PharmD Florian Lemaitre
email: florian.lemaitre@chu-rennes.fr

Has the time come for systematic therapeutic drug monitoring of first-line and WHO group-A antituberculosis drugs?

Keywords: antituberculous, pharmacokinetics, pharmacodynamics, exposure, rifampicin, isoniazid, ethambutol, pyrazynamide, fluoroquinolones, linezolid, bedaquiline

Tuberculosis (TB) is a major global health issue, with around 10 million people being infected each year and is the leading cause of mortality from infectious disease with 1.5 million death each year. Optimal TB treatment requires drugs combination for an adequate treatment duration due to persistent organisms, hardly accessible infection sites and high risk of resistance selection. This multidrug, longterm therapy raises the risk of patients' loss of adherence, adverse drug reaction and drug-drug interactions potentially leading to treatment failure. The high inter-patient variability of TB drugs exposure is another point eliciting the interest of therapeutic drug monitoring (TDM) to optimize treatment. Studies reported clinically relevant exposure thresholds, which might be proposed as targets to take a step in treatment personalization are discussed. Practical TDM strategies have also been reported to circumvent issues related to delayed drug absorption and the need for multiple samples when evaluating area under the curve of drug concentrations. The arisen of multi-drug Accepted manuscript / Final version resistant TB or extensively-drug resistant TB advocates as well for treatment individualization. Finally, the willingness to shorten the treatment duration while maintaining success is also a driver of ensuring adequate exposure to TB drugs with TDM. The aim of the present review is to underline the role of TDM for drug-susceptible and World Health Organization group-A TB drugs.

Introduction:

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis, is a major global health issue, with around 10 million people being infected each year and is the leading cause of mortality from infectious disease with 1.5 million death each year (1). Optimal TB treatment requires the association of anti-TB drugs for an adequate treatment duration due to persistent organisms, hardly accessible infection sites and high risk of resistance selection. Usual treatment relies on isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) combination, which can be formulated into fixeddose association. This long-term, multidrug therapy makes the adherence difficult for patients and threatens drug treatment exposure, which might be related to treatment outcome. These drugs also display pharmacokinetic variability leading to hardly predictable plasma drug exposure and finally drug exposure at the site of infection. For example, in a large cohort of tuberculosis patients identified sex, weight adjusted-dosage, drug formulation, liver parameters, HIV-status and albumin as related sources of pharmacokinetic variation for one or more of the HRZE drugs [START_REF] Mcilleron | Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients[END_REF]. Besides, TB treatment can lead to significant drug-drug interactions both within the TB therapy and towards drugs prescribed to patients outside of this indication. Therapeutic drug monitoring (TDM) can then be a tool to optimize TB treatment offering a strategy to maximize drug efficacy while limiting the onset of concentration-dependent adverse drug reaction (ADR). TB treatment is not limited to these four drugs used in susceptible infection. As drug resistance grows in the spectrum of Mycobacterium tuberculosis resulting in multi-drug resistant TB (MDR-TB) or extensively-drug resistant TB (XDR), second-line agents including fluoroquinolones, clofazimine, cycloserine, ethionamid, linezolid, aminoglycosides and pamino salicylic acid joined the therapeutic armamentarium and are added or replaced drugs in the HRZE treatment. Recently approved drugs, bedaquiline, delamanid and pretomanid also showed promising results. These agents may as well benefited from TDM. Globally, with a rate of treatment success reported to be approximately 85% for sensitive-TB but which can be as low as 57% with MDR-TB, TB treatment can still be improved and TDM is one of the levers allowing take a step in optimizing outcome (3). Shortening the TB treatment is now a commonly accepted objective and ensuring an adequate drug exposure with the use of TDM appears crucial in such strategies.

The aim of the present review is to underline the role of therapeutic drug monitoring during TB treatment. This review will be limited to the drugs used for drug-susceptible TB and World Health Organization (WHO) group A drugs for drug-resistant TB (table 1).

