Fixed-dose combination and therapeutic drug monitoring in tuberculosis: friend or foe?

To the Editor:

Tuberculosis (TB) remains one of the world's deadliest infectious diseases. The World Health Organization (WHO) estimated that, in 2014 alone, 9.6 million people fell ill with TB and 1.5 million died due to the disease [1]. South-East Asia and Western Pacific Regions accounted for 58% of these [1]. As most deaths from TB can now be prevented, efforts must be accelerated to ensure the targets of the Sustainable Development Goals are reached [1].

Drug-susceptible TB is treated with first-line anti-TB drugs, consisting of 2 months of isoniazid, rifampicin, pyrazinamide and ethambutol, thereafter continued with only isoniazid and rifampicin for 4 months [2]. This treatment regimen achieves success rates of approximately 85% worldwide [1]. However, there is room for improvement as non-adherence and inappropriate prescription of TB therapy are believed to be key reasons of TB treatment failure and development of drug resistance [3]. Therefore, one of the WHO strategies to combat active TB was the introduction of fixed-dose combination (FDC) formulations. FDC tablets, containing two to four first-line anti-TB drugs, are used to simplify TB treatment and thereby increase compliance and reduce prescription errors [4]. A recent meta-analysis of 13 randomised controlled trials (RCTs), showed non-significant differences in negative treatment outcomes following treatment with FDC or single drug formulations of TB-drugs [5].

Over the last few years it has become clear that drug exposure of anti-TB drugs is of importance. A meta-analysis of 13 randomised studies showed that microbiological failure and relapse occur more frequently in rapid acetylators of isoniazid than in slow acetylators. Observed pharmacokinetic variability was significantly associated with therapeutic failure and acquired drug resistance [6]. Although high doses of isoniazid and rifampicin have been shown to be well tolerated [7], increasing doses of ethambutol and pyrazinamide have been shown to cause ocular- and hepatotoxicity respectively [8]. Additionally, anti-TB drug-induced liver injury is not uncommon, particularly in the Chinese population with an incidence of 13% in a recent study [9].

Therapeutic drug monitoring (TDM) is a technique that allows individual dosing based on drug plasma concentrations. The use of TDM is considered useful for an effective and well-tolerated treatment regimen [10]. Problems related to TDM, for instance costs, logistics and invasiveness, can be addressed by using new tools such as limited sampling, dried blood spots (DBS) and simultaneous analysis of all first-line anti-TB drugs [8, 10, 11]. Ghimire et al. [11] suggest a programmatic setting for performing TDM with these new tools, which seems feasible for global use. Even though the costs of performing TDM are estimated to be US$560 for testing the four first-line drugs, this expense is negligible if a case of multidrug-resistant (MDR)-TB can be avoided [12].

However, the “number of patients needed to perform TDM”, defined by the number of patients who need to be subjected to TDM to prevent acquired MDR-TB in one patient will determine the true effectiveness of this health-care intervention. As variability in drug exposure and acquired drug resistance can differ per setting collection of local data is important to make a well-informed decision on implementation of TDM.

One might think that implementation of TDM in programmatic treatment will end the use of FDC, since each individual drug would have to be dosed based on the drug plasma concentration. However, the opposite may be true. Therefore, the aim of this contribution is to discuss the role of TDM in further improving efficacy, safety and tolerability of FDC regimens. To illustrate our proposal, we present practical advice for TDM and FDC tablet selection in a relevant clinical setting.

Given the overall relevance and availability of information, the chosen setting to exemplify this is China.

