisi 14. Telaah resiko hepatotoksik berdasarkan ragam kecepatan asetilasi NAT2 melibatkan 2.140 populasi dari 8 negara, sedangkan telaah resiko berdasarkan ragam alel CYP2E1 melibatkan 1.530 populasi dari 5 negara. Hasil telaah pustaka menunjukkan bahwa resiko hepatotoksik akibat induksi isoniazid pada populasi Indonesia yang memiliki enzim NAT2 asetilator lambat dan orang dengan CYP2E1*c1/c2, tiga kali lebih tinggi dari populasi lain di berbagai negara. Potensi resiko akan meningkat pada orang yang memiliki kombinasi NAT2 asetilator lambat dan CYP2E1*c1/c2.

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“…Such findings suggest that immunity across different populations will differ enough to render treatments that are effective in one region ineffective in others, further illustrating the need to optimize treatments to personal characteristics. Similarly, frequent variants exist in genes encoding drug-metabolizing enzymes, for example, N-acetyltransferase 2 (NAT2), which plays a role in the metabolism of the anti-TB drug isoniazid (INH) (Klein et al, 2016) (see below). To date, genetic predictors are not being used in the clinic for diagnostic and therapeutic purposes in infectious diseases, which is in stark contrast to their pervasive use in cancer and other diseases (Thanassoulis and Vasan, 2010;Tian et al, 2012;Verma, 2012;Demkow and Wolanczyk, 2017;Giudicessi et al, 2017).…”

Section: Challenges Of Universal Medicine and The Prospect Of More Pementioning

confidence: 99%

“…Since acetylhydrazide itself is further inactivated to diacetylhydrazide by NAT2, the relationship between NAT2 metabolizer status and liver toxicity results from the interplay of multiple pathways-an illustration that genetic effects can be complex even in a seemingly simple drug-effect relationship. A review by Klein et al (2016) suggests that INH dose reduction in slow acetylators relative to rapid acetylators does not reduce anti-TB efficacy while likely reducing liver toxicity. Another recent study has reported an association between anti-TB drugs and CYP2B6 polymorphisms and the risk of ATDH in a Chinese population (Wang et al, 2017).…”

Section: Do Genetic Variants Of the Host Influence Tb Drug Efficacy mentioning

confidence: 99%

Challenges of Immune Response Diversity in the Human Population Concerning New Tuberculosis Diagnostics, Therapies, and Vaccines

Azad

Lloyd

Sadée

et al. 2020

Front. Cell. Infect. Microbiol.

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Universal approaches to the prevention and treatment of human diseases fail to take into account profound immune diversity resulting from genetic variations across populations. Personalized or precision medicine takes into account individual lifestyle, environment, and biology (genetics and immune status) and is being adopted in several disease intervention strategies such as cancer and heart disease. However, its application in infectious diseases, particularly global diseases such as tuberculosis (TB), is far more complex and in a state of infancy. Here, we discuss the impact of human genetic variations on immune responses and how they relate to failures seen in current TB diagnostic, therapy, and vaccine approaches across populations. We offer our perspective on the challenges and potential for more refined approaches going forward.

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PharmGKB summary

Cited by 50 publications

References 97 publications

Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis

Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis

Resiko Hepatotoksik Populasi Indonesia Akibat Polimorfisme Enzim NAT2 dan CYP2E1 dalam Metabolisme Isoniazid

Challenges of Immune Response Diversity in the Human Population Concerning New Tuberculosis Diagnostics, Therapies, and Vaccines

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