Trial reportEuropean journal of clinical pharmacology2007
Dose-escalation study of isoniazid in healthy volunteers with the rapid acetylator genotype of arylamine N-acetyltransferase 2.
Trial report in European journal of clinical pharmacology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed.
- NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: a randomized controlled trial for pharmacogenetics-based therapy.European journal of clinical pharmacology · 2013Trial
- Application of an Open-Source Modular Framework for Pharmacokinetic, Pharmacodynamic, and Safety Simulations to Anti-Tuberculosis Drugs.CPT: pharmacometrics & systems pharmacology · 2026Article
- PBPK Modeling to Recommend Nevirapine Dosing in HIV and HIV-TB Co-infected Patients: Leveraging Enzyme Auto-Induction, Drug Interactions, and Ethnic Variability.The AAPS journal · 2025Article
- Risk adjustment model for tuberculosis compared to non-tuberculosis mycobacterium or latent tuberculosis infection: Center for Personalized Precision Medicine of Tuberculosis (cPMTb) cohort database.BMC pulmonary medicine · 2023Article
- Application of a physiologically based pharmacokinetic model to predict isoniazid disposition during pregnancy.Clinical and translational science · 2023Article
- Economic Evaluation of Multiple-Pharmacogenes Testing for the Prevention of Adverse Drug Reactions in People Living with HIV.ClinicoEconomics and outcomes research : CEOR · 2022Article
- PBPK Analysis to Study the Impact of Genetic Polymorphism of NAT2 on Drug-Drug Interaction Potential of Isoniazid.Pharmaceutical research · 2021Article
- The Influence of NAT2 Genotypes on Isoniazid Plasma Concentration of Pulmonary Tuberculosis Patients in Southern Thailand.Tuberculosis and respiratory diseases · 2020Article
- Modelling the long-acting administration of anti-tuberculosis agents using PBPK: a proof of concept study.The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease · 2018Article
- N-acetyltransferase gene polymorphisms & plasma isoniazid concentrations in patients with tuberculosis.The Indian journal of medical research · 2017Article
- A Physiologically Based Pharmacokinetic Model of Isoniazid and Its Application in Individualizing Tuberculosis Chemotherapy.Antimicrobial agents and chemotherapy · 2016Article
- Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring.European journal of clinical pharmacology · 2016Review
- Prevention of isoniazid toxicity by NAT2 genotyping in Senegalese tuberculosis patients.Toxicology reports · 2016Article
- Population pharmacokinetic analysis of isoniazid, acetylisoniazid, and isonicotinic acid in healthy volunteers.Antimicrobial agents and chemotherapy · 2015Article
- Hepatotoxic effects of therapies for tuberculosis.Nature reviews. Gastroenterology & hepatology · 2010Review
- Study of NAT2 gene polymorphisms in an Indian population: association with plasma isoniazid concentration in a cohort of tuberculosis patients.Molecular diagnosis & therapy · 2009Article
- Polymorphisms of promoter and coding regions of the arylamine N-acetyltransferase 2 (NAT2) gene in the Indonesian population: proposal for a new nomenclature.Journal of human genetics · 2008Article
- NAT2 gene polymorphisms in three indigenous groups in the Colombian Caribbean Coast region.Colombia medica (Cali, Colombia)Article
Corrections and comments
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveGenetic polymorphisms of arylamine N-acetyltransferase 2 (NAT2) result in large interindividual differences in the plasma concentration of isoniazid (INH). We hypothesized that the internationally recommended dosage should be increased for patients with two active NAT2 alleles (RA type) in order to achieve appropriate antituberculous efficiency; however, the pharmacokinetic effects of the dose increase have not been fully addressed. To estimate an optimal dosage for RA-type patients, we conducted a dose escalation study in healthy male volunteers carrying NAT2*4/*4.
methodsOral doses of 300 mg, 600 mg, and 900 mg of INH were administered to eight RA-type subjects, whereas 300 mg was administered to eight IA-type subjects with one active allele (NAT2*4). The pharmacokinetic parameters were estimated from plasma INH concentrations for 24 h postdose.
resultsThe ratio of the mean area under the plasma-concentration time curve (AUC) was not proportional to the doses (1:2.6:5.0 for 300:600:900-mg dose) in parallel to the plasma concentration at 1 h (C(1)) and 2 h (C(2)) after administration. Compared with the IA-type group given 300 mg, the RA-type group had lower pharmacokinetic parameters at 300 mg (AUC, 66%; C(1), 72%; C(2), 61%), but higher parameters at 600 mg (AUC, 175%; C(1), 196%; C(2), 170%). Plasma concentrations of the IA-type group were within the therapeutic range. An optimal INH dose was calculated as 430 mg (7.2 mg/kg) for RA-type subjects to obtain an AUC comparable with that in IA-type subjects dosed with 300 mg.
conclusionIn RA-type subjects, the pharmacokinetic parameters appeared to lack linearity with the increased dose of INH. We propose that the proper daily dose for RA-type patients is 1.5-times higher than that currently recommended.
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