Time-dependent changes in cyclosporine exposure: implications for achieving target concentrations

Abstract

This study analyzed early changes in trough blood cyclosporine concentrations and cyclosporine exposures after kidney transplantation. Seventy-two patients who received cyclosporine-based immunosuppressive therapy were intensively monitored (CO) during the first 6 months after transplantation. Full pharmacokinetic studies were performed at day 4, and months 2, 3, and 6 after transplantation. Mean steady-state, dose-adjusted trough cyclosporine blood concentrations increased from 1.1 f 0.60 (day 7) to 2.0 i 1.20 ng/ml per mg (day 30, P < 0.01). Steadystate, dose-adjusted cyclosporine exposure parameters (CO, Cmax, AUC, Cavg, and Cl2) were significantly lower at day 4 than at months 2, 3, and 6 after transplantation (P < 0.01). Initial cyclosporine doses produced target concentrations in only 30% of the patients at day 3. C2 was the single concentration that showed high and consistent correlation with serial AUC measurements (y2 2 0.76). The incidence of biopsy-proven acute rejection was 20.5% and was not associated with ethnicity, HLA mismatch, adjunctive therapy, or blood trough cyclosporine concentrations below 200 ng/ml at day 3. Significant time-dependent increases in steadystate cyclosporine exposure occur during the first month after kidney transplantation. Due to the low relative bioavailability early after surgery, higher doses and more frequent cyclosporine dose adjustments are necessary to produce target exposures early after transplantation.

Time-dependent pharmacokinetics of cyclosporine (NeoralR) in de novo renal transplant patients

“…dosing, is constant but it can change increasingly with time postoperatively. This tendency suggests the need for higher postoperative doses that may be tapered later on (8). This variation in F would affect the primary compartmental disposition parameters (e.g.…”

“…This last parameter varies widely between 21% and 73%, being lower immediately after renal allograft reception, and it is possibly a critical factor in explaining the observed unpredictability in the early kinetics, i.e. in the monitored blood concentration ( C b ) and the dose (3, 8).…”

Organization of a High-Volume Kidney Transplant Program???The ???Assembly Line??? Approach

“…These studies are important to identify better immunosuppressive regimens for our patients, taking into account the unique demography of our transplant population, which is quite different from that reported in the US or Europe. We have been participants in of the majority of international clinical trials and have also performed local research with immunosuppressive drugs including new combi- nations of cyclosporine (19,20); reduced doses of OKT3 (21), tacrolimus (22), sirolimus (23), everolimus (24), mycophenolate mofetil (25), and mycophenolate sodium (26); and FTY720 (27,28). To implement our research program, we have developed techniques to measure blood levels of sirolimus and mycophenolic acid (16,17).…”

Change of Cyclosporine Absorption over the Time After Kidney Transplantation

“…In addition, this requirement to higher initial doses of drug may be partly due to the low initial CsA absorption and the low relative bioavailability early after transplantation. Felipe et al reported a significant increasing time-dependent in steady state of CsA exposure occurred within the first month of kidney transplantation (14). It has been reported that a high intra-individual variability of C0 concentrations is associated with a greater incidence of acute and chronic rejection episodes, reduced 5-year graft survival and increased serum creatinine (15).…”