Summary of pharmacokinetics and pharmacodynamics of drugs used to treat TB

Rifampicin:

Rifampicin (RFP) is a rifamycin drug used to treat susceptible Mycobacterium tuberculosis infections.

The drug is usually given once a day (QD) at the dose of 10 mg/kg or 600 mg QD either orally (on an empty stomach) or intravenously but increased dosage up to 35 mg/kg/day reduces the time to sputum conversion [START_REF] Boeree | High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial[END_REF]. The drug presents a large inter-individual variability of its concentrations, a short half-life and is a potent metabolism inducer including its own metabolism [START_REF] Abulfathi | Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis[END_REF]. Among factors resulting in decrease exposure, sex, fixed-dose combination (FDC) and HIV-status can be cited. On the opposite, increase in weight-adjusted drug dosage and bilirubin level can lead to increase RFP exposure Accepted manuscript / Final version [START_REF] Mcilleron | Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients[END_REF]. The time to maximal concentration (T max ) is usually reached in 2 hours but with some patients and circumstances where delayed absorption and longer Tmax can be elicited for example by food intake or diabetes mellitus [START_REF] Kumar | Anti-tuberculosis drug concentrations in tuberculosis patients with and without diabetes mellitus[END_REF]. RFP inhibits DNA-dependent RNA polymerase bacterial enzymes and is active against extracellular and intracellular Mycobacterium tuberculosis. Peak concentration (C max ) and area under the curve of drug concentrations (AUC) correlates with the bactericidal efficacy and resistance onset of rifampicin in models [START_REF] Jayaram | Pharmacokineticspharmacodynamics of rifampin in an aerosol infection model of tuberculosis[END_REF][START_REF] Gumbo | Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin[END_REF]. Rifamipicin trough concentration (C min ) is frequently low / below the limit of quantification of method assays and then correlates poorly with the drug exposure (9).

Isoniazid:

Isonicotinyl hydrazine or isoniazid (INH) is a potent bactericidal drug against Mycobacterium tuberculosis acting as an inhibitor of mycolic acid synthesis, which are major constituents of the mycobacteria wall. The drug is administered at the dose of 4-5 mg/kg QD but some in-vitro data suggest that doses up to 10-15 mg/kg may be needed for resistant strains [START_REF] Lange | Perspectives for personalized therapy for patients with multidrug-resistant tuberculosis[END_REF]. INH is rapidly resorbed and C max occurs 1-2h after drug intake. INH is a substrate of the N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) metabolic enzymes. These enzymes are encoded by polymorphic genes, which can lead to different phenotypes. NAT2 produces acetylhydrazine which can then be transformed by CYP2E1 into hepatotoxins [START_REF] Erwin | Pharmacokinetics of isoniazid: The good, the bad, and the alternatives[END_REF]. Slow metabolizers for NAT2 are then at higher risk of hepatotoxicity [START_REF] Metushi | Mechanism of isoniazid-induced hepatotoxicity: then and now[END_REF]. On the other hand, rapid acetylators might be at higher risk of treatment failure as suggested by a randomized controlled trial where early failure where reduced in this sub-population of patients with the use of a pharmacogenetic-guided approach [START_REF] Azuma | NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month fourdrug standard treatment of tuberculosis: a randomized controlled trial for pharmacogeneticsbased therapy[END_REF]. Sex and FDC contribute to exposure decrease while age, weight-adjusted drug dosage increase, and increase in gamma-glutamyl transferase level increase drug exposure [START_REF] Mcilleron | Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients[END_REF]. The efficacy and resistance onset prevention has been shown to be related to the AUC/Minimum Inhibitory Concentration (MIC) and the C max /MIC ratios in pre-clinical models [START_REF] Gumbo | Isoniazid bactericidal activity and resistance emergence: integrating pharmacodynamics and pharmacogenomics to predict efficacy in different ethnic populations[END_REF].

