Dataset Information

Genetic Determinants of the Pharmacokinetic Variability of Rifampin in Malawian Adults with Pulmonary Tuberculosis.

ABSTRACT: Variable exposure to antituberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the SLCO1B1 locus on the plasma area under the concentration-time curve (AUC) of rifampin. We evaluated the contribution of single nucleotide polymorphisms (SNPs) in SLCO1B1 and other candidate genes (AADAC and CES-1) to interindividual pharmacokinetic variability in Malawi. A total of 174 adults with pulmonary TB underwent sampling of plasma rifampin concentrations at 2 and 6 h postdose. Data from a prior cohort of 47 intensively sampled, similar patients from the same setting were available to support population pharmacokinetic model development in NONMEM v7.2, using a two-stage strategy to improve information during the absorption phase. In contrast to recent studies in South Africa and Uganda, SNPs in SLCO1B1 did not explain variability in AUC0-? of rifampin. No pharmacokinetic associations were identified with AADAC or CES-1 SNPs, which were rare in the Malawian population. Pharmacogenetic determinants of rifampin exposure may vary between African populations. SLCO1B1 and other novel candidate genes, as well as nongenetic sources of interindividual variability, should be further explored in geographically diverse, adequately powered cohorts.

SUBMITTER: Sloan DJ

PROVIDER: S-EPMC5487625 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Genetic Determinants of the Pharmacokinetic Variability of Rifampin in Malawian Adults with Pulmonary Tuberculosis.

Sloan Derek J DJ McCallum Andrew D AD Schipani Alessandro A Egan Deirdre D Mwandumba Henry C HC Ward Steve A SA Waterhouse David D Banda Gertrude G Allain Theresa J TJ Owen Andrew A Khoo Saye H SH Davies Geraint R GR

Antimicrobial agents and chemotherapy 20170627 7

Variable exposure to antituberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the SLCO1B1 locus on the plasma area under the concentration-time curve (AUC) of rifampin. We evaluated the contribution of single nucleotide polymorphisms (SNPs) in SLCO1B1 and other candidate genes (AADAC and CES-1) to interindividual pharmacokinetic variability in Malawi. A total of 174 ...[more]

PMID: 28461315

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Project description:RationaleWe examined whether increased rifampin doses could shorten standard therapy for tuberculosis without increased toxicity.ObjectivesTo assess the differences across three daily oral doses of rifampin in change in elimination rate of Mycobacterium tuberculosis in sputum and frequency of rifampin-related adverse events.MethodsWe conducted a blinded, randomized, controlled phase 2 clinical trial of 180 adults with new smear-positive pulmonary tuberculosis, susceptible to isoniazid and rifampin. We randomized 1:1:1 to rifampin at 10, 15, and 20 mg/kg/d during the intensive phase. We report the primary efficacy and safety endpoints: change in elimination rate of M. tuberculosis log10 colony-forming units and frequency of grade 2 or higher rifampin-related adverse events. We report efficacy by treatment arm and by primary (area under the plasma concentration-time curve [AUC]/minimum inhibitory concentration [MIC]) and secondary (AUC) pharmacokinetic exposure.Measurements and main resultsEach 5-mg/kg/d increase in rifampin dose resulted in differences of -0.011 (95% confidence interval, -0.025 to +0.002; P = 0.230) and -0.022 (95% confidence interval, -0.046 to -0.002; P = 0.022) log10 cfu/ml/d in the modified intention-to-treat and per-protocol analyses, respectively. The elimination rate in the per-protocol population increased significantly with rifampin AUC0-6 (P = 0.011) but not with AUC0-6/MIC99.9 (P = 0.053). Grade 2 or higher rifampin-related adverse events occurred with similar frequency across the three treatment arms: 26, 31, and 23 participants (43.3%, 51.7%, and 38.3%, respectively) had at least one event (P = 0.7092) up to 4 weeks after the intensive phase. Treatment failed or disease recurred in 11 participants (6.1%).ConclusionsOur findings of more rapid sputum sterilization and similar toxicity with higher rifampin doses support investigation of increased rifampin doses to shorten tuberculosis treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01408914) .

Project description:The blood concentration of isoniazid (INH) is evidently affected by polymorphisms in N-acetyltransferase 2 (NAT2), an enzyme that is primarily responsible for the trimodal (i.e., fast, intermediate, and slow) INH elimination. The pharmacokinetic (PK) variability, driven largely by NAT2 activity, creates a challenge for the deployment of a uniform INH dosage in tuberculosis (TB) patients. Although acetylator-specific INH dosing has long been suggested, well-recognized dosages according to acetylator status remain elusive. In this study, 175 blood samples were collected from 89 pulmonary TB patients within 0.5 to 6 h after morning INH administration. According to their NAT2 genotypes, 32 (36.0%), 38 (42.7%), and 19 (21.3%) were fast, intermediate, and slow acetylators, respectively. The plasma INH concentration was detected by liquid chromatography-tandem mass spectrometry. Population pharmacokinetic (PPK) analysis was conducted using NONMEM and R software. A two-compartment model with first-order absorption and elimination well described the PK parameters of isoniazid. Body weight and acetylator status significantly affected the INH clearance rate. The dosage simulation targeting three indicators, including the well-recognized efficacy-safety indicator maximum concentration in serum (C max; 3 to 6??g/ml), the reported area under the concentration-time curve from 0 h to infinity (AUC0-?; ?10.52??g·h/ml), and the 2-h INH serum concentrations (?2.19??g/ml), was associated with the strongest early bactericidal activity. The optimal dosages targeting the different indicators varied from 700 to 900?mg/day, 500 to 600?mg/day, and 300?mg/day for the rapid, intermediate, and slow acetylators, respectively. Furthermore, a PPK model for isoniazid among Chinese tuberculosis patients was established for the first time and suggested doses of approximately 800?mg/day, 500?mg/day, and 300?mg/day for fast, intermediate, and slow acetylators, respectively, after a trade-off between efficacy and the occurrence of side effects.

Dataset Information

Genetic Determinants of the Pharmacokinetic Variability of Rifampin in Malawian Adults with Pulmonary Tuberculosis.

Publications

Genetic Determinants of the Pharmacokinetic Variability of Rifampin in Malawian Adults with Pulmonary Tuberculosis.

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