Advertisement

The Indian Journal of Pediatrics

, Volume 86, Issue 5, pp 468–478 | Cite as

Pharmacokinetics of First-Line Anti-Tubercular Drugs

  • Aparna Mukherjee
  • Rakesh LodhaEmail author
  • S. K. Kabra
Review Article

Abstract

Determining the optimal dosages of isoniazid, rifampicin, pyrazinamide and ethambutol in children is necessary to obtain therapeutic serum concentrations of these drugs. Revised dosages have improved the exposure of 1st line anti-tubercular drugs to some extent; there is still scope for modification of the dosages to achieve exposures which can lead to favourable outcome of the disease. High dose of rifampicin is being investigated in clinical trials in adults with some benefit; studies are required in children. Inter-individual pharmacokinetic variability and the effect of age, nutritional status, Human immunodeficiency virus (HIV) infection, acetylator genotype may need to be accounted for in striving for the dosages best suited for an individual.

Keywords

Anti tuberculosis drugs Isoniazid Ethambutol Pyrazinamide Rifampicin 

Notes

Authors’ Contributions

AM performed the literature search, drafted the manuscript. All authors were involved in writing the review manuscript. RL will act as guarantor for this paper.

Compliance with Ethical Standards

Conflict of Interest

None.

References

  1. 1.
    McCarver DG. Applicability of the principles of developmental pharmacology to the study of environmental toxicants. Pediatrics. 2004;113:969–72.Google Scholar
  2. 2.
    Pariente-Khayat A, Rey E, Gendrel D, et al. Isoniazid acetylation metabolic ratio during maturation in children. Clin Pharmacol Ther. 1997;62:377–83.Google Scholar
  3. 3.
    Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis. Drugs. 2002;62:2169–83.CrossRefGoogle Scholar
  4. 4.
    Brunton LL, Chabner BA, Knollmann BC. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. US: McGraw-Hill Medical; 2011.Google Scholar
  5. 5.
    Debré R. Systematic treatment of primary tuberculosis. Am Rev Tuberc. 1956;74:191–6.Google Scholar
  6. 6.
    Seth V, Beotra A, Seth SD, et al. Serum concentrations of rifampicin and isoniazid in tuberculosis. Indian Pediatr. 1993;30:1091–8.Google Scholar
  7. 7.
    Lanier VS, Russel WF Jr, Heaton A, Robinson A. Concentrations of active isoniazid in serum and cerebrospinal fluid of patients with tuberculosis treated with isoniazid. Pediatrics. 1958;21:910–5.Google Scholar
  8. 8.
    Akbani Y, Bolme P, Lindblad BS, Rahimtoola RJ. Control of streptomycin and isoniazid in malnourished children treated for tuberculosis. Acta Paediatr Scand. 1977;66:237–40.CrossRefGoogle Scholar
  9. 9.
    Seth V, Beotra A, Senwal OP, Mukhopadhyaya S. Monitoring of serum rifampicin and isoniazid levels in childhood tuberculosis. Am Rev Respir Dis. 1990;141:A337.Google Scholar
  10. 10.
    Seth V, Beotra A, Bagga A, Seth S. Drug therapy in malnutrition. Indian Pediatr. 1992;29:1341–6.Google Scholar
  11. 11.
    Seth V, Seth SD, Beotra A, Semwal OP, D’monty V, Mukhopadhya S. Isoniazid and acetylisoniazid kinetics in serum and urine in pulmonary primary complex with intermittent regimen. Indian Pediatr. 1994;31:279–85.Google Scholar
  12. 12.
    Roy V, Tekur U, Chopra K. Pharmacokinetics of isoniazid in pulmonary tuberculosis--a comparative study at two dose levels. Indian Pediatr. 1996;33:287–91.Google Scholar
  13. 13.
    Donald PR, Gent WL, Seifart HI, Lamprecht JH, Parkin DP. Cerebrospinal fluid isoniazid concentrations in children with tuberculous meningitis: the influence of dosage and acetylation status. Pediatrics. 1992;89:247–50.Google Scholar