Pyrazinamide:

Pyrazinamide (PZA) is a prodrug converting in vivo into its active component pyrazinoic acid. It inhibits semi-dormant, persisting microorganisms and has the ability to remain active in an acidic environment like inside macrophages, which makes its mechanism of action distinctive from other TB drugs. PZA is administered at the dose of 25 mg/kg/d QD. The dosage can be increased up to 35 mg/kg/d in some situations (notably in children) as the usual dosage may result in significant underexposure. Median C max obtained is usually around 50 µg/mL but can be lower in HIV patients particularly in case of profound immunodeficiency [START_REF] Chideya | Isoniazid, rifampin, ethambutol, and pyrazinamide pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort of adults with tuberculosis from Botswana[END_REF]. On the opposite, weight-adjusted dosage increase and bilirubin elevation are reported factors associated with increase in drug exposure [START_REF] Mcilleron | Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients[END_REF]. A pharmacokinetic/pharmacodynamics (PK/PD) approach using a hollow-fiber infection model revealed the EC 90 for PZA to be reached for a AUC 0-24 /MIC ratio above 209 [START_REF] Gumbo | Pharmacokinetics-pharmacodynamics of pyrazinamide in a novel in vitro model of tuberculosis for sterilizing effect: a paradigm for faster assessment of new antituberculosis drugs[END_REF]. The safety profile of PZA is dominated by the risk of hepatotoxicity and hyperuricemia.

Ethambutol:

Ethambutol (ETH) is considered as the fourth antituberculosis drug used in the prevention of RFP resistance in INH resistant strains. It is a bacteriostatic drug inhibiting the synthesis of the mycobacterial cell wall. The drug is usually administered at the dose of 15-20 mg/kg QD and up to 25 mg/kg. ETH presents a large PK variability but with few delayed absorption profiles [START_REF] Zhu | Pharmacokinetics of ethambutol in children and adults with tuberculosis[END_REF]. Sex, HIVstatus, increase in albumin level and ETH retreatment are associated with decrease in drug exposure.

Higher weight-adjusted doses and older patients had increased exposure [START_REF] Mcilleron | Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients[END_REF]. In models, the drug efficacy is best predicted by both C max /MIC and AUC/MIC ratios [START_REF] Alffenaar | Integrating Pharmacokinetics and Pharmacodynamics in Operational Research to End Tuberculosis[END_REF]. Optical neuropathy (i.e the most concerning adverse effect with the drug) seems to occur with a higher frequency in patients treated with higher dosage, suggesting an impact of exposure on toxicity [START_REF] Hasenbosch | Ethambutol-induced optical neuropathy: risk of overdosing in obese subjects[END_REF].

Fluoroquinolones:

Levofloxacin and moxifloxacin are the fluoroquinolnes recommended by WHO in case of drug-resistant TB (table 1). Moxifloxacin is also an attractive alternative to INH, ETH or as an add-on to HRZE therapy to shorten drug-susceptible TB treatment to a 4-month regimen but there are concerns that such a strategy might lead to increase relapses. These drugs are orally well resorbed and their T max are usually obtained 1 hour post-dose. As for other TB drugs, fluoroquinolones exhibit a large inter-individual variability of plasma exposure. For example, the moxifloxacin plasma exposure for patients treated with 400 mg/d can range up to nine-fold [START_REF] Pranger | Evaluation of moxifloxacin for the treatment of tuberculosis: 3 years of experience[END_REF]. Hollow fiber infection models show that a free AUC0- 24 /MIC ratio of 132.9 allows achieving 1.0 Log CFU kill relative to baseline for moxifloxacin in the acidified pH environment. Data from this model also suggest that increasing moxifloxacin dosage to 800 mg/d might influence the resistance emergence [START_REF] Gumbo | Pharmacokinetics-pharmacodynamics of pyrazinamide in a novel in vitro model of tuberculosis for sterilizing effect: a paradigm for faster assessment of new antituberculosis drugs[END_REF]. For levofloxacin, a (total drug) AUC 0-24 /MIC ratio of 146 might maximize bactericidal effect while an AUC 0-24 /MIC ratio of 360 should be targeted to avoid resistance selection [START_REF] Deshpande | Levofloxacin Pharmacokinetics/Pharmacodynamics, Dosing, Susceptibility Breakpoints, and Artificial Intelligence in the Treatment of Multidrug-resistant Tuberculosis[END_REF][START_REF] Heinrichs | Dose optimization of moxifloxacin and linezolid against tuberculosis using mathematical modeling and simulation[END_REF]. A dosage regimen of 750-1000 mg/d and 1500-1750 mg/d might be needed to reach PK/PD objectives with levofloxacin when MIC are 0.5 mg/L or 1 mg/mL, respectively [START_REF] Al-Shaer | Fluoroquinolones in Drug-Resistant Tuberculosis: Culture Conversion and Pharmacokinetic/Pharmacodynamic Target Attainment To Guide Dose Selection[END_REF]. Safety concerns with fluoroquinolones include: phototoxicity, tendinopathy, neurotoxicity and, mainly for moxifloxacin, QTc prolongation which can lead to arrhythmia. Some of these adverse drug reactions can be related to drug accumulation in patients [START_REF] Stahlmann | Risks associated with the therapeutic use of fluoroquinolones[END_REF].

