Division of Vascular Surgery and Kidney Transplant
Ospedale Maggiore – Policlinico, IRCCS
Division of Paediatric Nephrology, ICP
Ciclosporin represents the backbone of current immunosuppressive protocols in several paediatric kidney transplant centres. Its introduction in clinical practice in the mid-1980s yielded excellent results in kidney transplantation and allowed a dramatic reduction of steroid-related toxic effects such as hyperglycaemia, hypercholesterolaemia, aseptic necrosis, acne and osteoporosis. For the first time, the use of ciclosporin led to normal growth rates in paediatric kidney transplant recipients, and catch-up growth was sometimes observed.
The favourable pharmacokinetic profile of the microemulsion formulation of ciclosporin, Neoral (which has been available since 1993), is a great advantage in paediatric renal graft recipients, as it allows therapeutic drug monitoring for optimisation of ciclosporin exposure. However, although ciclosporin has been used in paediatric transplantation for almost 20 years, it has taken a long time to make progress with its use.
The importance of the therapeutic drug monitoring of ciclosporin (ie, measuring overall drug exposure within the dose interval using the area under the concentration–time curve [AUC]) was convincingly demonstrated by Kahan, who showed how a variable oral absorption is highly correlated with both occurrence of acute rejection episodes in the early posttransplant period and development of chronic rejection in the long run.(1,2) Therefore, the simple monitoring of ciclosporin blood concentration before the morning dose (known as trough level, or C(0)) is not adequate to capture the complexity of the pharmacokinetic and pharmacodynamic properties of ciclosporin.
Although the gold standard would be the full pharmacokinetic profile obtained by 12 blood samples drawn over a 12h period (AUC 0–12), this cannot always be performed, especially as a standard monitoring practice in the outpatient clinic. Therefore, abbreviated pharmacokinetic strategies, such as limited AUC or sparse sampling determination, have been proposed. For adult transplant recipients, a general agreement has recently been achieved for therapeutic monitoring of ciclosporin therapy.(3) The consensus document states that:
- The greatest immunosuppressive effect of ciclosporin occurs during the first 4h after administration; therefore, determination of AUC 0–4 is critical to ensure a favourable transplant outcome.
- C(0) correlates only poorly with AUC 0–4.
- C(2) (which represents ciclosporin blood concentration 2h after drug intake) is the most accurate single-sample marker for AUC 0–4.
- Targeting C(2) concentration as a strategy for post-transplant ciclosporin monitoring yields excellent graft outcomes by reducing acute rejection rate and nephrotoxicity episodes.
C(2)-monitoring in paediatric patients
Unfortunately, paediatric data currently available are insufficient for an exhaustive evaluation of the best monitoring strategy, and pharmacokinetics data cannot necessarily be extrapolated from the adult to the paediatric setting because of the important differences in ciclosporin metabolism between the two groups. Unquestionably, there is an age effect on ciclosporin absorption and metabolism. In fact, ciclosporin displays distinct pharmacokinetic properties in children: enhanced clearance rate, shorter drug half-life, highly variable bioavailability, faster drug elimination and significantly higher volume of distribution at steady state. Consequently, paediatric patients generally require higher doses of ciclosporin, and sometimes at more frequent interval, to achieve trough levels, C(max) levels and AUCs equivalent to those found in adults.(4) Therefore, a dosage based on body surface (mg/m(2)) rather than body weight (mg/kg) should be preferred in paediatric recipients to avoid the risk of underdosing. This is even more obvious in young children (<4 years old), who require a higher ciclosporin dose (50–80%) than adolescents when a posology based on mg/kg is used.(5) Age effects could be abolished by using the normalised AUC, which is obtained by dividing the AUC by the ciclosporin dose/m(2).