  14. 14.
    Rey E, Gendrel D, Treluyer JM, et al. Isoniazid pharmacokinetics in children according to acetylator phenotype. Fundam Clin Pharmacol. 2001;15:355–9.Google Scholar
  15. 15.
    Schaaf HS, Parkin DP, Seifart HI, et al. Isoniazid pharmacokinetics in children treated for respiratory tuberculosis. Arch Dis Child. 2005;90:614–8.Google Scholar
  16. 16.
    McIlleron H, Willemse M, Werely CJ, et al. Isoniazid plasma concentrations in a cohort of south African children with tuberculosis: implications for international pediatric dosing guidelines. Clin Infect Dis. 2009;48:1547–53.Google Scholar
  17. 17.
    Thee S, Detjen AA, Wahn U, Magdorf K. Isoniazid pharmacokinetic studies of the 1960s: considering a higher isoniazid dose in childhood tuberculosis. Scand J Infect Dis. 2010;42:294–8.CrossRefGoogle Scholar
  18. 18.
    Thee S, Seddon JA, Donald PR, et al. Pharmacokinetics of isoniazid, rifampin, and pyrazinamide in children younger than two years of age with tuberculosis: evidence for implementation of revised World Health Organization recommendations. Antimicrob Agents Chemother. 2011;55:5560–7.Google Scholar
  19. 19.
    Verhagen LM, López D, Hermans PWM, et al. Pharmacokinetics of anti-tuberculosis drugs in Venezuelan children younger than 16 years of age: supportive evidence for the implementation of revised WHO dosing recommendations. Tropical Med Int Health. 2012;17:1449–56.Google Scholar
  20. 20.
    Ramachandran G, Hemanth Kumar AK, Bhavani PK, et al. Age, nutritional status and INH acetylator status affect pharmacokinetics of anti-tuberculosis drugs in children. Int J Tuberc Lung Dis. 2013;17:800–6.Google Scholar
  21. 21.
    Ibrahim M, Engidawork E, Yimer G, Bobosha K, Aseffa A. Pharmacokinetics of isoniazid in Ethiopian children with tuberculosis in relation to the N-acetyltransferase 2 (NAT2) genotype. Afr J Pharm Pharmacol. 2013;7:1124–30.CrossRefGoogle Scholar
  22. 22.
    Mukherjee A, Velpandian T, Singla M, Kanhiya K, Kabra SK, Lodha R. Pharmacokinetics of isoniazid, rifampicin, pyrazinamide and ethambutol in Indian children. BMC Infect Dis. 2015;15:126.CrossRefGoogle Scholar
  23. 23.
    Jamis-Dow CA, Katki AG, Collins JM, Klecker RW. Rifampin and rifabutin and their metabolism by human liver esterases. Xenobiotica. 1997;27:1015–24.CrossRefGoogle Scholar
  24. 24.
    Chen J, Raymond K. Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor. Ann Clin Microbiol Antimicrob. 2006;5:3.CrossRefGoogle Scholar
  25. 25.
    Ellard GA, Fourie PB. Rifampicin bioavailability: a review of its pharmacology and the chemotherapeutic necessity for ensuring optimal absorption. Int J Tuberc Lung Dis. 1999;3:S301–8; discussion S317–21.Google Scholar
  26. 26.
    Acocella G, Buniva G, Flauto U. Absorption and elimination of the antibiotic rifampicin in newborns and children. Proceedings of the sixth International Congress of Chemotherapy. Tokyo: Univ Tokyo Press; 1970. p. 755–60.Google Scholar
  27. 27.
    Schaaf HS, Willemse M, Cilliers K, et al. Rifampin pharmacokinetics in children, with and without human immunodeficiency virus infection, hospitalized for the management of severe forms of tuberculosis. BMC Med. 2009;7:19.Google Scholar
  28. 28.
    Hussels H, Kroening U, Magdorf K. Ethambutol and rifampicin serum levels in children: second report on the combined administration of ethambutol and rifampicin. Pneumonologie. 1973;149:31–8.CrossRefGoogle Scholar
  29. 29.