Other WHO group A drugs

Limited data exists for other second-line agents. Among these drugs, linezolid and bedaquiline belong to the WHO group A classification, that is the most effective treatments for TB (table 1). Bedaquiline is an inhibitor of the subunit c and the subunit ε of the mycobacterial ATP synthase of Mycobacterium tuberculosis. The drug has a T max at 5h and is a CYP3A4 substrate with a long terminal half-life (around 170h). It requires then a 2-week loading dose to reach therapeutic steady-state concentrations. Its main metabolite M2 has a limited antimycobacterial activity [START_REF] Esposito | Bedaquiline and delamanid in tuberculosis[END_REF]. The drug is associated with Qtc Accepted manuscript / Final version prolongation. Svensson and Karlsson have modeled PK and PD data obtained from phase IIb revealing a probable relationship between drug exposure and culture conversion. In this study, the estimated EC 50 was 1.42 mg/L but should be considered informative only for MDR-TB patients (i.e the population of the phase IIb study) [START_REF] Svensson | Modelling of mycobacterial load reveals bedaquiline's exposureresponse relationship in patients with drug-resistant TB[END_REF].

Linezolid is an oxazolidinone drug and a recent option for MDR and XDR-TB. The AUC 0-24 /MIC is the best PK/PD parameter related to LNZ efficacy. During log-phase growth, a free linezolid AUC 0-24 /MIC of 35.6 has been reported as a target for resistance suppression in a hollow fiber infection model. To reach a 1.0 Log CFU/mL kill relative to baseline in the acidic phase, a free AUC 0-24 /MIC of 88.8 is proposed [START_REF] Heinrichs | Dose optimization of moxifloxacin and linezolid against tuberculosis using mathematical modeling and simulation[END_REF]. These values, given the protein binding of the drug, are closed to another PK/PD study showing that EC 80 is obtained with an AUC 0-24 /MIC of 119 and a 1.0 Log CFU/mL kill with an AUC 0-

Concentration-controlled studies in patients

Low exposure to anti-TB drugs is a frequent situation. Globally, using 2-hour post-dose as an indicator of exposure and a threshold of 8, 3, 2 and 35 µg/mL for RFP, INH, ETH and PZA, respectively, a metaanalysis of 41 studies showed that low exposure to be 67, 43, 27 and 12% for these drugs, respectively [START_REF] Mota | Therapeutic drug monitoring in anti-tuberculosis treatment: a systematic review and meta-analysis[END_REF]. In a large phase II, triple-blind, randomized, placebo-controlled, dose-ranging clinical trial comparing RFP delivered orally at 10, 15, or 20 mg/kg combined with weight-based INH, PZA and ETH, Peloquin and colleagues reported that 67% of patients in the 10 mg/kg group and 19% of patients in the 20 mg/kg did not reach the RIF C max threshold of 8 µg/mL. Fifty percent of the patients had INH and ETH below 2.3 µg/mL and 1.7 µg/mL respectively [START_REF] Peloquin | Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis[END_REF]. This low drug exposure can also be common in specific population such as HIV patients where, in patients receiving 600 mg daily, 77% of patients of small cohort presented a RFP peak concentration below 8 µg/mL [START_REF] Perlman | The clinical pharmacokinetics of rifampin and ethambutol in HIV-infected persons with tuberculosis[END_REF]. The large pharmacokinetic variability reported in the previous part explained at least partly these frequent low drug exposures.

