Therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) have become effective methods in determining and adjusting dose regimens of various drugs in clinical practice. With the latest development in technology, particularly in computer science, drug individualization has evolved to be more flexible and precise. However, these methods still have certain drawbacks and have not been applied on a grand scale. This review shall present the most basic concept of TDM and MIPD as well as current issues in their application.      

The aims of this systematic review are to provide knowledge concerning population pharmacokinetics of isoniazid (INH) and to identify factors influencing INH pharmacokinetic variability. Pubmed and Embase databases were systematically searched from inception to July, 2017. Relevant articles from reference lists were also included. All population pharmacokinetic studies of INH written in English, conducted in human (either healthy subjects or pulmonary tuberculosis patients) were included in this review. Ten studies were included in this review. Most studies characterized a two-compartment model with first-order kinetics for INH with a transit-compartment model for absorption suggested. Frequently reported significant predictors for INH clearance is NAT2 acetylator types (slow/intermediate/fast), while weight is a significant covariate for INH volume of distribution (both central and peripheral). In children, enzyme maturation had a profound affect on INH clearance. Keywords: Population pharmacokinetics, Isoniazid. References [1] World Health Organization, Global Tuberculosis Report 2019. https://apps.who.int/iris/bitstream/handle/10665/329368/9789241565714-eng.pdf (accessed 18 December 2019).[2] United Nations, Transforming our world: The 2030 agenda for sustainable development, New York, USA, 2015.[3] K. Takayama, L. Wang, H.L. David, Effect of isoniazid on the in vivo mycolic acid synthesis, cell growth, and viability of Mycobacterium tuberculosis, Antimicrob Agents Chemother 2.1 (1972) 29-35. https://doi.org/10.1128/aac.2.1.29 [4] A. Jindani, V.R. Aber, E. A. Edwards, D. A. Mitchison, The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis 121(6) (1980) 939-49. https://doi.org/10.1164/arrd.1980.121.6.939 [5] P.R. Donald, The influence of human N-acetyltransferase genotype on the early bactericidal activity of isoniazid. Clin Infect Dis 39(10) (2004) 1425-30. https://doi.org/10.1086/424999 [6] D.A. Mitchison, Basic mechanisms of chemotherapy, Chest 76(6 Suppl) (1979) 771-81. https://doi.org/10.1378/chest.76.6_supplement.771 [7] H. McIlleron et al., Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients, Antimicrob Agents Chemother 50(4) (2006) 1170-7. https://doi.org/10.1128/aac.50.4.1170-1177.2006 [8] S. Chideya et al., Isoniazid, rifampin, ethambutol, and pyrazinamide pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort of adults with tuberculosis from Botswana, Clin Infect Dis 48(12) (2009) 1685-94. https://doi.org/10.1086/599040 [9] N. Singh et al., Study of NAT2 gene polymorphisms in an Indian population: association with plasma isoniazid concentration in a cohort of tuberculosis patients. Mol Diagn Ther 13(1) (2009) 49-58. https://doi.org/10.1007/bf03256314 [10] N. Buchanan, C. Eyberg, M.D. Davis, Isoniazid pharmacokinetics in kwashiorkor. S Afr Med J 56(8) (1979) 299-300.