Isoniazid, pyrazinamide and rifampicin content variation in split fixed-dose combination tablets.

Thomas Pouplin,Julie Nguyen Pouplin,Pham Van Toi,Pham Nguyen Phuong,Jeremy Farrar,Daniel S Sem

doi:10.1371/journal.pone.0102047

Abstract

SettingIn most developing countries, paediatric tuberculosis is treated with split tablets leading to potential inaccuracy in the dose delivery and drug exposure. There is no data on the quality of first-line drugs content in split fixed-dose combination tablets.ObjectiveTo determine Isoniazid, Pyrazinamide and Rifampicin content uniformity in split FDC tablets used in the treatment of childhood tuberculosis.DesignDrug contents of 15 whole tablets, 30 half tablets and 36 third tablets were analysed by high performance liquid chromatography. The content uniformity was assessed by comparing drug content measured in split portions with their expected amounts and the quality of split portions was assessed applying qualitative specifications for whole tablets.ResultsAll whole tablets measurements fell into the USP proxy for the three drugs. But a significant number of half and third portions was found outside the tolerated variation range and the split formulation failed the requirements for content uniformity. To correct for the inaccuracy of splitting the tablets into equal portions, a weight-adjustment strategy was used but this did not improve the findings.ConclusionIn split tablets the content of the three drugs is non-uniform and exceeded the USP recommendations. There is an absolute need to make child-friendly formulations available for the treatment of childhood tuberculosis.

Highlights

Tuberculosis (TB) is an increasing global public health challenge which is highly dependent on social and economic factors that significantly affect health care delivery
A significant number of half and third portions was found outside the tolerated variation range and the split formulation failed the requirements for content uniformity
Tuberculosis in childhood is neglected with the evidence for treatment and clinical care mostly extrapolated from studies in adults [1]

Summary

Introduction

Tuberculosis (TB) is an increasing global public health challenge which is highly dependent on social and economic factors that significantly affect health care delivery. When patient’s body weight stands below 15 kilos, tablets are split in halves or third and in extremely rare case (i.e. new born) quarters are to be used This regimen is still based on a body-weight scale, for the youngest patients, body surface area scale has been proposed to enhance the exposure [5,8]. Active ingredients are confined and protected by a film-coating process, but the drug may not be uniformly distributed in split portions Breaking this layer increases the surface area, affects the stability of drugs and affects the bioavailability. This is especially expected for RIF, the most unstable of the three anti-TB drugs contained in the FDC tablets [9,10]. No quality assured version of such products is known to be readily available

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