Elsevier

Tuberculosis

Volume 92, Issue 1, January 2012, Pages 1-8
Tuberculosis

Review
Pyrazinamide pharmacokinetics and efficacy in adults and children

https://doi.org/10.1016/j.tube.2011.05.006Get rights and content

Summary

Pyrazinamide (PZA) is an essential sterilizing drug and with rifampicin enables six-month short-course antituberculosis chemotherapy. Despite routine use for nearly forty years uncertainty remains regarding the most appropriate PZA dosage for children. In view of this uncertainty literature relating to the efficacy and pharmacokinetics of PZA in children treated for tuberculosis and in adult volunteers and patients was reviewed. Making use of the PZA maximum concentration (Cmax) following various PZA dosages in different groups straight line regression of concentration on dosage was fitted through the origin by least squares and weighted for the numbers of subjects. The fitted line offers an approximation of the likely PZA Cmax that would result from a particular dosage. The slopes of Cmax/dosage of the fitted lines are 1.32 (SE 0.099) for paediatric patients, 1.36 (SE 0.051) for adult volunteers and 1.35 (SE 0.037) for adult patients; there is little difference between the Cmax concentrations achieved in children and adults, whether patients or healthy volunteers, following various mg/kg body weight dosages, suggesting that children and adults receiving the same mg/kg body weight PZA dosage will reach a similar Cmax. Children can receive the same mg/kg body weight PZA dosage as adults.

Highlights

► The literature describing the pharmacokinetics of PZA in children and adults is reviewed. ► The maximum serum concentrations of PZA reached in children following a range of dosages are compared to those reached in adults after the same dosages. ► The slopes of Cmax/dosage for paediatric patients (1.32; SE 0.099), adult volunteers (1.36; SE 0.037) and adult patients (1.35; SE 0.051) did not differ. ► Children receiving the same PZA dosage as adults will reach similar PZA serum concentrations.

Introduction

Pyrazinamide (PZA) is one of only five antituberculosis drugs currently recognized by World Health Organization (WHO) as essential and, in combination with rifampicin (RMP), makes possible short-course six-month antituberculosis regimens for most forms of tuberculosis. In contrast to usual paediatric practice, however, the same mg/kg body weight dosage of PZA has frequently been recommended for children and adults. This paper reviews publications providing details of PZA efficacy and pharmacokinetics after different dosages in adults and children and based on this evidence recommends an appropriate dosage of PZA for children.

Section snippets

Methods

This review emphasizes publications relating to the pharmacokinetics of PZA in children; papers giving details of pharmacokinetic findings in adults in relation to efficacy and dosage were also reviewed to provide perspective with regard to the childhood findings. The literature reviewed was obtained from an existing personal literature collection and a search of PubMed using the key words pyrazinamide, childhood, pharmacokinetics and pharmacodynamics, antituberculous and antimycobacterial.

The efficacy of PZA in relation to dosage

In 1945 Chorine reported that nicotinamide inhibited the growth of mycobacteria.1 This inhibitory effect, confirmed in experimental murine tuberculosis,2 led to the discovery of pyrazine-2-carboxylic acid amide (PZA) by groups from Lederle laboratories3 and Merck Laboratories.4 As was the case with isoniazid (INH), PZA had already been described previously,5 but its antibacterial qualities were not appreciated. The first report of the use of PZA in tuberculosis patients was by Yeager et al6 who

The pharmacokinetics of PZA

Assessed in both healthy adult volunteers and patients PZA is rapidly absorbed with a Tmax of approximately 1–2 h and a relatively long t1/2 of 8–11 h32, 33, 34 The serum concentrations of PZA increase in proportion to dosage and there is little intra-individual variation in absorption or excretion.32 The main metabolites of PZA are pyrazinoic acid, 5-hydroxy-pyrazinamide, 5-hydroxy-pyrazinoic acid, and pyrazinuric acid.32, 33 The absorption of PZA in volunteers has generally been described as

Discussion

This review provides a substantial amount of evidence that children are exposed to concentrations of PZA close to those of adults receiving equivalent mg/kg body weight dosages. Children could thus receive the same mg/kg dosages of PZA as adults and would reach the same degree of exposure to PZA as adults. In the case of children aged four years or less, however, circumspection is needed as some evidence suggests that such younger children receiving PZA dosages of 20–30 mg/kg are more likely to

Limitations

This review covers close to sixty years and analytical techniques, data analysis and presentation and regulations governing clinical trials have undergone radical changes during this period. None the less early papers, despite deficiencies, provide valuable insights into the efficacy and toxicity of agents due to the frequent use of monotherapy or two-drug therapy, which allows the actions of PZA to be more readily seen. In contrast to INH and RMP there is, however, relatively little data

Conclusion

This review demonstrates that in children similar mg/kg body weight dosages of PZA will lead to exposure to PZA serum or plasma concentrations similar to those in adults. In children younger than four years some data suggests that higher PZA dosages may be needed to reach concentrations similar to those in older children and adults, but more data is clearly needed for this group. In a recent revision of the dosages of antituberculosis agents to be used in children World Health Organization

Funding

None.

Competing interests

None declared.

Ethical approval

Not required.

Acknowledgements

This review was supported by a grant from WHO as part of the Better Medicines for Children project. The findings, interpretations and conclusions expressed in this paper are entirely those of the authors and should not be attributed in any manner whatsoever to WHO. PRD is supported by the National Research Foundation of South Africa.

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