    McCracken GH Jr, Ginsburg CM, Zweighaft TC, Clahsen J. Pharmacokinetics of rifampin in infants and children: relevance to prophylaxis against Haemophilus influenzae type b disease. Pediatrics. 1980;66:17–21.Google Scholar
  30. 30.
    Tan TQ, Mason EO Jr, Ou CN, Kaplan SL. Use of intravenous rifampin in neonates with persistent staphylococcal bacteremia. Antimicrob Agents Chemother. 1993;37:2401–6.CrossRefGoogle Scholar
  31. 31.
    Mahajan M, Rohatgi D, Talwar V, Patni SK, Mahajan P, Agarwal DS. Serum and cerebrospinal fluid concentrations of rifampicin at two dose levels in children with tuberculous meningitis. J Commun Dis. 1997;29:269–74.Google Scholar
  32. 32.
    Thee S, Detjen A, Wahn U, Magdorf K. Rifampicin serum levels in childhood tuberculosis. Int J Tuberc Lung Dis. 2009;13:1106–11.Google Scholar
  33. 33.
    Graham SM, Bell DJ, Nyirongo S, Hartkoorn R, Ward SA, Molyneux EM. Low levels of pyrazinamide and ethambutol in children with tuberculosis and impact of age, nutritional status, and human immunodeficiency virus infection. Antimicrob Agents Chemother. 2006;50:407–13.CrossRefGoogle Scholar
  34. 34.
    Roy V, Tekur U, Chopra K. Pharmacokinetics of pyrazinamide in children suffering from pulmonary tuberculosis. Int J Tuberc Lung Dis. 1999;3:133–7.Google Scholar
  35. 35.
    Zhu M, Starke JR, Burman WJ, et al. Population pharmacokinetic modeling of pyrazinamide in children and adults with tuberculosis. Pharmacotherapy. 2002;22:686–95.Google Scholar
  36. 36.
    Gupta P, Roy V, Sethi GR, Mishra TK. Pyrazinamide blood concentrations in children suffering from tuberculosis: a comparative study at two doses. Br J Clin Pharmacol. 2008;65:423–7.CrossRefGoogle Scholar
  37. 37.
    Thee S, Detjen A, Wahn U, Magdorf K. Pyrazinamide serum levels in childhood tuberculosis. Int J Tuberc Lung Dis. 2008;12:1099–101.Google Scholar
  38. 38.
    Arya DS, Ojha SK, Semwal OP, Nandave M. Pharmacokinetics of pyrazinamide in children with primary progressive disease of lungs. Indian J Med Res. 2008;128:611–5.Google Scholar
  39. 39.
    Roy V, Sahni P, Gupta P, Sethi GR, Khanna A. Blood levels of pyrazinamide in children at doses administered under the revised National Tuberculosis Control Program. Indian Pediatr. 2012;49:721–5.CrossRefGoogle Scholar
  40. 40.
    Thee S, Detjen A, Quarcoo D, Wahn U, Magdorf K. Ethambutol in paediatric tuberculosis: aspects of ethambutol serum concentration, efficacy and toxicity in children. Int J Tuberc Lung Dis. 2007;11:965–71.Google Scholar
  41. 41.
    Zhu M, Burman WJ, Starke JR, et al. Pharmacokinetics of ethambutol in children and adults with tuberculosis. Int J Tuberc Lung Dis. 2004;8:1360–7.Google Scholar
  42. 42.
    Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children. Geneva: World Health Organization; 2015.Google Scholar
  43. 43.
    World Health Organization. RAPID ADVICE Treatment of tuberculosis in children. Geneva, Switzerland: WHO, Geneva, Switzerland; 2010.Google Scholar
  44. 44.
    World Health Organization. Guidance for National Tuberculosis Programmes on the management of tuberculosis in children. Geneva, Switzerland: World Health Organization; 2006.Google Scholar
  45. 45.
    Kiser JJ, Zhu R, DʼArgenio DZ, et al. Isoniazid pharmacokinetics, pharmacodynamics, and dosing in south African infants. Ther Drug Monit. 2012;34:446–51.Google Scholar
  46. 46.
    Yang H, Enimil A, Gillani FS, et al. Evaluation of the adequacy of the 2010 revised World Health Organization recommended dosages of the first-line antituberculosis drugs for children: adequacy of revised dosages of TB drugs for children. Pediatr Infect Dis J. 2018;37:43–51.Google Scholar
