Table 2 Comparative plasma pharmacokinetics of antitubercular drugs in normal weight and overweight/obese individuals3.1 Medicines Recommended for DS-TB3.1.1 Rifampicin

Rifampicin is part of the standard first-line treatment regimen for DS-TB and is included in the WHO Model List of Essential Medicines as a single-dose oral formulation or as part of a fixed-dose regimen [6]. According to the WHO, the weight-based dose of rifampicin is 8–12 mg/kg body weight, resulting in a maximum recommended dose of 750 mg per day for adults weighing ≥ 65 kg [4]. Reference pharmacokinetic parameters of rifampicin in normal-weight patients with TB and in overweight or obese subjects are shown in Table 2. In a case report of an overweight patient with lymph node TB caused by Mycobacterium bovis, the dose of rifampicin had to be adjusted as the initially prescribed dose of 600 mg led to subtherapeutic plasma concentrations, with levels below the target therapeutic range of 6–10 μg/mL at 3 h after oral intake. Increasing the dose to 1200 mg daily (approximately 13 mg/kg) achieved the desired drug levels without causing hepatic side effects [7]. Similarly, in another case presentation of an obese patient with miliary and meningeal TB, serum levels reached the target Cmax of 8–24 μg/mL, measured 2 h after dosing, on a regimen of rifampicin 900 mg daily [8]. Although these cases suggest that higher doses of rifampicin may be required in obese patients, it is important to note that overall dose adjustments based solely on single pharmacokinetic parameters such as Cmax might be problematic, since AUC might be more relevant for achieving a certain therapeutic effect.

In recent years, multiple studies have evaluated the use of higher rifampicin doses in the treatment of normal-weight patients with TB, with no dose-limiting toxicities [9,10,11]. For instance, Peloquin et al. showed that patients receiving higher doses of 20 mg/kg body weight were more likely to achieve target therapeutic concentrations than those on standard dosing regimens [10]. Based on the safety of higher doses demonstrated in studies with normal-weight individuals, this could support the consideration of higher dosing strategies in obese patients, with careful therapeutic drug monitoring.

3.1.2 Isoniazid

According to WHO guidelines from 2022, the recommended dosing regimen for isoniazid is 4–6 mg/kg, with a maximum authorised dose of 375 mg for patients weighing > 65 kg [4]. As isoniazid is metabolised by the enzyme N-terminal acetyltransferase 2 gene *4 (NAT2*4), variations in NAT2*4 significantly affect how isoniazid is metabolised, and individuals can subsequently be classified as ‘slow’ or ‘fast’ acetylators [12]. Accordingly, fast metabolisers exhibit lower drug levels than slow metabolisers.

No studies have specifically investigated how weight affects isoniazid metabolism within the different classes of metabolisers. A case in an overweight patient with lymph node TB due to M. bovis showed that isoniazid 300 mg resulted in subtherapeutic plasma levels, whereas increasing the dose to 600 mg achieved therapeutic levels (2.5–5 mg/L at 2 h or 1.5–3 mg/L at 3 h after oral intake, respectively). It must be noted that, in this case, the acetylator status of the patient was not reported, and being a fast metaboliser could have contributed to the observed subtherapeutic levels at the initial dose [7].

3.1.3 Ethambutol

The recommended dose of ethambutol is 15–25 mg/kg with a maximum daily dose of 1600 mg regardless of weight [4]. Following this dosing range, the desired Cmax of ethambutol, measured 2 h after dosing, should be between 2 and 6 µg/mL [13]. Current dosing guidelines recommend using lean body weight (LBW) to calculate the dose in obese patients [14]. A similar approach was also recommended by a retrospective study that found an association between ethambutol-induced optic neuropathy and potential overdose when doses were based on total body weight rather than on LBW in obese patients [15]. However, using LBW might underestimate the dosing requirements for obese patients for borderline hydrophilic drugs such as ethambutol (pLog value of − 0.059) that distribute partially into adipose tissue, as it does not fully account for the expanded volume of distribution associated with higher body weights. In contrast, using modified ideal body weight (MIBW) with a correction factor of 0.4 could offer a more suitable dosing alternative by including a portion of the excess adipose tissue. This approach is recommended in the WHO guidelines from 2014, which offered slightly more detailed recommendations on dosing medications in obese patients than did the more recent 2022 guidelines [16]. In a case report of an obese individual with miliary and meningeal TB, therapeutic doses of ethambutol were reached with a regimen of 800 mg three times daily (≙ 27.5 mg/kg/day based on ideal body weight [IBW] or 20.3 mg/kg/day based on MIBW), without the occurrence of any drug-related adverse events [8].

