Simplified urine-based method to detect rifampin underexposure in adults with tuberculosis: a prospective diagnostic accuracy study

Abstract

Variable pharmacokinetics of rifampin in tuberculosis (TB) treatment can lead to poor outcomes. Urine spectrophotometry is simpler and more accessible than recommended serum-based drug monitoring, but its optimal efficacy in predicting serum rifampin underexposure in adults with TB remains uncertain. Adult TB patients in New Jersey and Virginia receiving rifampin-containing regimens were enrolled. Serum and urine samples were collected over 24 h. Rifampin serum concentrations were measured using validated liquid chromatography-tandem mass spectrometry, and total exposure (area under the concentration-time curve) over 24 h (AUC_0-24) was determined through noncompartmental analysis. The Sunahara method was used to extract total rifamycins, and rifampin urine excretion was measured by spectrophotometry. An analysis of 58 eligible participants, including 15 (26%) with type 2 diabetes mellitus, demonstrated that urine spectrophotometry accurately identified subtarget rifampin AUC_0-24 at 0-4, 0-8, and 0-24 h. The area under the receiver operator characteristic curve (AUC ROC) values were 0.80 (95% CI 0.67-0.90), 0.84 (95% CI 0.72-0.94), and 0.83 (95% CI 0.72-0.93), respectively. These values were comparable to the AUC ROC of 2 h serum concentrations commonly used for therapeutic monitoring (0.82 [95% CI 0.71-0.92], P = 0.6). Diabetes status did not significantly affect the AUC ROCs for urine in predicting subtarget rifampin serum exposure (P = 0.67-0.92). Spectrophotometric measurement of urine rifampin excretion within the first 4 or 8 h after dosing is a simple and cost-effective test that accurately predicts rifampin underexposure. This test provides critical information for optimizing tuberculosis treatment outcomes by facilitating appropriate dose adjustments.

Keywords: colorimetry; pharmacokinetics; rifampin; spectrophotometry; therapeutic drug monitoring; tuberculosis.

Fig 1

Individual serum rifampin concentration–time curves (mg/L) over the 8 h serum collection period. Time 0 designates time of the last rifampin dose. Blue lines designate participants who met or exceeded the Cmax 8 mg/L target conventionally used in the absence of AUC_0–24 (total serum exposure) values; gray lines depict participants who were under the Cmax target.

Fig 2

Cumulative urinary excretion of rifampin in milligrams over 24 h post-dose as measured by urine spectrophotometry. Each bar represents a participant (n = 58) in the study.

Fig 3

Receiver operator characteristic (ROC) curve for rifampin urinary dose excretion over 0–4, 0–8, and 0–24 h and 2 h serum prediction of total serum exposure in the dosing interval–area under the concentration time curve (AUC_0–24) of less than 35.4 mg·h/L for the n = 58 participants.