Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting.
In cynomolgus and rhesus monkeys, the dose-normalized exposure of cyclosporine administered orally as microemulsion preconcentrate (Neoral) was lower than that upon intramuscular administration. For oral administration, mean values ( +/- SD) of Cmax, 24-h area-under-the curve (AUC) and 24-h trough level, all normalized for a 1 mg/kg dose, were 20 +/- 9 ng x kg/mg x ml, 210 +/- 70 ng x h x kg/mg x ml and 2.6 +/- 0.9 ng x kg/mg x ml, respectively. For intramuscular administration, levels were about 5.5-fold, 9-fold and 22-fold higher. Based on pharmacokinetic data, the efficacy of oral cyclosporine treatment (without any other immunosuppressant) was evaluated in life-supporting cynomolgus monkey kidney allotransplantation. Rejection-free kidney allograft survival could be achieved using oral cyclosporine monotherapy with average 24-h trough concentrations above 100 ng/ml during maintenance treatment. Typically, daily oral doses of 100 mg/kg-150 mg/kg during the first two weeks post-transplantation, followed by daily 30 mg/kg-100 mg/kg dose levels during subsequent maintenance can result in long-term allograft survival, with 24-h average trough levels in individual animals during maintenance between 110 ng/ml and 700 ng/ml.
Schuurman
H J
HJ
Transplantation Research, Novartis Pharma AG, 4002 Basel, Switzerland. henk.schuurman@immergebt.com
Slingerland
W
W
Mennninger
K
K
Ossevoort
M
M
Hengy
J C
JC
Dorobek
B
B
Vonderscher
J
J
Ringers
J
J
Odeh
M
M
Jonker
M
M
D000284:Administration, Oral; D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007273:Injections, Intramuscular; D016030:Kidney Transplantation / Q000276:immunology*; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate
D007166:Immunosuppressive Agents; D016572:Cyclosporine