3.1.4 Pyrazinamide

The weight-based dose of pyrazinamide is 20–30 mg/kg with an upper limit of 2000 mg per day [17]. Following a dose of 25 mg/kg, serum levels have been observed to vary between 30 and 50 µg/mL [18]. Compared with ethambutol, pyrazinamide is a slightly more hydrophilic drug (pLog value of − 1.2) that therefore has a limited distribution into adipose tissue. Current guidelines do not provide established recommendations for dosing pyrazinamide in obese patients. Although using LBW is a common approach for hydrophilic drugs because of its limited distribution into fat tissue, it may underestimate the volume of distribution in certain cases [19]. Therefore, although LBW remains a reasonable option, MIBW could also be considered as an alternative [14, 16, 17]. However, using total body weight would likely result in overdosing in obese individuals because of the hydrophilic nature of the drug [19].

In a case report of an obese patient weighing 166 kg, pyrazinamide was administered at a daily dose of 3000 mg (≙ 34.4 mg/kg/day based on IBW or 25.3 mg/kg/day based on MIBW). However, treatment with pyrazinamide had to be discontinued after 45 days due to hepatotoxicity as confirmed by a 10-fold increase in serum transaminase levels [8].

3.2 Medicines Recommended for MDR-TB: WHO Group A3.2.1 Fluoroquinolones (Levofloxacin/Moxifloxacin)

Fluoroquinolones are considered the main class of second-line drugs for the treatment of TB when resistance or intolerance to first-line drugs occurs. Among these, levofloxacin and moxifloxacin are preferred because of their superior in vitro efficacy, especially when compared with earlier-generation fluoroquinolones such as ciprofloxacin [14].

Recently, in a hollow fibre model, an AUC0–24/minimum inhibitory concentration (AUC0–24/MIC) ratio of 146 was identified as the optimal target for maximum efficacy of levofloxacin against M. tuberculosis, suggesting a high likelihood of improved clinical outcomes in patients with MDR-TB [20]. Deshpande et al. showed that doses of up to 1500 mg of levofloxacin were required for optimal microbial eradication [20]. For moxifloxacin, the desired AUC0–24/MIC ratio has been identified as ≥ 53. A daily dose of moxifloxacin 800 mg was considered to be highly effective in killing M. tuberculosis and preventing the development of drug resistance [21].

In 2011, Cook et al. [22] found that the Cmax and volume of distribution of levofloxacin were similar in obese individuals with TB and healthy obese individuals in a selected cohort. However, there was considerable variability in how quickly levofloxacin was cleared from the body within the obese population. In particular, the healthy obese group showed a marked increase in levofloxacin clearance, which could be attributed to their higher creatinine clearance rates. As a result, the AUC in the obese cohort was significantly reduced compared with that typically seen in normal-weight individuals. In contrast, the acutely ill cohort treated with levofloxacin had an AUC comparable to that of normal-weight individuals [22]. Luque et al. [23] demonstrated that, when levofloxacin is administered based on actual body weight (4 mg/kg/12 h) in an obese patient, Cmax and clearance rates are comparable to those observed in normal-weight individuals receiving a standard dose of 750 mg every 24 h. Overall, studies on dose adjustment of levofloxacin in obese or overweight patients are inconclusive. Although one study supports the need for dosage adjustment based on actual body weight [23], another describes pharmacokinetics comparable to those in normal-weight individuals [22].

