Population Pharmacokinetic Modelling of Pyrazinamide and Pyrazinoic Acid in Patients with Multi-Drug Resistant Tuberculosis

  • Pierre MugaboEmail author
  • Mwila Mulubwa
Original Research Article


Background and Objectives

Pyrazinamide, a drug used in the regimen for the treatment of drug-sensitive tuberculosis, is also used for the treatment of multidrug-resistant tuberculosis (MDR-TB). We aimed to describe the population pharmacokinetics of pyrazinamide and its major metabolite, pyrazinoic acid, in patients with MDR-TB and characterise the effects of demographic variables.


This was a non-randomised clinical study involving 51 adult patients admitted for the intensive phase of MDR-TB treatment. Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8, 16 and 24 h after drug administration. Plasma concentrations of pyrazinamide and pyrazinoic acid were analysed using a validated LC–MS/MS method. Nonlinear mixed-effects modelling using Monolix 2018R1 software was employed to estimate population pharmacokinetic parameters.


A one-compartment pharmacokinetic model with transit compartment absorption process and first-order elimination best described the pyrazinamide and pyrazinoic acid concentration–time data. The estimated population pharmacokinetic parameters were 0.7 h, 3.38 h−1, 57.1 l, 4.37 L/h and 10.5 L/h for mean transit time, absorption rate constant, apparent distribution volume for pyrazinamide, and apparent clearance for pyrazinamide and pyrazinoic acid (CLm/F), respectively. These parameters were not affected by patient age, HIV status or sex. The parameter variability in CLm/F was the highest (83.5%), while the rest of the parameters ranged from 16.2 to 58%.


The developed population pharmacokinetic model adequately described the disposition of pyrazinamide and pyrazinoic acid and can be useful for dose determination of pyrazinamide in patients with MDR-TB.



The authors acknowledge the Brewelskloof Hospital authorities for permission to conduct the study; the staff members at Brewelskloof Hospital for their support; the Pharmaceutical Services, Provincial Administration of the Western Cape for supplying anti-tuberculosis tablets; the Department of Health, Province of the Western Cape for permission to conduct the study; and the patients who participated in the study.

Compliance with Ethical Standards


The South African Medical Research Council and the University of the Western Cape financially supported this research project.

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

The study was approved by the ethics committee of the University of the Western Cape (Ref: 07/6/12) and the University of Cape Town (Ref: 777/2014). The principles outlined in the declaration of Helsinki were adhered to when conducting the study.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

13318_2018_540_MOESM1_ESM.tif (246 kb)
Supplementary material 1 (TIFF 245 kb)