[11] U.S. Food and Drug Administration (1999), "Guidance for Industry. Populationpharmacokinetics",Retrieved from http://www.fda.gov/downloads/Drugs/.../Guidances/UCM072137.pdf[12] D. R Mould, R. N. Upton, Basic concepts in population modeling, simulation, and model‐based drug development, CPT: pharmacometrics & systems pharmacology 1(9) (2012) 1-14. https://doi.org/10.1038/psp.2012.4 [13] P. Denti et al., Pharmacokinetics of isoniazid, pyrazinamide, and ethambutol in newly diagnosed pulmonary TB patients in Tanzania, PLoS ONE 10(10) (2015), e0141002. https://doi.org/10.1371/journal.pone.0141002 [14] B. Guiastrennec et al., Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications, Clin Pharmacol Ther 104(4) (2017), 733-741. https://doi.org/10.1002/cpt.987 [15] M. Kinzig-Schippers et al., Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses?, Antimicrobial Agents and Chemotherapy 49(5) (2005), 1733-1738. https://doi.org/10.1128/aac.49.5.1733-1738.2005 [16] J.J. Kiser et al., Isoniazid pharmacokinetics, pharmacodynamics, and dosing in South African infants, Therapeutic Drug Monitoring 34(4) (2012) 446-451. https://doi.org/10.1097/ftd.0b013e31825c4bc3 [17] L. Lalande, Population modeling and simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of isoniazid in lungs, Antimicrobial Agents and Chemotherapy 59(9) (2015) 5181-5189. https://doi.org/10.1128/aac.00462-15 [18] C. Magis-Escurra et al., Population pharmacokinetics and limited sampling strategy for first-line tuberculosis drugs and moxifloxacin, International Journal of Antimicrobial Agents 44(3) (2014) 229-234. https://doi.org/10.1016/j.ijantimicag.2014.04.019 [19] C.A. Peloquin et al., Population pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide, Antimicrobial Agents and Chemotherapy 41(12) (1997) 2670-2679. https://doi.org/10.1128/aac.41.12.2670 [20] K.Y. Seng et al., Population pharmacokinetic analysis of isoniazid, acetylisoniazid, and isonicotinic acid in healthy volunteers, Antimicrobial Agents and Chemotherapy 59(11) (2015) 6791-6799. https://doi.org/10.1128/aac.01244-15 [21] J.J. Wilkins et al., Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients, British Journal of Clinical Pharmacology 72(1) (2011) 51-62. https://doi.org/10.1111/j.1365-2125.2011.03940.x [22] S.P. Zvada et al., Population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children with tuberculosis: In silico evaluation of currently recommended doses, Journal of Antimicrobial Chemotherapy 69(5) (2014) 1339-1349. https://doi.org/10.1093/jac/dkt524 [23] World Health Organization, Guidance for national tuberculosis programmes on the management of tuberculosis in children (No. WHO/HTM/TB/2014.03). World Health Organization, 2014.[24] World Health Organization, & Stop TB Initiative (World Health Organization), Treatment of tuberculosis: guidelines. World Health Organization, 2010.[25] J.S. Starke, S.M, Tuberculosis in: James D. Cherry, Ralph D. Feigin (Eds.), Textbook of Pediatric Infectious Diseases., Saunders: Philadelphia, 1998 pp. 1196-1238. [26] J.G. Pasipanodya, S. Srivastava, T. Gumbo, Meta-analysis of clinical studies supports the pharmacokinetic variability hypothesis for acquired drug resistance and failure of antituberculosis therapy, Clinical Infectious Diseases 55(2) (2012) 169-177. https://doi.org/10.1093/cid/cis353

We conducted this research to determine the NAT2 gene-phenotype characteristics and pharmacokinetics (PK) parameters of isoniazid among patients with non-MDR pulmonary tuberculosis. Data were collected from 132 patients diagnosed with newly acquired or relapsed tuberculosis and treated at 03 hospitals: Hanoi Lung Hospital, Central Lung Hospital, and National K74 Hospital. PK samples were collected one day from the 10th – 14th day after commencing treatment. The average age of the recruited patients was 45.43 ± 15.76 years; the majority were male (74.24%). The slow and medium acetylator types, as indicated by NAT2 phenotypes, were the two major types (37.88% and 35.6%, respectively). 61.12% of the patients had their Bayesian isoniazid-acetyl isoniazid population PK modeling - determined Cmax value within the therapeutic range of 3 – 6 µg/mL. Acelytator type showed a statistically significant correlation with Cmax. Keywords: Isoniazid, pharmacokinetics, Cmax, tuberculosis.

