Kibleur Yves, Brochart Hervé, Schaaf Hendrik S, Diacon Andre H, Donald Peter R
Lucane Pharma, 172 rue de Charonne, 75011, Paris cedex, France,
Clin Drug Investig. 2014 Apr;34(4):269-76. doi: 10.1007/s40261-014-0172-7.
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.
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.
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.
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.
耐多药结核病（MDR-TB）的再度流行引发了人们对对氨基水杨酸（PAS）及其他有效药物的新关注。一种胃内滞留型颗粒制剂（PAS-GR）的设计初衷是使其耐受性优于早期的PAS剂型，因间氨基酚生成减少而不良反应更少。PAS-GR颗粒中PAS的释放比早期制剂更慢。然而，药代动力学数据有限，仅有少数研究有助于确定最佳的PAS-GR给药方案。对优化后者的研究兴趣仍在持续，近期数据有助于更好地确定成人和儿童的最佳PAS-GR给药方案。本文借鉴这些近期研究，综合不同人群组的药代动力学结果，并与体外数据及早期药代动力学研究结果进行比较，以探讨PAS-GR最适宜的给药方案。
对相当于1g酸PAS的各种PAS和PAS-GR制剂进行了体外溶出度比较研究及体外-体内相关性研究。还收集了近期和早期临床研究之间的回顾性比较数据，以阐明成人和儿童PAS-GR的给药方案。
成人耐多药结核病患者每日两次或三次服用4g剂量方案后的暴露情况证实，两种给药方案均可使用。然而，每日两次给药方案在每日三次给药方案后血浆浓度“过高”的可能性方面并无任何安全余量，且当漏服一剂时可能导致剂量不足，因为依从性通常会随时间降低。
基于现有数据和实际考虑，在医院环境中，PAS-GR每日三次服用4g的给药方案应是首选剂量，基于PAS的最低抑菌浓度，该方案仍是全天候抑制分枝杆菌的最佳方案。在耐多药结核病成人患者及医院环境中，每日两次服用4g的给药方案并无安全优势。由于依从性对治疗效果至关重要，如果患者漏服一剂，每日三次服用4g的给药方案可能更具宽容性。