  1. 1.
    World Health Organization. Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update, Geneva, Switzerland: World Health Organization, 2017. Accessed 21 Mar 2018.
  2. 2.
    World Health Organization. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis, Geneva, Switzerland: World Health Organization Press, 2014. Accessed 7 May 2018.
  3. 3.
    Zhang Y, Wade MM, Scorpio A, Zhang H, Sun Z. Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid. J Antimicrob Chemother. 2003;52:790–5.CrossRefGoogle Scholar
  4. 4.
    Lacroix C, Hoang TP, Nouveau J, Guyonnaud C, Laine G, Duwoos H, et al. Pharmacokinetics of pyrazinamide and its metabolites in healthy subjects. Eur J Clin Pharmacol. 1989;36:395–400.CrossRefGoogle Scholar
  5. 5.
    Vayre P, Chambraud E, Fredj G, Thuillier A. Pharmacokinetic study of pyrazinamide and pyrazinoic acid in subjects with normal renal function and patients with renal failure. Therapie. 1989;44:1–4.Google Scholar
  6. 6.
    Lacroix C, Tranvouez JL, Phan TH, Duwoos H, Lafont O. Pharmacokinetics of pyrazinamide and its metabolites in patients with hepatic cirrhotic insufficiency. Arzneimittelforschung. 1990;40:76–9.Google Scholar
  7. 7.
    Vinnard C, Ravimohan S, Tamuhla N, Pasipanodya J, Srivastava S, Modongo C, et al. Pyrazinamide clearance is impaired among HIV/tuberculosis patients with high levels of systemic immune activation. PLoS One. 2017;12:e0187624.CrossRefGoogle Scholar
  8. 8.
    Wilkins JJ, Langdon G, McIlleron H, Pillai GC, Smith PJ, Simonsson US. Variability in the population pharmacokinetics of pyrazinamide in South African tuberculosis patients. Eur J Clin Pharmacol. 2006;62:727–35.CrossRefGoogle Scholar
  9. 9.
    Perlman DC, Segal Y, Rosenkranz S, Rainey PM, Peloquin CA, Remmel RP, et al. The clinical pharmacokinetics of pyrazinamide in HIV-infected persons with tuberculosis. Clin Infect Dis. 2004;38:556–64.CrossRefGoogle Scholar
  10. 10.
    World Health Organization. WHO treatment guidelines for drug-resistant tuberculosis 2016 update, Geneva, Switzerland: World Health Organization, 2016. Accessed 15 Mar 2018.
  11. 11.
    General Assembly of the World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. J Am Coll Dent. 2014;81:14.Google Scholar
  12. 12.
    United States Food and Drug Administration. Guidance for Industry Bioanalytical Method Validation, Rockville, USA: Food and Drugs Administration, 2013. Accessed 14 Apr 2018.
  13. 13.
    Niu J, Scheuerell C, Mehrotra S, Karan S, Puhalla S, Kiesel BF, et al. Parent-metabolite pharmacokinetic modeling and pharmacodynamics of veliparib (ABT-888), a PARP inhibitor, in patients with BRCA 1/2–mutated cancer or PARP-sensitive tumor types. J Clin Pharmacol. 2017;57:977–87.CrossRefGoogle Scholar
  14. 14.
    National Center for Biotechnology Information. PubChem Compound Database; CID = 1046. Accessed 2 July 2018.
  15. 15.
    National Center for Biotechnology Information. PubChem Compound Database; CID = 1047, Accessed 2 July 2018.
  16. 16.
    Monolix version 2018R1. Antony, France: Lixoft SAS, 2018. Accessed 3 Mar 2018.
  17. 17.
    Feng Y, Pollock BG, Coley K, Marder S, Miller D, Kirshner M, et al. Population pharmacokinetic analysis for risperidone using highly sparse sampling measurements from the CATIE study. Br J Clin Pharmacol. 2008;66:629–39.Google Scholar
  18. 18.
    Savic RM, Jonker DM, Kerbusch T, Karlsson MO. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn. 2007;34:711–26.CrossRefGoogle Scholar
  19. 19.
    Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet. 2009;24:25–36.CrossRefGoogle Scholar
  20. 20.
    Lavielle M, Ribba B. Enhanced method for diagnosing pharmacometric models: random sampling from conditional distributions. Pharm Res. 2016;33:2979–88.CrossRefGoogle Scholar
  21. 21.
    Chirehwa MT, McIlleron H, Rustomjee R, Mthiyane T, Onyebujoh P, Smith P, et al. Pharmacokinetics of pyrazinamide and optimal dosing regimens for drug-sensitive and -resistant tuberculosis. Antimicrob Agents Chemother. 2017;61:e00490.CrossRefGoogle Scholar
  22. 22.
    Zhu M, Starke JR, Burman WJ, Steiner P, Stambaugh JJ, Ashkin D, et al. Population pharmacokinetic modeling of pyrazinamide in children and adults with tuberculosis. Pharmacotherapy. 2002;22:686–95.CrossRefGoogle Scholar
  23. 23.
    Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT. Pharmacokinetic interactions with rifampicin. Clin Pharmacokinet. 2003;42:819–50.CrossRefGoogle Scholar
  24. 24.
    Yew WW. Clinically significant interactions with drugs used in the treatment of tuberculosis. Drug Saf. 2002;25:111–3.CrossRefGoogle Scholar
  25. 25.
    Yukawa E, To H, Ohdo S, Higuchi S, Aoyama T. Population-based investigation of valproic acid relative clearance using nonlinear mixed effects modeling: influence of drug–drug interaction and patient characteristics. J Clin Pharmacol. 1997;37:1160–7.CrossRefGoogle Scholar
  26. 26.
    Weiner IM, Tinker JP. Pharmacology of pyrazinamide: metabolic and renal function studies related to the mechanism of drug-induced urate retention. J Pharmacol Exp Ther. 1972;180:411–34.Google Scholar
  27. 27.
    Inayat N, Shah RH, Lakhair MA, Sahito R. Hyperuricemia and arthralgia during pyrazinamide therapy in patients with pulmonary tuberculosis. Pak J Chest Med. 2017;22:154–8.Google Scholar
  28. 28.
    Via LE, Savic R, Weiner DM, Zimmerman MD, Prideaux B, Irwin SM, et al. Host-mediated bioactivation of pyrazinamide: implications for efficacy, resistance, and therapeutic alternatives. ACS Infect Dis. 2015;1:203–14.CrossRefGoogle Scholar
  29. 29.
    McIlleron H, Wash P, Burger A, Norman J, Folb PI, Smith P. Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients. Antimicrob Agents Chemother. 2006;50:1170–7.CrossRefGoogle Scholar
  30. 30.
    Peloquin CA, Jaresko GS, Yong C, Keung AC, Bulpitt AE, Jelliffe RW. Population pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide. Antimicrob Agents Chemother. 1997;41:2670–9.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.School of PharmacyUniversity of the Western CapeBellvilleSouth Africa

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