New concepts in cyclosporine pharmacokinetic and dynamic monitoring: the impact of concomitant immunosuppression on target C₂ concentrations

Abstract 

Background

There is a correlation between cyclosporine (CsA) pharmacokinetics (PK) and pharmacodynamics (PD), especially 2 hours after drug administration.

Aim

To evaluate the relationship between CsA PK and PD profiles in two groups of stable renal transplant patients treated with CsA alone or CsA plus mycophenolate mofetil (CsA+MMF), so as to define the best target for C₂ and clarify the impact of concomitant immunosuppression.

Methods

Thirty-eight stable renal transplant recipients were treated with CsA (n = 20) or CsA+MMF (n = 18). Twelve nontreated normal healthy controls (NHC) were also included. Calcineurin activity (CNa), IL-2 production, and CsA levels were measured at 0 and 2 hours postdose.

Results

There were no significant differences in median CsA C₂ values and CNa between the CsA alone and the CsA+MMF groups (388 μg/L and 497.5 μg/L and CNa 2h; 3.92% alkaline phosphatase [AP]; 3.94% AP, respectively). In vitro production of IL-2 was significantly lower in the CsA+MMF group than in the CsA group (median IL-2 2h: 280.52 ng/L, 169.48 ng/L, P < .001). The correlations (r) between C₂ and CNa 2h were: CsA r = 0.74; CsA+MMF r = 0.84 (P < .001 in both cases).

Conclusions

In stable renal transplant patients, median CsA C₂ values below 500 μg/L were associated with inhibition of CNa and IL-2 synthesis. CNa and IL-2 production may be good biological markers of CsA immunosuppression. The measurement of CNa depends mainly on CsA concentration, whereas in vitro IL-2 production reflects the effect of both CsA and MMF. Further studies are necessary to define the optimal C₂ target concentration and the possible impact of concomitant immunosuppression.