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      A proposal for an individualized pharmacogenetic-guided isoniazid dosage regimen for patients with tuberculosis

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          Abstract

          Background/aim

          Isoniazid (INH) is an essential component of first-line anti-tuberculosis (TB) treatment. However, treatment with INH is complicated by polymorphisms in the expression of the enzyme system primarily responsible for its elimination, N-acetyltransferase 2 (NAT2), and its associated hepatotoxicity. The objective of this study was to develop an individualized INH dosing regimen using a pharmacogenetic-driven model and to apply this regimen in a pilot study.

          Methods

          A total of 206 patients with TB who received anti-TB treatment were included in this prospective study. The 2-hour post-dose concentrations of INH were obtained, and their NAT2 genotype was determined using polymerase chain reaction and sequencing. A multivariate regression analysis that included the variables of age, sex, body weight, and NAT2 genotype was performed to determine the best model for estimating the INH dose that achieves a concentration of 3.0–6.0 mg/L. This dosing algorithm was then used for newly enrolled 53 patients.

          Results

          Serum concentrations of INH were significantly lower in the rapid-acetylators than in the slow-acetylators (2.55 mg/L vs 6.78 mg/L, median, P<0.001). A multivariate stepwise linear regression analysis revealed that NAT2 and body weight independently affected INH concentrations: INH concentration (mg/L) =13.821–0.1× (body weight, kg) −2.273× (number of high activity alleles of NAT2; 0, 1, 2). In 53 newly enrolled patients, the frequency at which they were within the therapeutic range of 3.0–6.0 mg/L was higher in the model-based treatment group compared to the standard treatment group (80.8% vs 59.3%).

          Conclusion

          The use of individualized pharmacogenetic-guided INH dosage regimens that incorporate NAT2 genotype and body weight may help to ensure achievement of therapeutic concentrations of INH in the TB patients.

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          Most cited references 20

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          Therapeutic drug monitoring in the treatment of tuberculosis: an update.

          Tuberculosis (TB) is the world's second leading infectious killer. Cases of multidrug-resistant (MDR-TB) and extremely drug-resistant (XDR-TB) have increased globally. Therapeutic drug monitoring (TDM) remains a standard clinical technique for using plasma drug concentrations to determine dose. For TB patients, TDM provides objective information for the clinician to make informed dosing decisions. Some patients are slow to respond to treatment, and TDM can shorten the time to response and to treatment completion. Normal plasma concentration ranges for the TB drugs have been defined. For practical reasons, only one or two samples are collected post-dose. A 2-h post-dose sample approximates the peak serum drug concentration (Cmax) for most TB drugs. Adding a 6-h sample allows the clinician to distinguish between delayed absorption and malabsorption. TDM requires that samples are promptly centrifuged, and that the serum is promptly harvested and frozen. Isoniazid and ethionamide, in particular, are not stable in human serum at room temperature. Rifampicin is stable for more than 6 h under these conditions. Since our 2002 review, several papers regarding TB drug pharmacokinetics, pharmacodynamics, and TDM have been published. Thus, we have better information regarding the concentrations required for effective TB therapy. In vitro and animal model data clearly show concentration responses for most TB drugs. Recent studies emphasize the importance of rifamycins and pyrazinamide as sterilizing agents. A strong argument can be made for maximizing patient exposure to these drugs, short of toxicity. Further, the very concept behind 'minimal inhibitory concentration' (MIC) implies that one should achieve concentrations above the minimum in order to maximize response. Some, but not all clinical data are consistent with the utility of this approach. The low ends of the TB drug normal ranges set reasonable 'floors' above which plasma concentrations should be maintained. Patients with diabetes and those infected with HIV have a particular risk for poor drug absorption, and for drug-drug interactions. Published guidelines typically describe interactions between two drugs, whereas the clinical situation often is considerably more complex. Under 'real-life' circumstances, TDM often is the best available tool for sorting out these multi-drug interactions, and for providing the patient safe and adequate doses. Plasma concentrations cannot explain all of the variability in patient responses to TB treatment, and cannot guarantee patient outcomes. However, combined with clinical and bacteriological data, TDM can be a decisive tool, allowing clinicians to successfully treat even the most complicated TB patients.
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            Therapeutic drug monitoring in the treatment of tuberculosis.

