Evolving Larger: Dosing Anti-Tuberculosis (TB) Drugs in an Obese World

Current clinical practice guidelines recommend dosing anti-tuberculosis drugs according to ideal body weight and provide dosing caps for most first-line agents. However, this recommendation may be placing corpulent patients with tuberculosis at risk as increased total body weight is associated with an increased risk of clinical failure. Patients with diabetes are at an increased risk of developing tuberculosis and typically weigh more than patients with tuberculosis alone. All these factors in-combination stress the importance of evaluating the effect of weight on the pharmacokinetics of first-line anti-tuberculosis drugs. Multiple studies suggest the use of total body weight based dosing for rifampin. Less data are available for pyrazinamide and ethambutol, but both appear to be candidates for total body weight based dosing. The study evaluating levofloxacin concluded that no adjustment is required. However, the larger variability in obese patients is concerning as to whether "one size fits all" dosing is optimal for levofloxacin. The vast majority of the isoniazid's pharmacokinetic variability is due to NAT2*4 status. However, more extensive analysis of slow and fast metabolizers is needed to determine the effect of weight within each subgroup. Moxifloxacin does not appear to be affected by weight, but doses of at least 800 mg are likely needed to optimize its pharmacokinetic/pharmacodynamic target attainment. Future pharmacokinetic evaluations should focus on recruiting a wide range of patient weights. These analyses should take advantage of the full weight distribution instead of arbitrarily dichotomizing patients into obese vs. non-obese persons. A subsequent evaluation of the safety and effectiveness of optimized dosing regimens is needed.