In our strategy to combine TDM and FDC, we included first-line drugs (i), available FDC tablets (ii), choice of FDC tablets in combination with TDM (iii) and logistical considerations (iv). For this example we have made the following assumptions. i) Based on previous studies, early dose adjustment of pyrazinamide, rifampicin and isoniazid are needed in order to prevent acquired drug resistance 2 months after start of treatment and improve long-term treatment outcome [13]. ii) Current standard TB treatment for adults consists of isoniazid 5 mg·kg⁻¹; rifampicin 10 mg·kg⁻¹; pyrazinamide 25 mg·kg⁻¹ and ethambutol 15 mg·kg⁻¹, dependent on weight [2]. FDC tablets based on these doses have been developed to enable weight-banded dosing. iii) TDM is suggested only in patients with a higher risk of insufficient plasma concentrations [10], since it is neither feasible nor cost-effective to perform TDM in all patients [12]. TDM should be performed 2 weeks after start of drug-susceptible anti-TB treatment. Based on plasma concentrations, the appropriate FDC tablets can be selected. Two weeks after dose adjustment, the drug concentrations have to be confirmed. In the continuation phase, the appropriate FDC combination of rifampicin and isoniazid can be selected, based on earlier measured drug concentrations. We consider drug exposure that differs at least 25% from target concentrations as clinically relevant, in accordance with Drug regulatory agencies' guidelines. iv) Patients from rural areas in China could use dried blood spots sampling for TDM at a community health centre, to enable TDM in resource-limited settings.

The results of these assumptions have led to a practical and simple approach for FDC tablet selection and implementation of TDM in a clinical setting, exemplified in figure 1. In the case of drug exposure below the target value, the dose should be increased. The plasma concentration of the drug showing the lowest concentration is the starting point for increasing the daily dose FDC containing all four first-line anti-TB drugs. Although one may be worried about toxic concentrations of the other drugs, this is suspected to be overestimated as the percentage of the dose increase did not exceed 25%. Only when pyrazinamide or ethambutol are above target value, is the dose lowered, as higher doses of isoniazid and rifampicin are considered to be safe and well tolerated [7]. Although limited evidence suggests a higher dose of pyrazinamide is safe [14], we recommend caution while waiting for the results from clinical trials. However, pyrazinamide has been found to play an important role in anti-TB treatment; therefore, it should not be ignored, but adjusted, keeping toxicity in mind [13]. Additionally, follow-up measurements after dose adjustment assure that dose interventions are successful and too high drug exposure will not go unnoticed. The role of ethambutol in first-line anti-TB treatment is still up for debate, however the WHO no longer recommends omission of ethambutol and therefore it was incorporated in figure 1 [2].

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FIGURE 1

Example of fixed-dose combination (FDC) and therapeutic drug monitoring (TDM) in a programmatic setting in China. Following referral from all levels of health facilities, tuberculosis (TB) diagnosis is made by sputum smear and radiographic examination, followed by starting standard treatment with first-line anti-TB drugs isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) in a TB-designated hospital/clinic. The community health centre is appointed to commence directly observed treatment, short course. Blood sample collection is to be performed by the designated hospital/clinic after 2 weeks of treatment as part of TDM. After 2 weeks, plasma concentrations can be measured again by dried blood spot (DBS) sampling at the community health centre and if the plasma concentrations of isoniazid, rifampicin and/or pyrazinamide are too low, 1x HR or 1x HRZ is added. ^#: the number of FDCs daily is based on the weight of the patient: 30–37 kg=2; 38–54 kg=3; 55–70 kg=4 and ≥71 kg=5. HR=75/150 mg HRZ=80/120/250 mg, HRZE=75/150/400/275 mg.

Furthermore, TDM can also be used to detect non-adherence early-on, which is thought to be one of the reasons of failure, relapse and resistant TB [3]. This is especially useful in China, where there is a high prevalence of non-adherence to TB treatment as well as resistant TB, with 11% of all TB cases being MDR-TB [1, 15]. Detecting non-adherence by plasma sampling is a more reliable and practical method than urine testing, since drug plasma concentrations cannot be determined from urine. Additionally, since the rapid acetylator status is most common amongst the Asian population, TDM might also be of importance in this subpopulation in preventing suboptimal plasma-concentrations of isoniazid [6].

In settings with limited resources, we suggest to prioritise TDM for selected patients, such as patients with slow sputum conversion, risk of drug–drug interactions and comorbidities increasing the risk of low drug exposure (such as diabetes mellitus, HIV, gastro-intestinal disorders and other malabsorption diseases) [10].

We favour the use of FDC to simplify treatment and encourage the implementation of TDM. Recommendations in WHO and scientific communities' TB treatment guidelines about how and when to perform TDM should not only facilitate individual physicians in optimising treatment, but also facilitate policy makers in implementing TDM into National programmes.