Urine colorimetry for therapeutic drug monitoring of pyrazinamide during tuberculosis treatment.

Abstract

OBJECTIVES:

Pyrazinamide is a key drug in the first-line treatment regimen for tuberculosis, with a potent sterilizing effect. Although low pyrazinamide peak serum concentrations (Cmax) are associated with poor treatment outcomes, many resource-constrained settings do not have sufficient laboratory capacity to support therapeutic drug monitoring (TDM). The objective of this study was to determine whether a colorimetric test of urine can identify tuberculosis patients with adequate pyrazinamide exposures, as defined by serum Cmax above a target threshold.

METHODS:

In the derivation study of healthy volunteers, three dose sizes of pyrazinamide were evaluated, and intensive pharmacokinetic blood sampling was performed over an 8-h period, with a timed urine void at 4h post-dosing. Pyrazinamide in urine was isolated by spin column centrifugation with an exchange resin, followed by colorimetric analysis; the absorbance peak at 495nm was measured. The urine assay was then evaluated in a study of 39 HIV/tuberculosis patients in Botswana enrolled in an intensive pharmacokinetic study. Receiver operating characteristics (ROC) curves were used to measure diagnostic accuracy. The guideline-recommended pyrazinamide serum Cmax target of 35mg/l was evaluated in the primary analysis; this target was found to be predictive of favorable outcomes in a clinical study. Following this, a higher serum Cmax target of 58mg/l was evaluated in the secondary analysis.

RESULTS:

At the optimal cut-off identified in the derivation sample, the urine colorimetric assay was 97% sensitive and 50% specific to identify 35 of 39 HIV/tuberculosis patients with pharmacokinetic target attainment, with an area under the ROC curve of 0.81 (95% confidence interval 0.60-0.97). Diagnostic accuracy was lower at the 58mg/l serum Cmax target, with an area under the ROC curve of 0.68 (95% confidence interval 0.48-0.84). Men were less likely than women to attain either serum pharmacokinetic target.

CONCLUSIONS:

The urine colorimetric assay was sensitive but not specific for the detection of adequate pyrazinamide pharmacokinetic exposures among HIV/tuberculosis patients in a high-burden setting.

• Authors: Isaac Zentner, Chawangwa Modongo, Nicola M Zetola, Jotam G Pasipanodya, Shashikant Srivastava, Scott K Heysell, Stellah Mpagama, Hans P Schlect, Tawanda Gumbo, Gregory P Bisson, Christopher Vinnard
• Journal: International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases (Int J Infect Dis) Vol. 68 Pg. 18-23 (Mar 2018) ISSN: 1878-3511 [Electronic] Canada
• PMID: 29253711 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Pyrazinamide

Topics

• Adult
• Botswana
• Colorimetry
• Cross-Over Studies
• Dose-Response Relationship, Drug
• Drug Monitoring
• Female
• HIV Infections (drug therapy, urine)
• Humans
• Male
• Non-Randomized Controlled Trials as Topic
• Pyrazinamide (pharmacokinetics, therapeutic use, urine)
• Reproducibility of Results
• Sensitivity and Specificity
• Treatment Outcome
• Tuberculosis (drug therapy, urine)
• Young Adult