1. Urine colorimetry for therapeutic drug monitoring of pyrazinamide during tuberculosis treatment
- Author
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Stellah G. Mpagama, Tawanda Gumbo, Christopher Vinnard, Jotam G. Pasipanodya, Chawangwa Modongo, Nicola M. Zetola, Gregory P. Bisson, Scott K. Heysell, Shashikant Srivastava, Hans P. Schlect, and Isaac Zentner
- Subjects
Adult ,Male ,0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,Tuberculosis ,Non-Randomized Controlled Trials as Topic ,030106 microbiology ,HIV Infections ,Urine ,Sensitivity and Specificity ,Gastroenterology ,lcsh:Infectious and parasitic diseases ,Young Adult ,03 medical and health sciences ,Pharmacokinetics ,Internal medicine ,medicine ,Humans ,lcsh:RC109-216 ,Botswana ,Cross-Over Studies ,Dose-Response Relationship, Drug ,Receiver operating characteristic ,medicine.diagnostic_test ,business.industry ,Reproducibility of Results ,General Medicine ,Pyrazinamide ,medicine.disease ,Confidence interval ,Treatment Outcome ,Infectious Diseases ,Therapeutic drug monitoring ,Colorimetry ,Female ,Drug Monitoring ,business ,Blood sampling ,medicine.drug - 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. Keywords: Tuberculosis, Pyrazinamide, Pharmacokinetics, Human immunodeficiency virus, Point-of-care testing
- Published
- 2018