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Dose Regimen of Para-Aminosalicylic Acid Gastro-Resistant Formulation (PAS-GR) in Multidrug-Resistant Tuberculosis

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Abstract

Background and Objectives

Resurgence of multidrug-resistant tuberculosis (MDR-TB) has raised a renewed interest in para-aminosalicylic acid (PAS) and other efficacious drugs. A gastro-resistant granule formulation (PAS-GR) was designed to be better tolerated than earlier forms of PAS, with fewer adverse effects from reduced production of meta-aminophenol. PAS release from PAS-GR granules is slower than with earlier formulations. Pharmacokinetic data are, however, limited and only a few studies have assisted in defining the best PAS-GR dose regimen. Interest in refining the latter continues and recent data contributed in better defining the optimal PAS-GR dose regimen in adults and children. The present paper draws on these recent studies, synthesizes pharmacokinetic results from different population groups, and draws comparisons with in vitro data and the results of earlier pharmacokinetic studies in order to discuss the most appropriate dosing regimen for PAS-GR.

Methods

A comparative in vitro dissolution study was carried out with a 1 g acid PAS equivalent of various formulations of PAS and PAS-GR and in vitro–in vivo correlations. Retrospective comparisons between recent and earlier clinical studies were also gathered to clarify the dose regimen of PAS-GR in adults and children.

Results

Exposure after a 4 g twice- or three times daily dose regimen in adult MDR-TB patients confirmed that both dose regimens can be used. The twice-daily dose regimen does not, however, confer any safety margin over the potentiality of “too” high plasma concentrations after a three times daily dose regimen and may lead to under-dosage when a dose is missed, as compliance often decreases over time.

Conclusions

Based on available data and practical considerations, a 4 g three times daily dose regimen of PAS-GR should be the preferred dose in hospital settings, where it remains the best regimen to cover the around-the-clock suppression of mycobacteria based on the minimal inhibitory concentration for PAS. In MDR-TB adults and in hospital settings, there is no safety advantage in administering a regimen of 4 g twice daily. As compliance is critical to the effectiveness of the treatment, a 4 g three times daily dose regimen may be more forgiving if the patient misses a dose.

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Authors and Affiliations

  1. Lucane Pharma, 172 rue de Charonne, 75011, Paris cedex, France

    Yves Kibleur

  2. RD Pharmagal SAS, Bld Gonthier d’Andernach, Parc d’Innovation, 67400, Illkirch, France

    Hervé Brochart

  3. Department of Paediatrics and Child Health and Desmond Tutu TB Centre, Faculty of Medicine and Health Sciences, University of Stellenbosch, Tygerberg, 7505, South Africa

    Hendrik S. Schaaf & Peter R. Donald

  4. Department of Molecular Biology and Human Genetics, and the MRC Centre for Molecular and Cellular Biology, DST/NRF Centre of Excellence for Biomedical TB Research, Faculty of Medicine and Health Sciences, University of Stellenbosch, Tygerberg, 7505, South Africa

    Andre H. Diacon

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  1. Yves Kibleur
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  2. Hervé Brochart
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  3. Hendrik S. Schaaf
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  4. Andre H. Diacon
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  5. Peter R. Donald
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Correspondence to Yves Kibleur.

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Kibleur, Y., Brochart, H., Schaaf, H.S. et al. Dose Regimen of Para-Aminosalicylic Acid Gastro-Resistant Formulation (PAS-GR) in Multidrug-Resistant Tuberculosis. Clin Drug Investig 34, 269–276 (2014). https://doi.org/10.1007/s40261-014-0172-7

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  • DOI: https://doi.org/10.1007/s40261-014-0172-7

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