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

Abstract

ObjectivePharmacokinetic 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.DesignProspective diagnostic accuracy study.SettingInpatient wards and outpatient clinics, northern Tanzania.PatientsChildren aged 4–17 years were consecutively recruited on initiation of WHO-approved treatment regimens.InterventionsSamples 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 (AUC0-24); urine at post-dose intervals of 0–4, 4–8 and 8–24 hours, with rifampin excretion amount measured onsite by spectrophotometry.Main outcome measuresReceiver operating characteristic (ROC) curve for percentage of rifampin dose excreted in urine measured by spectrophotometry to predict serum rifampin AUC0–24target of 31.7 mg*hour/L.Results89 children, 52 (58%) female, with median age of 9.1 years, had both serum and urine collection. Only 59 (66%) reached the serum AUC0–24target, 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 AUC0–24target was 69.3% (95% CI 56.7% to 81.8%), p=0.007.ConclusionsUrine spectrophotometry correlated with a clinically relevant serum target for rifampin, representing a step toward personalised dosing for children in TB-endemic settings.

Development and Validation of a UPLC-MS/MS Method for Therapeutic Drug Monitoring, Pharmacokinetic and Stability Studies of First-Line Antituberculosis Drugs in Urine

“…The test is not useful for monitoring INH ingestion 24 h after the dose [ 41 ]. While urine colorimetric testing is promising for the measurement of drug exposure and dose adjustment at the point of care [ 13 , 14 , 15 ] comparatively, LC-MS/MS methods offer simultaneous analysis of multiple TB drugs with high sensitivity and selectivity conducive to pharmacokinetic/pharmacodynamics study for clinical trials among more representative populations, or for testing drug exposure in operational research settings as new drug regimens are rolled out to diverse (nonclinical trial) populations. Additionally, LC-MS/MS requires relatively low sample volumes and involves simple nonselective sample preparation techniques [ 25 ].…”

“…Urine testing may allow a simpler sample collection and acceptability in supporting optimal drug pharmacokinetics, adherence, and use in understanding the performance of new drug regimens in diverse communities [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Although urine assays encounter greater challenges than plasma assays, largely owing to nonspecific binding and variations in urine pH and salt concentration [ 19 ], urine holds numerous advantages as a matrix for pharmacokinetics and TDM.…”

Isoniazid urine spectrophotometry for prediction of serum pharmacokinetics in adults with TB

“… 18 - 20 We have demonstrated the quantification of other anti-TB medications in different patient populations using a low-cost spectrophotometer with laboratory methods available in most clinical settings. 21 - 23…”