  47. 47.
    Aruldhas BW, Hoglund RM, Ranjalkar J, et al. Optimization of dosing regimens of isoniazid and rifampicin in children with tuberculosis in India. Br J Clin Pharmacol. 2018 Dec 26. [Epub ahead of print], 2019.  https://doi.org/10.1111/bcp.13846.
  48. 48.
    de Steenwinkel JEM, Aarnoutse RE, de Knegt GJ, et al. Optimization of the rifampin dosage to improve the therapeutic efficacy in tuberculosis treatment using a murine model. Am J Respir Crit Care Med. 2013;187:1127–34.Google Scholar
  49. 49.
    Horita Y, Alsultan A, Kwara A, et al. Evaluation of the adequacy of WHO revised dosages of the first-line antituberculosis drugs in children with tuberculosis using population pharmacokinetic modeling and simulations. Antimicrob Agents Chemother. 2018;62:pii:e00008–18.Google Scholar
  50. 50.
    Srivastava S, Deshpande D, Magombedze G, Gumbo T. Efficacy versus hepatotoxicity of high-dose rifampin, pyrazinamide, and moxifloxacin to shorten tuberculosis therapy duration: there is still fight in the old warriors yet! Clin Infect Dis. 2018;67:S359–64.CrossRefGoogle Scholar
  51. 51.
    Boeree MJ, Heinrich N, Aarnoutse R, et al. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis. 2017;17:39–49.Google Scholar
  52. 52.
    Velásquez GE, Brooks MB, Coit JM, et al. Efficacy and safety of high-dose rifampin in pulmonary tuberculosis. A randomized controlled trial. Am J Respir Crit Care Med. 2018;198:657–66.Google Scholar
  53. 53.
    Svensson EM, Svensson RJ, Te Brake LHM, et al. The potential for treatment shortening with higher rifampicin doses: relating drug exposure to treatment response in patients with pulmonary tuberculosis. Clin Infect Dis. 2018;67:34–41.CrossRefGoogle Scholar
  54. 54.
    Hiruy H, Rogers Z, Mbowane C, et al. Subtherapeutic concentrations of first-line anti-TB drugs in south African children treated according to current guidelines: the PHATISA study. J Antimicrob Chemother. 2015;70:1115–23.Google Scholar
  55. 55.
    Dayal R, Singh Y, Agarwal D, et al. Pharmacokinetic study of isoniazid and pyrazinamide in children: impact of age and nutritional status. Arch Dis Child. 2018;103:1150–4.Google Scholar
  56. 56.
    Mlotha R, Waterhouse D, Dzinjalamala F, et al. Pharmacokinetics of anti-TB drugs in Malawian children: reconsidering the role of ethambutol. J Antimicrob Chemother. 2015;70:1798–803.Google Scholar
  57. 57.
    Ramachandran G, Kumar AKH, Kannan T, et al. Low serum concentrations of rifampicin and pyrazinamide associated with poor treatment outcomes in children with tuberculosis related to HIV status. Pediatr Infect Dis J. 2016;35:530–4.Google Scholar
  58. 58.
    Pouplin T, Bang ND, Toi PV, et al. Naïve-pooled pharmacokinetic analysis of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of Vietnamese children with tuberculous meningitis. BMC Infect Dis. 2016;16:144.Google Scholar
  59. 59.
    Jeena PM, Bishai WR, Pasipanodya JG, Gumbo T. In silico children and the glass mouse model: clinical trial simulations to identify and individualize optimal isoniazid doses in children with tuberculosis. Antimicrob Agents Chemother. 2011;55:539–45.CrossRefGoogle Scholar
  60. 60.
    Schaaf HS, Parkin DP, Seifart HI, et al. Isoniazid pharmacokinetics in children treated for respiratory tuberculosis. Arch Dis Child. 2005;90:614–8.Google Scholar
  61. 61.
    Mehta S. Drug disposition in children with protein energy malnutrition. J Pediatr Gastroenterol Nutr. 1983;2:407–17.CrossRefGoogle Scholar
  62. 62.
    Oshikoya KA, Senbanjo IO. Pathophysiological changes that affect drug disposition in protein-energy malnourished children. Nutr Metab. 2009;6:50.Google Scholar
