Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting

Abstract

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 ( f SD) of C,,,, 24-h area-under-the curve (AUC) and 24-h trough level, all normalized for a 1 mg/kg dose, were 20 k 9 ng kgfmg ml, 210 k 70 ng h kg/mg ml and 2.6 * 0.9 ng kg/mg 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. Rej ection-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 mgfkg-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 ngfml and 700 ngtml.

Advantages of using tetrahydrofuran–water as mobile phases in the quantitation of cyclosporin A in monkey and rat plasma by liquid chromatography–tandem mass spectrometry

“…However, this reduced sensitivity could be well compensated by more injection volume, and the improved sensitivity offered by today's greatly improved mass spectrometers. CyA pharmacokinetics and observed concentrations were comparable to literature values [19,20]. In all, the use of THF-water mobile phase offered some unique advantages, and this approach could be an additional tool in the field of xenobiotic bioanalysis, which currently largely relies on the use of acetonitrile-water and methanol-water mobile phases.…”

An Evaluation of 20 Years of EU Framework Programme-Funded Immune-Mediated Inflammatory Translational Research in Non-Human Primates

“…The focus in CFIT on interference with immune activation/tolerance is evidenced by references (28, 32–36) and the focus on somatic gene therapy/stem cells by (29–31). The development and improvement of non-invasive methods has resulted in three additional publications (20, 56, 57). The focus of the PCDD program on tolerance induction is unfortunately not reflected in publications, illustrating the already mentioned difficulty in tolerance induction in the pathogen-educated primate immune system.…”

“…During the CFIT program, one of the aims was to develop non-invasive diagnostic parameters, which has resulted in a number of important developments for in vitro and ex vivo analysis (20, 56, 57). These refinements are implemented in subsequent studies.…”

New Immunosuppressants: Immunosuppression and Immunomodulation

“…Major side effects of cyclosporine include nephrotoxicity, hepatotoxicity, neurotoxicity, and hypertension [50]. The side effect pattern of everolimus in patients can be expected to be similar to that of rapamycin [51]: thrombocytopenia, hyperlipidemia and gastrointestinal disorders.…”