Riboflavin as an Oral Tracer for Monitoring Compliance in Clinical Research



V.M. Sadagopa Ramanujam*, Karl E. Anderson, James J. Grady, Fatima Nayeem, Lee-Jane W. LuAffiliation: Department of Preventive Medicine and Community Health, the University of Texas Medical Branch, Galveston, TX 77555-1109, USA



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© 2011 Ramanujam et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Department of Preventive Medicine and Community Health, the University of Texas Medical Branch, 700 Harborside Drive, Galveston, TX 77555-1109, USA; Tel: (409) 772- 4661; Fax: (409) 772-6287; E-mail: sramanuj@utmb.edu


Abstract

We studied urinary riboflavin as an objective biomarker of compliance in clinical research using a simplified method amenable to high throughput analysis. Six healthy women not taking vitamin supplements ingested a study pill containing riboflavin (32 mg) as an inactive tracer and the soy isoflavones daidzin (0.243 mmole) and genistin (0.222 mmole) as active ingredients once daily for four days. Riboflavin and metabolites of the isoflavones were measured in urine samples obtained before and after each pill. Urinary excretion of riboflavin and metabolites of both isoflavones peaked within 8 hrs and remained higher than baseline for 24 hrs. Urinary excretion of riboflavin was also measured in 152 additional women with unrestricted dietary supplement intakes. Mean and median urinary riboflavin concentrations in these women were 0.42 and 0.31µg/mL, respectively, compared to 0.2µg/mL during a riboflavin-restricted diet. Receiver operating characteristics (ROC) curves indicated that urinary riboflavin within 24 hrs after a 32 mg dose would perform well as a measure of compliance (all areas under the ROC curves ≥ 0.84. Samples collected during the initial 8 hrs after pill ingestion performed better as a compliance measure than later collections. In summary, compliance in a clinical study can be monitored in real time by incorporating 32 mg of riboflavin into study pills, with compliance indicated by urinary riboflavin levels increasing over individual baselines or to ≥1.0 µg/mL, with a false positive rate of being classified as compliant at <5%.

Keywords: biomarker, compliance monitoring, clinical trial, riboflavin.