Vietnam is among 30 high TB ​​burden countries even though the Vietnam National TB Program has made great efforts to detect and treat tuberculosis. Objectives: Assessment of Mycobacterial level in sputum before treatment, and susceptibility to the first line anti-TB drugs of M. tuberculosis strains isolated from TB patients with AFB (+) and non-multidrug-resistant. Moreover, factors influencing MGIT outcome after the first 8 weeks of first-line anti-TB drugs therapy in patients with pulmonary tuberculosis was also analysed. Methodology: An observational, analytical study was performed in 128 patients with non-multidrug-resistant pulmonary tuberculosis AFB (+) for evaluating the level of Mycobacteria in sputum before treatment by smear microscopy method; the susceptibility of M. tuberculosis isolated from sputum of the patient was analysed by Lowenstein - Jensen method. Factors affecting positive MGIT results after 2 months of treatment were determined by multivariate logistics regression. Results: The patients had AFB 3+ were 28% in new cases and 24,5% retreatment patients. The rate of M. tuberculosis strains was susceptible to the first line anti-TB drugs in new cases was higher than retreatment patients. The percentage of any anti-TB drug resistance in retreatment tuberculosis was 59,6%, higher than that of new case TB (23,6%). There was high rate of M. tuberculosis strains resistant to Streptomycin and Isoniazid (12,5% and 16,8% for new cases; 42,3% and 36,5% for retreatment cases, respectively). Large radiographic chest lesions and high AFB levels in pre-treatment sputum were factors associated with a positive MGIT result after the first 8 weeks of treatment. Conclusion: Most of TB patients had high level of Mycobacteria in sputum samples collected before treatment. The percentage of M. tuberculosis strains isolated from sputum of pulmonary non MDR-TB patients had any anti-TB drug resistance were high. High Mycobacteria level in pre-treatment sputum and radiographic chest lesions related to positive MGIT result after the first 8 weeks of treatment. Keywords Pulmonary tuberculosis, first-line anti-TB drugs, anti-TB drug resistance, susceptibility, M. tuberculosis. References [1] World Health Organization, Global Tuberculosis Report 2020. Tuberculosis profiles: Viet Nam (2020) Available: https://worldhealthorg.shinyapps.io/tb_profiles/?_inputs_&entity_type=%22country%22&lan=%22EN%22&iso2=%22VN%22 (accessed 10 April 2020).[2] L.T. Luyen, N.V. Hung, Methods for Diagnosis in Tuberculosis, in Le Thi Luyen (Ed), Tuberculosis - Textbook for General Medical Students. Vietnam National University Press, Hanoi, 2020, pp: 47-69 (in Vietnamese).[3] Ministry of Health - National Tuberculosis Programme Guideline for Standard Operating Procedures of Microbiology Laboratory Methods for Mycobacteria. Vietnam National Tuberculosis Programme, Hanoi (2013) (in Vietnamese).[4] Ministry of Health (2018) Guideline for Management, Diagnosis and Treatment for Tuberculosis. (in Vietnamese) Available: https://kcb.vn/vanban/quyet-dinh-so-3216-qd-byt-ngay-23-5-2018-ve-viec-ban-hanh-huong-dan-chan-doan-dieu-tri-va-du-phong-benh-lao (Accessed 12 January 2019)[5] A.P. Ralph, M. Ardian, A. Wiguna et al. A simple, valid, numerical score for grading chest x-ray severity in adult smear-positive pulmonary tuberculosis. Thorax 2010 Oct;65(10):863-869. https://doi.org/10.1136/thx.2010.136242[6] C.T. Minh, L.T. Luyen, N.T.L. Huong et al. Plasma concentration of anti-tubeculosis drugs in pulmonary tuberculosis patients, who treatment in National Tuberculosis and Lung Diseases Hospital 2008 Journal of Practical Medicine 651(2009) 50-53 (in Vietnamese).[7] N.V. Nhung, N.B. Hoa, D.N. Sy, C.M. Hennig, A.S. Dean (2015) The fourth national anti-tuberculosis drug resistance survey in Viet Nam. Int J Tuberc Lung Dis. Jun 2015 19(6) 670-675. https://doi.org/10.5588/ijtld.14.0785[8] N.T. Hang, S. Maeda, L.T. Lien, et al. Primary drug-resistant tuberculosis in Hanoi, Viet Nam: present status and risk factors. PloS one 8(8) (2013) e71867. https://doi.org/10.1371/journal.pone.0071867[9] R. Hafner, J.A. Cohn, D.J. Wright, et al. Early bactericidal activity of isoniazid in pulmonary tuberculosis. Optimization of methodology. The DATRI 008 Study Group. Am J Respir Crit Care Med 156 (1997) 918–923. https://doi.org/10.1164/ajrccm.156.3.9612016[10] A. Jindani, V.R. Aber, E.A. Edwards, D.A. Mitchison. The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am J Respir Crit Care Med. 121(1980)(6) 939-949. Available: https://www.atsjournals.org/doi/10.1164/arrd.1980.121.6.939 (Accessed 12 January 2019).[11] H.L. Rieder. Intervention for Tuberculosis Control and Elimination. International Union of Tuberculosis and Lung Diseases, Paris, France, 2002.