In paediatric renal transplant patients, the correlation between ciclosporin exposure and blood concentration at single points has been evaluated in several retrospective studies. Our research team found a strong correlation between C(2) and AUC 0–4 in a cohort of stable, long-term paediatric recipients.(6) Furthermore, a recent study by Dello Strologo(7) showed that C(2) can reflect AUC 0–12 or AUC 0–8 in all age groups, even in small children (3–7 years old) receiving ciclosporin every 8h. C(2) levels have also been correlated with kidney function: in stable paediatric transplant recipients, Pape showed that C(2) levels <750ng/ml correlate with a fairly significantly higher percentage of decline in glomerular filtration rate than C(2) levels >750ng/ml.(8) Recently, our team reported that chronic allograft nephropathy was more frequent in stable paediatric renal transplant patients who have been persistently exposed to low C(2) levels, and a multivariate analysis established C(2), rather than C(0), as one of the main variables that correlates the most with the development of chronic allograft nephropathy (ESOT 2003, personal communication).
The importance of attaining adequate ciclosporin exposure in the immediate post-transplant weeks has been demonstrated in adults, and appropriate guidelines will hopefully be available shortly from the MO2ART (Monitoring Of 2-hour Neoral Absorption in Renal Transplantation) study.(9) The monitoring of ciclosporin pharmacokinetics during this crucial period is of particular importance in paediatric transplantation, as the increased risk of acute rejection compared with the adult population is well documented.(10) This could be explained by the relatively high incidence of poor ciclosporin absorbers among children; this can be easily identified by a routine therapeutic drug monitoring strategy.
Therefore, prospective studies in de-novo kidney transplant recipients should be planned. To date, only one retrospective analysis has underlined the importance of C(2) monitoring in de-novo renal transplant paediatric recipients. Patients achieving C(2) levels >1.5mg/ml five days after the operation experienced no acute rejection in the first six months, compared with a 50% rejection rate among patients with C(2) levels <1.5mg/ml (p<0.05). Furthermore, renal function did not appear to be adversely influenced by higher C(2) levels.(11) A prospective, observational, open-label study on C(2) monitoring in de-novo paediatric kidney transplantation is ongoing in five Italian paediatric kidney transplant centres. Ciclosporin was tailored on C(2) targets rather than C(0). The interim analysis of the database confirmed that the strong correlation (r=0.98) between C(2) and AUC 0–4 persisted steadily over time, up to one year post-transplantation. Furthermore, any correlation between C(2) levels and nephrotoxicity was present, and the proposed C(2) targets granted an adequate exposure to ciclosporin, as confirmed by the number of acute rejection episodes (ATS 2004, personal communication).
In paediatric renal transplant recipients, C(2) monitoring reflects ciclosporin absorption and exposure better than C(0). Therapeutic targets to prevent acute rejection and chronic allograft nephropathy should soon be defined. However, further testing is warranted to tailor the ideal ciclosporin dose for each individual patient. In fact, ciclosporin C(2) targets also need to be determined for different immunosuppressive regimens, including combinations of ciclosporin with mycophenolate mofetil or mammalian target-of-rapamycin (mTOR) inhibitors, and combinations of immunoprophylaxis with anti-interleukin-2 receptors or antithymocyte globulin (ATG).
Although calcineurin inhibitor-sparing immunosuppressive regimens have been hypothesised, we believe that more research needs to be carried out to exploit the potential of ciclosporin fully.
- Kahan BD, Welsh M, Schoenberg L, et al. Transplantation 1996;62:599-606.
- Lindholm A, Kahan BD. Clin Pharmacol Ther 1993;54:205-18.
- Levy G, Thervet E, Lake J, et al. Transplantation 2002: 73:12-8.
- Hoyer PF, Brodehl J, Ehrich JH, et al. Pediatr Nephrol 1991;5:630-8.
- Kovarik JM, Hoyer PF, Ettenger R, et al. Pediatr Nephrol 2003;18:1275-9.
- Ferraresso M, Ghio L, Tirelli S, et al. Transplant Proc 2004; 36:685.
- Dello Strologo L, Pontesilli C, Rizzoni G, et al. Transplantation 2003;76:444-5.
- Pape L, Lehnhardt A, Latta K, et al. Clin Transplant 2003;17:546-8.
- Thervet E, Pfeffer P, Scolari MP, et al. Transplantation 2003;76:903-8.
- Nashan B, Cole E, Levy G, et al. Transplantation 2002;73:S3-11.
- Trompeter R, Fitzpatrick M, Hutchinson C, et al. Pediatr Transplant 2003;7:282-8.