             C Peloquin (2001)
            Therapeutic drug monitoring (TDM) is a standard clinical technique used for many disease states, including many infectious diseases. As for these other conditions, the use of TDM in the setting of tuberculosis (TB) allows the clinician to make informed decisions regarding the timely adjustment of drug therapy. Such adjustments may not be required for otherwise healthy individuals who are responding to the standard, four-drug TB regimens. However, some patients are slow to respond to treatment, have drug-resistant TB, are at risk of drug-drug interactions or have concurrent disease states that significantly complicate the clinical situation. Such patients may benefit from TDM and early interventions may preclude the development of further drug resistance. It is not possible to collect multiple blood samples in the clinical setting for logistical and financial reasons. Therefore, one typically is limited to one or two time points. When only one sample can be obtained, the 2-hour post-dose concentrations of isoniazid, rifampin, pyrazinamide and ethambutol are usually most informative. Unfortunately, low 2-hour values do not distinguish between delayed absorption (late peak, close to normal range) and malabsorption (low concentrations at all time points). A second sample, often collected at 6-hour post-dose, can differentiate between these two scenarios. The second time point can also provide some information about clearance and half-life, assuming that drug absorption was nearly completed by 2 hours. TDM requires that samples are promptly centrifuged, and that the serum is promptly harvested and frozen. Isoniazid and ethionamide, in particular, are not stable in human serum at room temperature. Rifampin is stable for more than 6 hours under these conditions. During TB treatment, isoniazid causes the greatest early reduction in organisms and is considered to be one of the two most important TB drugs, along with rifampin. Although isoniazid is highly active against TB, low isoniazid concentrations were associated with poorer clinical and bacteriological outcomes in US Public Health Services (USPHS) TB Trial 22. Several earlier trials showed a clear dose-response for rifampin and pyrazinamide, so low concentrations for those two drugs also may correlate with poorer treatment outcomes. At least in USPHS TB Trial 22, the rifampin pharmacokinetic parameters were not predictive of the outcome variables. In contrast, low concentrations of unbound rifapentine may have been responsible, in part, for the worse-than-anticipated performance of this drug in clinical trials. The 'second-line' TB drugs, including p-aminosalicylic acid, cycloserine and ethionamide, are relatively weak TB drugs. Under the best conditions, treatment with these drugs takes over 2 years, as opposed to 6 to 9 months with isoniazid- and rifampin-containing regimens. Therefore, TB centres such as National Jewish Medical and Research Center in Denver, CO, USA, measure serum concentrations of the 'second-line' TB drugs early in the course of treatment. That way, poor drug absorption can be dealt with in a timely manner. This helps to minimise the time that patients are sputum smear- and culture-positive with multidrug-resistant TB, and may prevent the need for even longer treatment durations. Patients with HIV are at particular risk for drug-drug interactions. Because the published guidelines typically reflect interactions only between two drugs, these guidelines are of limited value when the patient is treated with three or more interacting drugs. Under such complicated circumstances, TDM often is the best available tool for sorting out these interactions and placing the patient the necessary doses that they require. TDM is only one part of the care of patients with TB. In isolation, it is of limited value. However, combined with clinical and bacteriological data, it can be a decisive tool, allowing the clinician to successfully treat even the most complicated TB patients.
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              Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses?

              Isoniazid is metabolized by the genetically polymorphic arylamine N-acetyltransferase type 2 (NAT2). A greater number of high-activity alleles are related to increased acetylation capacity and in some reports to low efficacy and toxicity of isoniazid. The objective of this study was to assess individual isoniazid exposure based on NAT2 genotype to predict a personalized therapeutic dose. Isoniazid was administered to 18 healthy Caucasians (age 30 +/- 6 years, body weight 74 +/- 10 kg, five women) in random order as a 200-mg infusion, a 100-mg oral, and a 300-mg oral single dose. For the assessment of NAT2 genotype, common single nucleotide polymorphisms identifying 99.9% of variant alleles were characterized. Noncompartmental pharmacokinetics and compartmental population pharmacokinetics were estimated from isoniazid plasma concentrations until 24 h postdose by high-pressure liquid chromatography. The influence of NAT2 genotype, drug formulation, body weight, and sex on dose-normalized isoniazid pharmacokinetics was assessed by analysis of variance from noncompartmental data and confirmed by population pharmacokinetics. Eight high-activity NAT2*4 alleles were identified. Sex had no effect; the other factors explained 93% of the variability in apparent isoniazid clearance (analysis of variance). NAT2 genotype alone accounted for 88% of variability. Individual isoniazid clearance could be predicted as clearance (liters/hour) = 10 + 9 x (number of NAT2*4 alleles). To achieve similar isoniazid exposure, current standard doses presumably appropriate for patients with one high-activity NAT2 allele may be decreased or increased by approximately 50% for patients with no or two such alleles, respectively. Prospective clinical trials are required to assess the merits of this approach.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                30 September 2015
                : 9
                : 5433-5438
                Affiliations
                [1 ]Department of Clinical Pharmacology, Inje University College of Medicine, Inje University Busan Paik Hospital, Busan, Korea
                [2 ]Department of Clinical Pharmacology, Konkuk University Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
                [3 ]Division of Pulmonary and Critical Care Medicine, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea
                [4 ]Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
                [5 ]Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
                [6 ]Department of Laboratory Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
                Author notes
                Correspondence: Won-Jung Koh, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-ro, Gangnam-gu, Seoul, Korea, Email wjkoh@ 123456skku.edu
                Soo-Youn Lee, Departments of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-ro, Gangnam-gu, Seoul, Korea, Email suddenbz@ 123456skku.edu
                Article
                dddt-9-5433
                10.2147/DDDT.S87131
                4598210
                © 2015 Jung et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                inh regimen, tuberculosis, pharmacogenomics, nat2 genotype

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