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Variability in the population pharmacokinetics of pyrazinamide in South African tuberculosis patients

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

An Erratum to this article was published on 20 July 2006

An Erratum to this article was published on 20 July 2006

Abstract

Objective

This study was designed to characterize the population pharmacokinetics of pyrazinamide in South African pulmonary tuberculosis patients, with special reference to interindividual and interoccasional variability (IIV and IOV, respectively).

Methods

Concentration-time measurements obtained from 227 patients receiving oral doses of pyrazinamide were pooled to create a dataset containing 3,092 data points spanning multiple dosing occasions. The software program NONMEM was used to analyze the data.

Results

A one-compartment model with first-order absorption, including a zero-order component describing release from formulation, and first-order elimination best described the data. The absorption rate constant was estimated to be bimodally distributed between two distinct subgroups, fast and slow, in approximately even proportion. Absorption rate was threefold greater in fast absorbers (3.56 h−1) in comparison to slow absorbers (1.25 h−1). Typical values of oral clearance and apparent volume of distribution were estimated as 3.42 L h−1 and 29.2 l, respectively. IOV was supported in oral clearance (0.0238, variance) and absorption rate (0.623, variance). The duration of zero-order absorption was estimated as 0.290 h, and was quite variable between patients (0.957, variance).

Conclusion

The absorption of pyrazinamide in the studied population was highly variable and two separate subpopulations were identified. IOV accounted for a proportion of the variability in clearance and the absorption rate constant.

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Acknowledgements

We thank Jean van Dyk, Rudy Onia, Afia Fredericks and Alicia Evans for their invaluable technical and logistical assistance. We also wish to thank Bernard Fourie for allowing the use of some of the data included in this study. This research was co-funded by the South African Medical Research Council and by the Division of Clinical Pharmacology of the Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa. All work described here was carried out with full written ethical approval from the University of Cape Town, Brewelskloof Hospital and the D P Marais SANTA Centre, and complies fully with South African legal requirements for biomedical research.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Justin J. Wilkins, Grant Langdon, Helen McIlleron & Peter J. Smith

  2. Division of Pharmacokinetics and Drug Therapy, Department of Biopharmaceutical Sciences, Uppsala University, Uppsala, Sweden

    Justin J. Wilkins, Grant Langdon & Ulrika S. H. Simonsson

  3. Modeling & Simulation, Clinical Development & Medical Affairs, Novartis Pharmaceuticals AG, Basel, Switzerland

    Goonaseelan (Colin) Pillai

  4. Division of Clinical Pharmacology K45 Old Main Building, Groote Schuur Hospital, Observatory 7925, Cape Town, South Africa

    Helen McIlleron

Authors
  1. Justin J. Wilkins
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  2. Grant Langdon
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  3. Helen McIlleron
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  4. Goonaseelan (Colin) Pillai
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  5. Peter J. Smith
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  6. Ulrika S. H. Simonsson
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Corresponding author

Correspondence to Helen McIlleron.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00228-006-0178-z

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Wilkins, J.J., Langdon, G., McIlleron, H. et al. Variability in the population pharmacokinetics of pyrazinamide in South African tuberculosis patients. Eur J Clin Pharmacol 62, 727–735 (2006). https://doi.org/10.1007/s00228-006-0141-z

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  • DOI: https://doi.org/10.1007/s00228-006-0141-z

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