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

• Published in: Archives of disease in childhood Vol. 108; no. 8; pp. 616 - 621
• Main Authors: Thomas, Tania A, Lukumay, Saning'o, Yu, Sijia, Rao, Prakruti, Siemiątkowska, Anna, Kagan, Leonid, Augustino, Domitila, Mejan, Paulo, Mosha, Restituta, Handler, Deborah, Petros de Guex, Kristen, Mmbaga, Blandina, Pfaeffle, Herman, Reiss, Robert, Peloquin, Charles A, Vinnard, Christopher, Mduma, Estomih, Xie, Yingda L, Heysell, Scott K
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and Royal College of Paediatrics and Child Health 01-08-2023; BMJ Publishing Group LTD
• Subjects: Age; Antitubercular Agents - pharmacokinetics; Antitubercular Agents - therapeutic use; Body Composition; Body mass index; Body Weight; Child; Child Health; Children; Chromatography; Communicable Diseases; Concentration time; Death; Demographics; Dosage; Drug administration; Drug dosages; Drug resistance; Excretion; Female; Global Health; Guidelines; Humans; Infectious Disease Medicine; Intervals; Liquid chromatography; Male; Mass spectrometry; Mass spectroscopy; Medical diagnosis; Narcotics; National Standards; Original research; Outcomes of Treatment; Paediatrics; Patients; Pediatrics; Pharmacokinetics; Prospective Studies; Rifampin; Rifampin - pharmacokinetics; Rifampin - therapeutic use; Sampling; Scientific Concepts; Scientific imaging; Software; Spectrophotometry; Statistical Analysis; Treatment Outcome; Tuberculosis; Tuberculosis - diagnosis; Tuberculosis - drug therapy; Urine; United States > US; Tanzania; Infectious Disease Medicine; Child Health; Global Health; Communicable Diseases; Paediatrics
• ISSN: 0003-9888; 1468-2044
• DOI: 10.1136/archdischild-2022-325250

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 AUC0–24 target 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 AUC0–24 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 AUC0–24 target 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.