Abstract
Purpose: The pharmacokinetics (PK) of anti-tuberculosis drugs, including their bioavailability (BA), significantly impacts the efficacy and effectiveness of tuberculosis (TB) treatment regimens. Rifampicin, one of the most important drugs in the treatment of drug-sensitive tuberculosis, has been used increasingly in fixed-dose combinations (FDCs). This paper reviews and analyzes available data on BA and PK of rifampicin with a focus on FDCs, from published studies and reports. Methods: Using PubMed as the primary database, Cochrane and other relevant databases, a systematic review of literature was conducted to identify studies on the bioavailability and efficacy of rifampicin in FDCs versus single drug formulations. A number of keywords including “bioavailability”, “rifampicin”, “fixed dose combinations”, and “pharmacokinetics” were used in various combinations. The search covered the period 1980 to 2016. Priority was given to articles on rifampicin bioavailability in fixed dose combinations used in the program setting, and human studies that used the World Health Organization (WHO) approved BA/PK protocol and sample size (≥22 patients). Findings: More than 450 original peer-reviewed articles, reviews and reports, were assessed for this analysis. Eleven papers, which included data from high-TB-burden countries (South Africa, India, and China), raised significant concerns about rifampicin bioavailability within FDCs; the authors of the studies discussed multiple factors associated with low bioavailability, including drug formulation and quality, storage environment, patient factors, and concomitant diseases. Implications: Recent studies and reviews point to the problem of low bioavailability of rifampicin in fixed dose combinations. However, in the field, it remains a hidden or unrecognized factor leading to poor treatment outcomes. It is difficult to study the issue thoroughly unless there is awareness among TB program personnel of its existence, and adequate laboratory and research support is available to national tuberculosis programs (NTPs). In stemming the tide of tuberculosis multi-drug resistance (MDR) and extensive drug resistance (XDR), it is paramount to ensure that rifampicin bioavailability is adequate in FDCs, and to detect and address any deviation from recommended target ranges. There is a need for strategies to minimize the undesirable clinical effects of reduced rifampicin bioavailability in FDCs, and for effective utilization of quality-assured drugs within NTPs programs; these can help NTPs support effective case management in line with the international TB care standards, while taking into consideration the factors affecting drug absorption and therapeutic concentration.
Highlights
The emergence of drug-resistant tuberculosis (DR-TB) is a majorSadaphal P, Chakraborty K, Almossawi HM, Pillay Y, Roscigno G, Kaul A, Kak N, Matji R, Mvusi L, Destefano A
Eleven papers, which included data from high-TB-burden countries (South Africa, India, and China), raised significant concerns about rifampicin bioavailability within fixed-dose combinations (FDCs); the authors of the studies discussed multiple factors associated with low bioavailability, including drug formulation and quality, storage environment, patient factors, and concomitant diseases
In the review of full-text articles and original papers, priority was given to articles on rifampicin bioavailability in fixed dose combinations used in the program setting
Summary
The emergence of drug-resistant tuberculosis (DR-TB) is a majorSadaphal P, Chakraborty K, Almossawi HM, Pillay Y, Roscigno G, Kaul A, Kak N, Matji R, Mvusi L, Destefano A. Rifampicin Bioavailability in Fixed-Dose Combinations for Tuberculosis Treatment: Evidence and Policy Actions. Journal of Lung Health and Diseases public health concern across the globe and in tuberculosis (TB) high-burden countries. There are alarming reports of increasing drug resistance from various parts of the world which potentially threaten to disrupt the gains achieved in tuberculosis (TB) control over the last decade and global progress towards achieving the targets of the End TB strategy. In 2017, there were 558,000 new TB cases with resistance to rifampicin, the most effective first-line drug, of which 82% had multidrug-resistant TB (MDR-TB). MDR-TB is essentially a man-made phenomenon and arises due to inadequate treatment of drug-sensitive TB (DS-TB). The prevalence of MDR-TB mirrors the functional state and efficacy of tuberculosis control programs in the country
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