  63. 63.
    Oshikoya KA, Sammons HM, Choonara I. A systematic review of pharmacokinetics studies in children with protein-energy malnutrition. Eur J Clin Pharmacol. 2010;66:1025–35.CrossRefGoogle Scholar
  64. 64.
    Eriksson M, Bolme P, Habte D, Paalzow L. INH and streptomycin in Ethiopian children with tuberculosis and different nutritional status. Acta Paediatr Scand. 1988;77:890–4.CrossRefGoogle Scholar
  65. 65.
    World Health Organization. Global tuberculosis control - surveillance, planning, financing. Geneva, Switzerland: WHO; 2008.Google Scholar
  66. 66.
    McIlleron H, Willemse M, Schaaf HS, Smith PJ, Donald PR. Pyrazinamide plasma concentrations in young children with tuberculosis. Pediatr Infect Dis J. 2011;30:262–5.CrossRefGoogle Scholar
  67. 67.
    Pharmacokinetics of isoniazid, rifampicin, pyrazinamide and ethambutol in HIV-infected Indian children. - PubMed - NCBI [Internet]. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27084822. Accessed 29 Jan 2019.
  68. 68.
    Daskapan A, Idrus LR, Postma MJ, et al. A systematic review on the effect of HIV infection on the pharmacokinetics of first-line tuberculosis drugs. Clin Pharmacokinet. 2018 Nov 8. [Epub ahead of print].  https://doi.org/10.1007/s40262-018-0716-8.
  69. 69.
    Weiner M, Peloquin C, Burman W, et al. Effects of tuberculosis, race, and human gene SLCO1B1 polymorphisms on rifampin concentrations. Antimicrob Agents Chemother. 2010;54:4192–200.Google Scholar
  70. 70.
    Ramesh K, Hemanth Kumar AK, Kannan T, et al. SLCO1B1 gene polymorphisms do not influence plasma rifampicin concentrations in a south Indian population. Int J Tuberc Lung Dis. 2016;20:1231–5.Google Scholar
  71. 71.
    Sloan DJ, McCallum AD, Schipani A, et al. Genetic determinants of the pharmacokinetic variability of rifampin in Malawian adults with pulmonary tuberculosis. Antimicrob Agents Chemother. 2017;61:pii:e00210–7.Google Scholar
  72. 72.
    Kumar AKH, Chandrasekaran V, Kumar AK, et al. Food significantly reduces plasma concentrations of first-line anti-tuberculosis drugs. Indian J Med Res. 2017;145:530–5.Google Scholar
  73. 73.
    Requena-Méndez A, Davies G, Waterhouse D, et al. Intra-individual effects of food upon the pharmacokinetics of rifampicin and isoniazid. J Antimicrob Chemother. 2019;74:416–24.Google Scholar
  74. 74.
    Rockwood N, Pasipanodya JG, Denti P, et al. Concentration-dependent antagonism and culture conversion in pulmonary tuberculosis. Clin Infect Dis. 2017;64:1350–9.Google Scholar
  75. 75.
    Impact of nonlinear interactions of pharmacokinetics and MICs on sputum bacillary kill rates as a marker of sterilizing effect in tuberculosis. - PubMed - NCBI [Internet]. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25313213. Accessed 29 Jan 2019.
  76. 76.
    Swaminathan S, Pasipanodya JG, Ramachandran G, et al. Drug concentration thresholds predictive of therapy failure and death in children with tuberculosis: bread crumb trails in random forests. Clin Infect Dis. 2016;63:S63–74.Google Scholar
  77. 77.
    Guiastrennec B, Ramachandran G, Karlsson MO, et al. Suboptimal antituberculosis drug concentrations and outcomes in small and HIV-coinfected children in India: recommendations for dose modifications. Clin Pharmacol Ther. 2018;104:733–41.Google Scholar

Copyright information

© Dr. K C Chaudhuri Foundation 2019

Authors and Affiliations

  1. 1.Department of PediatricsAll India Institute of Medical SciencesNew DelhiIndia

Personalised recommendations