Drug resistant TB is currently a global challenge causing high risk of death and expanding the disease. This study explores the prevalence of drug resistance in newly diagnosed and recurrent TB patients and identifies the association between NAT2 gene polymorphism distribution and acetylator phenotype of NAT2 gene and the two study groups. The study results show that the newly diagnosed TB had l lower male ratio and younger age in comparison to the recurrent TB. Newly diagnosed group was more sensitive to first line TB drugs. However, both groups had significant resistance ratio in relation to INH and SM. Finally, the allele and acetylator phenotype frequency of NAT2 showed the significant association with TB status. The study concludes that the newly diagnosed and recurrent TB patients expressed differently in their profiles concerning patient’s background, drug resistance and NAT2 allele distribution. Keywords Drug resistance, INH, NAT2 polymorphism, newly diagnosed TB, recurrent TB1. References [1] WHO, Global Tuberculossi report, https://www.who.int/tb/publications/global_report/en/, 2018 (accessed 16 April 2019).[2] Hoàng Thị Phượng, Nghiên cứu đặc điểm lâm sàng, cận lâm sàng, tính kháng thuốc của vi khuẩn ở bệnh nhân lao phổi mới kết hợp bệnh đái tháo đường, Luận văn tiến sĩ Y học, trường Đại học Y Hà Nội, 2009.[3] S. Guaoua, I. Ratbi, F.Z. Laarabi, S.A. Elalaoui, IC. Jaouad, A. Barkat, A. Sefiani, Distribution of allelic and genotypic frequencies of NAT2 and CYP2E1 variants in Moroccan population, BMC Genet. 15 (2014) 156.[4] A. Toure, M. Cabral, A. Niang, C. Diop, A. Garat, L. Humbert, M. Fall, A. Diouf, F. Broly, M. Lhermitte, D. Allorge, Prevention of isoniazid toxicity by NAT2 genotyping in Senegalese tuberculosis patients, Toxicol Rep. 3 (2016) 826-831.[5] M. Majumder, N. Sikdar, S. Ghosh, B. Roy, Polymorphisms at XPD and XRCC1 DNA repair loci and increased risk of oral leukoplakia and cancer among NAT2 slow acetylators, Int J Cancer. 120(10) (2007) 2148-2156.[6] S. Morita, M. Yano, T. Tsujinaka, Y. Akiyama, M. Taniguchi, K. Kaneko, H. Miki, T. Fujii, K. Yoshino, H. Kusuoka, M. Monden, Genetic polymorphisms of drug-metabolizing enzymes and susceptibility to head-and-neck squamous-cell carcinoma, Int J Cancer. 80(5) (1999) 685-688.[7] Hoàng Hà, Nghiên cứu một số đặc điểm lâm sàng, cận lâm sàng, sinh học của vi khuẩn ở bệnh nhân lao phổi điều trị lại, Luận án tiến sỹ Y học, Trường Đại học Y Hà Nội, 2009.[8] S. Wattanapokayakit, T. Mushiroda, H. Yanai, N. Wichukchinda, C. Chuchottawon, S. Nedsuwan, A. Rojanawiwat, S. Denjanta, T. Kantima, J. Wongyai, W. Suwankesawong, W. Rungapiromnan, R. Kidkeukarun, W. Bamrungram, A. Chaiwong, S. Suvichapanich, S. Mahasirimongkol, K. Tokunaga, NAT2 slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients, Int J Tuberc Lung Dis. 20(10) (2016) 1364-1369.[9] Đinh Ngọc Sỹ, Chiến lược quản lý bệnh lao đa kháng thuốc tại Việt Nam, Tạp chí khoa học Hội Phổi Pháp - Việt. 2(3) (2011) 40-42.[10] Nguyễn Thu Hà, Trần Văn Sáng, Đinh Ngọc Sỹ, Lâm sàng, cận lâm sàng và tính kháng thuốc của vi khuẩn lao ở bệnh nhân lao phổi tái phát, JFran Viet Pneu. 2(3) (2011) 63-67.[11] D. Tu, L. Zhang, J. Su, Resistance and efficacy of treatment in relapse pulmonary tuberculosis, Zhonghua Jie He He Hu Xi Za Zhi. 23 (11) (2000) 666-668