title: 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.
authors.affiliation: Department of Transplantation, Hôpital Edouard Herriot , Lyon , France .
authors.forename: Hua
authors.initials: H
authors.lastname: Pan
authors.forename: Aram
authors.initials: A
authors.lastname: Gazarian
authors.forename: Samuel
authors.initials: S
authors.lastname: Buff
authors.forename: Federico
authors.initials: F
authors.lastname: Solla
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gagnieu
authors.forename: Olivia
authors.initials: O
authors.lastname: Leveneur
authors.forename: Dorothée
authors.initials: D
authors.lastname: Watrelot-Virieux
authors.forename: Stéphane
authors.initials: S
authors.lastname: Morisset
authors.forename: Mohamad
authors.initials: M
authors.lastname: Sobh
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Michallet
authors.forename: Thierry
authors.initials: T
authors.lastname: Roger
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dubernard
authors.forename: Mauricette
authors.initials: M
authors.lastname: Michallet
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D019540:Area Under Curve; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D011897:Random Allocation; D013552:Swine; D023001:Transplantation Tolerance / Q000187:drug effects*
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003404:Creatinine
keywords: Acute renal effects; cyclosporine A; newborn swine; pharmacokinetics; transplantation