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

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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.

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Abbreviations

BDDCS:

Biopharmaceutics Drug Disposition Classification System

fe:

Fraction excreted unchanged in the urine

FN:

False negative

FP:

False positive

NME:

New molecular entity

PPV:

Positive predictive value

NPV:

Negative predictive value

ROC:

Receiver Operating Characteristic

TN:

True negative

TP:

True positive

US FDA:

United States Food and Drug Administration

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Funding statement

CMR was partially supported by award #T32GM007546 from the National Institutes of General Medical Sciences and the Eunice Kennedy Shriver National Institute of Child Health & Human Development. NOB is supported by Award Number T32GM008425 from the National Institute of General Medical Sciences.

Data availability statement

All data generated or analyzed during this study are included in this article.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington, USA

    Nadia O. Bamfo & Connie M. Remsberg

  2. Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Nadia O. Bamfo

  3. Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children’s Mercy Kansas City, Kansas City, Missouri, USA

    Chelsea Hosey-Cojocari

  4. Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, California, USA

    Leslie Z. Benet

Authors
  1. Nadia O. Bamfo
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  2. Chelsea Hosey-Cojocari
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  3. Leslie Z. Benet
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  4. Connie M. Remsberg
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Contributions

Original study conception and design was completed by Leslie Benet, Connie Remsberg, and Chelsea Hosey. The literature review and data analysis were performed by Nadia Bamfo, Connie Remsberg, and Chelsea Hosey. The initial draft of the manuscript was written by Nadia Bamfo and Connie Remsberg and critically revised by Chelsea Hosey and Leslie Benet.

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Correspondence to Connie M. Remsberg.

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Bamfo, N.O., Hosey-Cojocari, C., Benet, L.Z. 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 38, 1139–1156 (2021). https://doi.org/10.1007/s11095-021-03076-y

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