Besides, a number of studies explored the impact of TB drug exposure on treatment efficacy or drugrelated adverse events.

In a randomized controlled trial comparing RFP 10 mg/kg, 15 mg/kg and 20 mg/kg, Velazquez and colleagues showed that in the per protocol population, but not in the intention-to-treat population, that RIF AUC 0-6h correlated with the Log colony forming unit in the sputum of patients [START_REF] Velásquez | Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial[END_REF] In a South-African study conducted in patients hospitalized during the first 2 months and treated for TB with RFP (600 mg or 450 mg if bodyweight was less than 50 kg), INH (300 mg/d), PZA [START_REF] Pranger | Evaluation of moxifloxacin for the treatment of tuberculosis: 3 years of experience[END_REF][START_REF] Deshpande | Levofloxacin Pharmacokinetics/Pharmacodynamics, Dosing, Susceptibility Breakpoints, and Artificial Intelligence in the Treatment of Multidrug-resistant Tuberculosis[END_REF][START_REF] Heinrichs | Dose optimization of moxifloxacin and linezolid against tuberculosis using mathematical modeling and simulation[END_REF][START_REF] Al-Shaer | Fluoroquinolones in Drug-Resistant Tuberculosis: Culture Conversion and Pharmacokinetic/Pharmacodynamic Target Attainment To Guide Dose Selection[END_REF][START_REF] Stahlmann | Risks associated with the therapeutic use of fluoroquinolones[END_REF][START_REF] Esposito | Bedaquiline and delamanid in tuberculosis[END_REF][START_REF] Svensson | Modelling of mycobacterial load reveals bedaquiline's exposureresponse relationship in patients with drug-resistant TB[END_REF][START_REF] Srivastava | Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis[END_REF][START_REF] Mota | Therapeutic drug monitoring in anti-tuberculosis treatment: a systematic review and meta-analysis[END_REF][START_REF] Peloquin | Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis[END_REF][START_REF] Perlman | The clinical pharmacokinetics of rifampin and ethambutol in HIV-infected persons with tuberculosis[END_REF][START_REF] Velásquez | Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial[END_REF][START_REF] Weiner | Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine[END_REF][START_REF] Pasipanodya | Serum drug concentrations predictive of pulmonary tuberculosis outcomes[END_REF][START_REF] Sekaggya-Wiltshire | Delayed Sputum Culture Conversion in Tuberculosis-Human Immunodeficiency Virus-Coinfected Patients With Low Isoniazid and Rifampicin Concentrations[END_REF][START_REF] Lee | Linezolid for treatment of chronic extensively drug-resistant tuberculosis[END_REF] mg/kg/d) and ETH (15 mg/kg/d), Pasipanodya and colleagues explored the predicting factors for sputum conversion at month-2 as well as long-term outcomes. Using a CART analysis, they identified the PZA peak > 58.3 µg/mL followed by a RFP peak > 6.6 µg/mL and a INH peak > 8.8 µg/mL to be the main factors for sputum conversion [START_REF] Pasipanodya | Serum drug concentrations predictive of pulmonary tuberculosis outcomes[END_REF]. Regarding long-term outcomes, 25% of patients had poor outcome (mainly relapses or failures) and AUC 0-24 of PZA, RFP, and INH were the most predictive factors of patients' clinical course. Thresholds associated where 363 µg.h/mL for PZA, 13 µg.h/mL for RFP, and 52 µg.h/mL for INH. Having all the 3 drugs exposure above these thresholds was associated with a 88% chance of treatment success while success was just 48% in patients with only 1 drug above the threshold. Recently, a large (n=268) prospective, observational study conducted in HIV-infected patients in Uganda showed that patients with at least one TB-drug with a low C max (<3 µg/mL for INH, <8 µg/mL for RFP, <20 µg/mL for PZA, <2 µg/mL for ETH) presented less sputum conversion during treatment [START_REF] Sekaggya-Wiltshire | Delayed Sputum Culture Conversion in Tuberculosis-Human Immunodeficiency Virus-Coinfected Patients With Low Isoniazid and Rifampicin Concentrations[END_REF]. In this study, patients had an adjusted 60% and 74% reduction chance of culture conversion with one drug and two drugs below the recommended C max , respectively, when compared with patients having no TB-drugs below the recommended C max threshold. Despite a high proportion of patients with low exposure, the treatment failure rate in this study was low (4.4%).