For moxifloxacin, pharmacokinetic parameters appear to remain stable in the presence of morbid obesity, so no dose adjustments are generally recommended [24].

When prescribing fluoroquinolones, it is important to consider their potential adverse event profile. Common side effects include gastrointestinal disturbances, whereas more serious, although rare, complications such as central nervous system effects, tendon rupture, and QT interval prolongation have also been reported. In particular, moxifloxacin has been more frequently associated with QT prolongation than has ciprofloxacin [25, 26]. As a result, close clinical monitoring is recommended when high doses of fluoroquinolones are used.

3.2.2 Bedaquiline

The recommended bedaquiline dosing regimen for MDR-TB in adults is 400 mg daily for the initial 2 weeks, followed by 200 mg three times per week for the following 22 weeks [27]. Although there are currently no specific guidelines for adjusting the dose of bedaquiline in obese patients, population pharmacokinetic models have investigated the role of body weight on bedaquiline pharmacokinetics, with inconclusive results [28, 29]. Svensson et al. [28] found that allometric scaling with weight (0.75 for clearance, 1.0 for volume) improved model fit, suggesting that higher body weight may influence bedaquiline pharmacokinetics, supporting the potential need for weight-based dose adjustments in heavier patients. In contrast, McLeay et al. [29] found no significant effect of weight on clearance, which they attributed to the confounding effect of lower clearance in sicker patients with MDR-TB and a non-stratified weight distribution.

Additionally, in 2021, Alghamdi et al. [30] suggested that weight-based dosing may be necessary for optimal bedaquiline drug exposure, as they observed a negative correlation between body weight and bedaquiline minimum blood plasma concentration. However, the median weight in the study was 64.0 kg (interquartile range 56.0–71.0), so the implications for obese populations remain unexplored [30].

Peak plasma levels are generally reached approximately 5 h after dosing. Both peak concentration and AUC increase in direct proportion to dose, up to the highest doses tested: a single 700 mg dose and multiple daily 400 mg doses [31]. Bedaquiline has a significant terminal serum half-life of approximately 5 months and is metabolised in the liver, mainly via the cytochrome P450-3A4 pathway. Therefore, potential drug interactions must be carefully considered [14, 32]. Given that obese individuals tend to have a higher fat mass, it is possible that bedaquiline’s lipophilicity (logP value of 7.13) could result in prolonged drug retention in these patients. Whether this duration would be influenced in obese patients, and whether this might have an impact on the emergence of bedaquiline resistance, are important questions that need further investigation.

3.2.3 Linezolid

In the latest WHO guidelines, from 2022, treatment with linezolid 600 mg/day was suggested for patients with MDR-TB as part of a 6-month regimen with BPaLM [5].

The results presented in Table 2 show that an increase in body weight tended to result in lower plasma concentrations of linezolid. Overall, the data indicate that the pharmacokinetics of linezolid could be significantly impacted by the level of obesity, and standard dosages might be inadequate. However, given the safety profile of linezolid, any dose adjustments should still be determined after individual risk-benefit assessment, ideally with therapeutic drug monitoring.

3.3 Medicines Recommended for MDR-TB: WHO Group B3.3.1 Clofazimine

Clofazimine is prescribed at a dose of 100 mg/day and is included in combination therapy regimens for the treatment of MDR-TB [27]. Pharmacokinetic studies are limited, but one suggested that body fat significantly affected drug levels, indicating potential benefits from personalised dosing, particularly in women but also in the obese population [33].

3.3.2 Cycloserine/Terizidone

Terizidone, a second-line option for treating MDR-TB, is a structural analogue consisting of two cycloserine molecules. It is thought to be as effective as cycloserine, but with a reduced risk of adverse effects, including neuropsychiatric reactions, making it a preferable alternative. However, pharmacokinetic studies of both terizidone and cycloserine in obese populations are lacking, and even data in normal-weight populations are limited. A standard dosing for an adult patient is 5–7 mg/kg twice daily, with a maximum daily dose of 1000 mg [27]. For cycloserine, therapeutic peak levels for the treatment of TB range from 20 to 35 μg/mL [34].

