Sex-dependent variability of isoniazid and rifampicin serum levels in patients with tuberculosis

Introduction: Drug-sensitive TB (DS-TB) is treated with isoniazid, rifampicin, ethambutol, and pyrazinamide. Factors like fast-metabolizing enzymes, malabsorption, and drug interactions can influence serum drug levels. Current TB treatment guidelines recommend weight-adapted dosing without considering sex differences. This study examines drug levels of isoniazid and rifampicin in TB patients treated between 2019 and 2023 at our center focusing on sex-specific aspects.

Methods: Patients diagnosed with TB and available serum levels of isoniazid or rifampicin between 2019 and 2023 were retrospectively identified. Serum levels were measured using liquid chromatography-mass spectrometry and high-performance liquid chromatography. Patients were stratified by sex and a linear regression mixed effect model was used to assess predictors for different serum levels.

Results: The study included 281 single therapeutic drug monitoring (TDM) measurements from 59 patients (28 women, 47.5%). For isoniazid, no sex-specific differences in serum drug levels were identified. On the other hand, female sex was a significant predictor of higher rifampicin plasma levels (coefficient 4.16, 95% CI 0.74-7.59, p = 0.009). Only 38.2% of rifampicin serum level measurements in male patients were within target range, the majority (40/68, 58.8%) were below range and only 2 (2.9%) TDM-levels were above range. Women displayed higher overall rifampicin serum levels than men (median 13.7 mg/l vs. 7.1 mg/l, p = 0.04), although weight adjusted doses were not significantly different (median 10.0 mg/kg vs. 9.8 mg/kg p = 0.56). Adverse effects were noted in 42.9% (42/98) of measurements in women and 29.5% (54/183) of measurements in men (p = 0.03).

Discussion: Rifampicin levels were significantly lower in men compared to women, despite weight-adjusted dosing. Clinicians should consider TDM and potential sex differences when treating patients with TB.