Another large (n=225) study conducted in Botswana has assessed the relationship between TB-drug exposure and clinical outcome in HIV (69%) and non-HIV patients. Patients received 300 mg INH, 450 mg RFP, 1000 mg ETH and 1500 mg PZA if their weight was below 50 kg and 400 mg INH, 600 mg RFP, 1200 mg ETH and 2000 mg PZA if their weight exceeded 50 kg. In this study, poor treatment outcomes occurred three-times higher in patients with PZA C max below 35 µg/mL (50.0 versus 15.7%, p<0.01) regardless of HIV infection status [START_REF] Chideya | Isoniazid, rifampin, ethambutol, and pyrazinamide pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort of adults with tuberculosis from Botswana[END_REF].

In a small (n=41) randomized study comparing linezolid 600 mg versus 300 mg in chronic resistant tuberculosis, Lee and colleagues did not find any relationship between peak or trough concentration and time to culture conversion. However, the group taking 600 mg had an 2.7 times increased risk of adverse events when compared to the 300 mg group [START_REF] Lee | Linezolid for treatment of chronic extensively drug-resistant tuberculosis[END_REF]. A post-hoc analysis of the data obtained from this study identified a threshold of C min of 2 µg/mL for ADR. Every patients presenting a Cmin above 2 µg/mL had ADRs, a rate falling to 58% of patients when C min was below 2 µg/mL [START_REF] Lee | Linezolid for treatment of chronic extensively drug-resistant tuberculosis[END_REF].

The case for TB meningitis may require higher drug exposure. In a randomized intensification treatment study, Te Brake et al. explored the relationship between anti-TB drugs exposure and survival in this indication. Patients received standard RFP (10 mg/kg orally) or intensified RFP (13 mg/kg intravenously) treatment combined with either standard moxifloxacin (400 mg/d), high dose moxifloxacin (800 mg/d) or ETH (750 mg/d). All patients also received INH 300 mg, PZA 1500 mg and corticosteroids. There was a relationship between RFP exposure and survival and concentrationresponse curves allows estimating a minimum target AUC 0-6h of 70 µg.h/mL, AUC 0-12h of 1156 µg.h/mL and a C max of 22 µg/mL [START_REF] Brake | Pharmacokinetic/pharmacodynamic analysis of an intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis[END_REF].

Finally, the field is still lacking of a randomized clinical trial aiming at comparing the benefit of a TDMguided over a standard approach.

Accepted manuscript / Final version

Proposed exposure threshold based on clinical data are summarized in table 2.