3.4 Medicines Recommended for MDR-TB: WHO Group C (for Ethambutol and Pyrazinamide see 3.2)3.4.1 Delamanid

Delamanid may be considered for the treatment of patients with pulmonary MDR-TB, especially when an appropriate and tolerable regimen cannot be formulated with standard second-line drugs. Pharmacokinetic data are lacking, particularly in the obese and overweight population, because of its novelty on the market. Current dosing recommendations are 100 mg twice daily, whereas Cmax is reached 4 h after ingestion [35].

3.4.2 Carbapenems Plus Clavulanate

The use of carbapenems, such as imipenem–cilastatin or meropenem, in combination with clavulanate, a beta-lactamase inhibitor, has shown bactericidal effects against M. tuberculosis. Since clavulanate is not available by itself, it must be administered as part of the amoxicillin–clavulanate combination. The requirement for intravenous administration of carbapenems limits their use, particularly in maintaining a regimen outside of hospital settings [14].

For normal-weight adults, the standard dosing for imipenem–cilastatin is 1000 mg twice daily, whereas for meropenem a dosing of 2000 mg two to three times per day is common [27]. In patients with morbid obesity, meropenem has a reduced peak concentration and an increased volume of distribution, as shown in Table 2. Although pharmacokinetic parameters are altered to some extent by obesity, the clinical impact on dose adjustment may be limited.

3.4.3 Aminoglycosides

Amikacin is the aminoglycoside of choice in the treatment of MDR-TB because of its widespread availability and the feasibility of monitoring serum levels. The use of streptomycin is limited to cases with confirmed in vitro susceptibility, no previous use, and contraindication to amikacin [14]. Monitoring serum drug levels is essential for all aminoglycosides to reduce the risk of nephrotoxicity and ototoxicity. The maximum recommended daily dose for both amikacin and streptomycin is 1000 mg [14, 27]. In MDR-TB, the target Cmax of amikacin is recommended as 40–50 mg/L [36].

Aminoglycosides are highly hydrophilic (pLog value of − 8.6 for amikacin and − 7.6 for streptomycin) and therefore have limited distribution into adipose tissue. Consequently, dosing based on actual body weight in obese patients would result in supratherapeutic drug concentrations. Given aminoglycosides' strong affinity for lean body mass and only minimal diffusion into the water content of adipose tissue, dosing based on LBW should be considered. However, the 2014 WHO guidelines and several other studies have recommended the use of MIBW in cases of markedly obese individuals where LBW may underestimate the volume of distribution [16, 37, 38]. Regardless of the dosing approach, therapeutic drug monitoring remains essential to ensure that drug levels remain within a safe therapeutic range.

3.4.4 Ethionamide/Prothionamide

Ethionamide can be considered for the treatment of drug-resistant TB if the bacterial strain is confirmed to be susceptible. The recommended dosage range for ethionamide or prothionamide is 15–20 mg/kg, not to exceed 1000 mg daily. To reduce gastrointestinal side effects, it is recommended to increase the dose of ethionamide gradually over a period of 2 weeks [14, 27].

3.4.5 Para-aminosalicylic Acid

Para (p)-aminosalicylic acid treatment should also be started by gradually increasing the dose over 2 weeks. The preferred dose is 4 g twice daily, up to a maximum of 12 g per day. To reduce the risk of gastrointestinal side effects, it is best not to co-administer it with ethionamide [14, 27]. Pharmacokinetic data are generally lacking for normal-weight individuals, and particularly for overweight or obese individuals.

3.5 Other Antitubercular Drugs3.5.1 Pretomanid

Pretomanid can be administered at 200 mg daily as part of various MDR-TB regimens in combination with bedaquiline, linezolid, and optionally moxifloxacin or clofazimine [39, 40]. Studies examining alternative dosing regimens for other population groups are generally lacking, particularly for the overweight and obese population.