Predicting the Effective Dose of 5-Aminolevulinic Acid to Protect Humans From Renal Ischemia-Reperfusion Injury: A Study in Micro Miniature Pigs

Background: In rodent models, 5-aminolevulinic acid (5-ALA) was shown to prevent renal ischemia-reperfusion injury, but the data did not allow estimation of the human equivalent dose (HED). Therefore, this study evaluated the renal effects of 5-ALA and estimated the HED in micro miniature pigs, which have a metabolism closer to that of humans. Methods: We analyzed the efficacy and pharmacokinetics of 5-ALA by administering it to nine micro miniature pigs 2 days before renal ischemia-reperfusion injury. A pathological score was calculated on the basis of renal tissue damage; the blood concentration of 5-ALA required to prevent damage was estimated from the expected pathological score by back-calculating it from the obtained approximate expression. The pharmacokinetics data obtained in phase 1 human trials (5-ALA dose vs. blood concentration curve) were used to calculate the HED. Results: Dose-dependent improvement in tissue damage (rated as a pathological score) was confirmed 7 days after reperfusion. In each animal, the blood concentrations of 5-ALA correlated with the pathological score. We estimated that doses of approximately 1.6 mg/kg and 13.4 mg/kg would be required to obtain histopathology scores of 4 and 3.7 in humans, respectively. Conclusions: This is the first study to show that the HED of 5-ALA can be calculated from efficacy and pharmacokinetics data obtained in micro miniature pigs. J Curr Surg. 2021;000(000):000-000 doi: https://doi.org/10.14740/jcs429