Pharmacokinetics of First-Line Antituberculosis Drugs Among Underweight Adults and Children: A Systematic Review

Background: Underweight is common among people with tuberculosis (TB) and may alter the absorption, distribution, metabolism, and elimination of first-line antituberculosis drugs. However, the direction, consistency, and clinical significance of these effects remain uncertain. Objective: To review associations between underweight and related nutritional phenotypes and first-line antituberculosis drug pharmacokinetics in adults and children. Methods: PubMed, Embase, Web of Science, ProQuest, CINAHL, grey literature sources, and citation tracking were searched through May 2026. Eligible studies evaluated nutritional status in relation to pharmacokinetic outcomes for isoniazid, rifampicin, pyrazinamide, or ethambutol. Pharmacokinetic parameters, achieved mg/kg dose, treatment timing, dose or body-size adjustment, and target attainment were extracted where reported. Longitudinal studies were synthesized separately from cross-sectional and model-based studies. Findings were synthesized narratively because of heterogeneity in nutritional definitions, dosing, endpoints, and analytical methods. Results: Twenty-eight studies involving 3,992 participants were included; 16/28 (57.1%) enrolled children and 12/28 (42.9%) adults. Among cross-sectional or model-based studies, lower exposure associated with an adverse nutritional phenotype was reported in 4/21 isoniazid studies, 7/18 rifampicin studies, 5/14 pyrazinamide studies, and 1/8 ethambutol studies. Longitudinal studies showed variable changes during nutritional rehabilitation or treatment. These directional findings were descriptive and did not account for differences in study size, effect magnitude, or precision. Risk of bias was moderate in 26/28 studies (92.9%). Achieved mg/kg dose was inconsistently reported or adjusted for, and few studies reported target attainment by nutritional phenotype. Conclusions: Underweight and related nutritional phenotypes may be associated with altered pharmacokinetics, but current evidence does not establish an independent causal effect. Observed differences may reflect changes in drug disposition, achieved dose, treatment timing, weight change without dose reassignment, comorbidities, and disease severity. Current evidence does not support routine dose adjustment based solely on anthropometric status. Prospective studies should report longitudinal dosing, evaluate clinically relevant target attainment, and assess targeted therapeutic drug monitoring and model-informed precision dosing.