TDM implementation in clinical practice

As already stated, when measuring plasma trough concentrations, observed values are frequently below the limit of quantification of assay methods. This implies that C min is not an appropriate surrogate for AUC and then, for drug exposure. C max can be proposed as an alternative to C min but has also some disadvantages. Hence, some patients display delayed drug absorption resulting in delayed T max . That is why a two sampling-time scheme (2h and 6h post-dose) has been proposed by authors to maximize the probability for accessing C max in both absorption profiles [START_REF] Alsultan | Therapeutic drug monitoring in the treatment of tuberculosis: an update[END_REF]. An intermediate sampling time at 4h may also provide information as it is frequently proposed as a time-point in limited sampling strategies [START_REF] Van Beek | A Model-Informed Method for the Purpose of Precision Dosing of Isoniazid in Pulmonary Tuberculosis[END_REF][START_REF] Van Den Elsen | Limited Sampling Strategies Using Linear Regression and the Bayesian Approach for Therapeutic Drug Monitoring of Moxifloxacin in Tuberculosis Patients[END_REF]. The best pharmacokinetic parameter for evaluating drug exposure remains AUC but requires several samples along the drug interval, particularly with drugs like TB drugs with various absorption profiles, and is hardly compatible with clinical practice. To circumvent this limitation, limited sampling strategies have been developed for most of TB-drugs [START_REF] Medellín-Garibay | Limited sampling strategies to predict the area under the concentration-time curve for rifampicin[END_REF][START_REF] Pranger | Limited-sampling strategies for therapeutic drug monitoring of moxifloxacin in patients with tuberculosis[END_REF][START_REF] Alffenaar | Limited sampling strategies for therapeutic drug monitoring of linezolid in patients with multidrugresistant tuberculosis[END_REF][START_REF] Magis-Escurra | Population pharmacokinetics and limited sampling strategy for first-line tuberculosis drugs and moxifloxacin[END_REF][START_REF] Alsultan | Limited sampling strategy and target attainment analysis for levofloxacin in patients with tuberculosis[END_REF]. They allow accessing AUC with a limited number of samples, limiting then the burden of venipunctures for patients and making it more suitable for outpatient clinic. The development of a robust limited sampling approach allowing estimating AUC of antituberculosis drugs administered in combination, irrespective of the route of administration and with or without food is a still a milestone to reach in the field despite preliminary interesting results [START_REF] Saktiawati | Optimal Sampling Strategies for Therapeutic Drug Monitoring of First-Line Tuberculosis Drugs in Patients with Tuberculosis[END_REF]. Other recent strategies such as dried blood spots and saliva measurements might also help implementing TDM of TB drugs and makes it easier evaluating drug exposure [START_REF] Vu | Dried blood spots: a new tool for tuberculosis treatment optimization[END_REF][START_REF] Van Den Elsen | Systematic Review of Salivary Versus Blood Concentrations of Antituberculosis Drugs and Their Potential for Salivary Therapeutic Drug Monitoring[END_REF].

Conclusion:

TDM is a tool of added value in the management of patients treated with anti-TB drugs. Because of the high variability of drug exposure and the existence of threshold associated with treatment outcome, TDM may help improving the TB treatment. While it is usually restricted to specific situation such as patients having a slow treatment response with sputum smears culture positive after 2 months, patients with poor drug resorption and in drug-drug interaction context, the overview of the literature shows that there is a potential place for systematic TDM in that era.

  Considering INH, a retrospective study conducted in patients treated with drug-susceptible TB during continuous treatment phase with once weekly INH/RFP or twice-weekly INH/rifapentine evaluated the impact of INH exposure on treatment efficacy. In the INH/rifapentine group only, INH exposure was lower in patients with treatment failure (AUC 0-12h = 36.0 µg.h/mL vs 55.9 µg.h/mL in the cure group). Exposure was not different in the INH/RFP arm (32).

Table 1 . Drug-susceptible and group-A drugs according to the WHO classification Groups Drugs Drug-susceptible

 1

	Rifampicin
	Isoniazid
	Ethambutol
	Pyrazinamide

Table 2 . Exposure threshold with clinically demonstrated relevant impact to guide TB treatment using TDM. TB Drugs Exposure index threshold Cmin (µg/mL) Cmax (µg/mL) AUC (µg.h/mL)

 2

	Rifampicin	8 (22) 1	13
	Isoniazid	3	52
	Pyrazinamide	35	363
	Linezolid	< 2 2

/MIC of 73.6[START_REF] Srivastava | Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis[END_REF].

Result with brackets is for TB meningitis;

Threshold to prevent adverse drug reactionAccepted manuscript / Final version