Rifampin urinary excretion to predict serum targets in children with tuberculosis: a prospective diagnostic accuracy study.

Abstract

Pharmacokinetic variability drives tuberculosis (TB) treatment outcomes but measurement of serum drug concentrations for personalised dosing is inaccessible for children in TB-endemic settings. We compared rifampin urine excretion for prediction of a serum target associated with treatment outcome. Prospective diagnostic accuracy study. Inpatient wards and outpatient clinics, northern Tanzania. Children aged 4-17 years were consecutively recruited on initiation of WHO-approved treatment regimens. Samples were collected after directly observed therapy at least 2 weeks after initiation in the intensive phase: serum at pre-dose and 1, 2 and 6 hours post-dose, later analysed by liquid chromatography-tandem mass spectrometry for calculation of rifampin total exposure or area under the concentration time curve (AUC_0-24); urine at post-dose intervals of 0-4, 4-8 and 8-24 hours, with rifampin excretion amount measured onsite by spectrophotometry. Receiver operating characteristic (ROC) curve for percentage of rifampin dose excreted in urine measured by spectrophotometry to predict serum rifampin AUC_0-24 target of 31.7 mg*hour/L. 89 children, 52 (58%) female, with median age of 9.1 years, had both serum and urine collection. Only 59 (66%) reached the serum AUC_0-24 target, reflected by a range of urine excretion patterns. Area under the ROC curve for percentage of rifampin dose excreted in urine over 24 hours predicting serum AUC_0-24 target was 69.3% (95% CI 56.7% to 81.8%), p=0.007. Urine spectrophotometry correlated with a clinically relevant serum target for rifampin, representing a step toward personalised dosing for children in TB-endemic settings.