Oral cyclosporine A in neonatal swines for transplantation studies

Abstract

The purpose of this study is to define the optimal dose of oral cyclosporine A (CsA) microemulsion in newborn swine for transplantation studies and to describe its pharmacokinetics and acute renal effects in short-term administration. Thirteen neonatal pigs were randomized into four groups: one control and three groups with CsA administration at 4, 8 and 12 mg/kg/d for 15 days (D). Blood samples were collected on D 0, 2, 4, 9 and 14 to determine the changes of the CsA trough concentrations, the creatinine (Cr) and blood urea nitrogen (BUN) serum concentrations. On D 14, blood samples were collected every hour from 1 h to 10 h after CsA administration to determine the area under the curve (AUC). On D 15, kidneys were removed for histological analysis. We observed a stabilization of CsA trough concentrations from D 4 to D 14. On D 14, in the three treated groups, CsA trough concentrations were 687 ± 7, 1200 ± 77 and 2211 ± 1030 ng/ml, respectively; AUC (0–10 h) were 6721 ± 51 ng·h/ml in group 4 mg/kg/d, 13431 ± 988 ng·h/ml in group 8 mg/kg/d and 28264 ± 9430 ng·h/ml in group 12 mg/kg/d. Cr concentrations were not significantly different among the four groups; but compared to control group, BUN concentrations of the three treated groups increased significantly. CsA was well tolerated; neither acute, severe adverse event nor renal histological abnormality was observed. In conclusion, a 15-d course of oral CsA treatment ranged from 4 to 12 mg/kg/d is safe for newborn pigs, which need much lower CsA dose than adult pigs to reach comparable trough level and AUC. As immunosuppressive therapy in newborn pigs, we recommend a CsA dose of 4 mg/kg/d to achieve a trough blood concentration between 400 and 800 ng/ml.

• Acute renal effects
• cyclosporine A
• newborn swine
• pharmacokinetics
• transplantation

Acknowledgements

The authors thank Mr. R. Roume and Mr. R. Lasseur from Institut Claude Bourgelat, VetAgro Sup-Campus Vétérinaire de Lyon for logistical support and animal care; Pr. J-M. Bonnet from Unité de Physiologie, Pharmacodynamie et Thérapeutique, VetAgro Sup-Campus Vétérinaire de Lyon; and Pr. L. Juillard from Néphrologie, Hôpital Edouard Herriot, Hospices Civils de Lyon for their help on the analysis of CsA nephrotoxicity in neonatal pigs; Dr. D. Sachs from Transplantation Biology Research Center, Massachusetts General Hospital, and Harvard Medical School, Boston, for his help on the analysis of CsA nephrotoxicity and immunosuppressive therapy in neonatal pigs.

Declaration of interest

The authors declare that there are no conflicts of interest. This study was supported by the Fondation Centaure (France) and the National Natural Science Foundation, no. 30901365 (China).