Urine colorimetry for therapeutic drug monitoring of pyrazinamide during tuberculosis treatment

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

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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 4 h post-dosing. Pyrazinamide in urine was isolated by spin column centrifugation with an exchange resin, followed by colorimetric analysis; the absorbance peak at 495 nm 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 35 mg/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 58 mg/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 58 mg/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.

Original languageEnglish (US)
Pages (from-to)18-23
Number of pages6
JournalInternational Journal of Infectious Diseases
Volume68
DOIs
StatePublished - Mar 1 2018
Externally publishedYes

Keywords

  • Human immunodeficiency virus
  • Pharmacokinetics
  • Point-of-care testing
  • Pyrazinamide
  • Tuberculosis

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

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