TY - JOUR
T1 - Urine colorimetry for therapeutic drug monitoring of pyrazinamide during tuberculosis treatment
AU - Zentner, Isaac
AU - Modongo, Chawangwa
AU - Zetola, Nicola M.
AU - Pasipanodya, Jotam G.
AU - Srivastava, Shashikant
AU - Heysell, Scott K.
AU - Mpagama, Stellah
AU - Schlect, Hans P.
AU - Gumbo, Tawanda
AU - Bisson, Gregory P.
AU - Vinnard, Christopher
N1 - Funding Information:
This work was supported by a Grand Challenges and Explorations grant from the Bill and Melinda Gates Foundation (to Dr Vinnard) and the National Institute of Allergy and Infectious Diseases (NIAID) ( R21AI104441 to Dr Bisson, K23AI102639 to Dr Vinnard). Dr Vinnard receives internal support from the Public Health Research Institute, Rutgers, The State University of New Jersey . The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2017 The Authors
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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.
KW - Human immunodeficiency virus
KW - Pharmacokinetics
KW - Point-of-care testing
KW - Pyrazinamide
KW - Tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=85043317840&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85043317840&partnerID=8YFLogxK
U2 - 10.1016/j.ijid.2017.12.017
DO - 10.1016/j.ijid.2017.12.017
M3 - Article
C2 - 29253711
AN - SCOPUS:85043317840
SN - 1201-9712
VL - 68
SP - 18
EP - 23
JO - International Journal of Infectious Diseases
JF - International Journal of Infectious Diseases
ER -