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Abstract: TH-PO370

A Systematic Meta-Analysis on Interspecies Differences in Renal Drug Clearance

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Jansen, Katja, Utrecht University, Utrecht, Netherlands
  • Pou casellas, Carla, University Medical Center Utrecht, Utrecht, Netherlands
  • Wever, Kimberley, Radboud university medical centre, Nijmegen, Netherlands
  • Groenink, Lucianne, Utrecht University, Utrecht, Netherlands
  • Masereeuw, Rosalinde, Utrecht Institute for Pharmaceutical Sciences, Utrecht,, Utrecht, Netherlands
Background

Various animal models are used to study drug efficacy and safety prior to approval for human use. Renal clearance (CLr) is a standard pharmacokinetic measure, for which animal data is extrapolated to humans by allometric scaling, using exponents of 0.55-0.75. It is worth noting that the physiological system of waste removal is designed to exactly meet the demand set by metabolic rate, which in turn scales with body weight to the power of 0.75 (Kleiber’s law). Thus, human CLr should be predictable based on body weight by scaling with 0.75. The exponents used in literature aim for best fit, thus deviations from 0.75 might result from biological interspecies differences. Using the allometric exponent of 0.75, our study aimed at quantifying interspecies differences in renal drug clearance. To find possible mechanistic explanations for these differences, we related them to the physicochemical properties of drugs.

Methods


Using PubMed and EMBASE, we systematically reviewed literature on human and animal CLr measures for 20 renally excreted drugs. Based on the human data and simple allometric principles, we calculated the CLr value expected for the respective animal body weight. Subsequently, average fold errors (AFEs) were calculated as the ratio between the literature-derived CLr values and the expected CLr values. Finally, we quantified mean differences (MDs) in AFEs between animals and humans.

Results

Based on 264 included studies, we calculated AFEs ranging from 0.45-3.05 for mice, 0.77-3.34 for rats, 0.28-1.61 for rabbits, 0.27-3.4 for dogs, 0.57-1.78 for monkeys and 1.01-1.31 for humans. Comparing animal to human AFEs, we determined for all drugs an average MD [95% CI] of 0.01 [-0.23, 0.26] for mice, 0.47 [0.17, 0.77] for rats, 0.17 [-0.12, 0.45] for rabbits, 0.23 [-0.13, 0.56] for dogs and -0.08 [-0.33, 0.16] for monkeys. Only for rats, the overall effect size was significantly different from humans. Subgroup analyses showed no clear relation to physicochemical drug properties.

Conclusion

In general, animal models are good predictors for human drug clearance using simple allometry. However, rats (the most popular animal model) significantly overestimate human CLr, which could explain the exponent deviation in literature and suggest that rat models should be used with caution.

Funding

  • Government Support - Non-U.S.