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Bamfo NO, Hosey-Cojocari C, Benet LZ, et al. Examination of Urinary Excretion of Unchanged Drug in Humans and Preclinical Animal Models: Increasing the Predictability of Poor Metabolism in Humans. Pharm Res. 2021;38(7):1139-1156doi: 10.1007/s11095-021-03076-y.
Bamfo, N. O., Hosey-Cojocari, C., Benet, L. Z., & Remsberg, C. M. (2021). Examination of Urinary Excretion of Unchanged Drug in Humans and Preclinical Animal Models: Increasing the Predictability of Poor Metabolism in Humans. Pharmaceutical research, 38(7), 1139-1156. https://doi.org/10.1007/s11095-021-03076-y
Bamfo, Nadia O, et al. "Examination of Urinary Excretion of Unchanged Drug in Humans and Preclinical Animal Models: Increasing the Predictability of Poor Metabolism in Humans." Pharmaceutical research vol. 38,7 (2021): 1139-1156. doi: https://doi.org/10.1007/s11095-021-03076-y
Bamfo NO, Hosey-Cojocari C, Benet LZ, Remsberg CM. Examination of Urinary Excretion of Unchanged Drug in Humans and Preclinical Animal Models: Increasing the Predictability of Poor Metabolism in Humans. Pharm Res. 2021 Jul;38(7):1139-1156. doi: 10.1007/s11095-021-03076-y. Epub 2021 Jul 12. PMID: 34254223.
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Pharm Res. 2021 Jul;38(7):1139-1156. doi: 10.1007/s11095-021-03076-y. Epub 2021 Jul 12.

Examination of Urinary Excretion of Unchanged Drug in Humans and Preclinical Animal Models: Increasing the Predictability of Poor Metabolism in Humans.

Pharmaceutical research

Nadia O Bamfo, Chelsea Hosey-Cojocari, Leslie Z Benet, Connie M Remsberg

Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington, USA.
  2. Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
  3. Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri, USA.
  4. Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, California, USA.
  5. Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington, USA. [email protected].

PMID: 34254223 DOI: 10.1007/s11095-021-03076-y

Abstract

PURPOSE: A dataset of fraction excreted unchanged in the urine (fe) values was developed and used to evaluate the ability of preclinical animal species to predict high urinary excretion, and corresponding poor metabolism, in humans.

METHODS: A literature review of fe values in rats, dogs, and monkeys was conducted for all Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3 and 4 drugs (n=352) and a set of Class 1 and 2 drugs (n=80). The final dataset consisted of 202 total fe values for 135 unique drugs. Human and animal data were compared through correlations, two-fold analysis, and binary classifications of high (fe ≥30%) versus low (<30%) urinary excretion in humans. Receiver Operating Characteristic curves were plotted to optimize animal fe thresholds.

RESULTS: Significant correlations were found between fe values for each animal species and human fe (p<0.05). Sixty-five percent of all fe values were within two-fold of human fe with animals more likely to underpredict human urinary excretion as opposed to overpredict. Dogs were the most reliable predictors of human fe of the three animal species examined with 72% of fe values within two-fold of human fe and the greatest accuracy in predicting human fe ≥30%. ROC determined thresholds of ≥25% in rats, ≥19% in dogs, and ≥10% in monkeys had improved accuracies in predicting human fe of ≥30%.

CONCLUSIONS: Drugs with high urinary excretion in animals are likely to have high urinary excretion in humans. Animal models tend to underpredict the urinary excretion of unchanged drug in humans.

© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Keywords: BDDCS; Fraction excreted unchanged; animal models; poorly-metabolized drugs; renal clearance

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