Short sirolimus half-life in pediatric renal transplant recipients on a calcineurin inhibitor-free protocol

Abstract

Immunosuppression with SRL may provide an opportunity to avoid long-term exposure to the nephrotoxicity of CNI. Thus, we have initiated an experimental protocol of IL-2r antibody induction, prednisone, MMF and SRL in pediatric renal transplant recipients (median age 15.5 yr, IQR 8.5, range 1.3-21.7). The recipients were treated with daclizumab every 2 wk for the first 2 months, prednisone on a tapering schedule, MMF at 1200 mg/m(2)/day and SRL given b.i.d. The SRL was dosed to achieve defined target whole blood 12-h trough levels. We performed 24 SRL PK profiles in 13 stable pediatric renal transplant recipients at 1 and 3 months post-transplant. Half-life (T(1/2)) and terminal T(1/2) were 9.7 (7.1-24.6) and 10.8 (4.4-95.2) hours (median, range) respectively at month 1, and were 9.6 (5-17.8) and 12.1 (4.7-71.0) hours respectively at month 3. SRL trough levels correlated with AUC (r(2) = 0.84, p < 0.001). There was no relationship between SRL and mycophenolic acid (MPA) AUC values (r(2) = 0.04). During the first 3 months post-transplant only one patient experienced severe neutropenia and another patient had subclinical (histologic) evidence of a mild acute rejection episode with no change in renal function. We conclude that the T(1/2) of SRL in pediatric renal transplant recipients not treated with CNI is much shorter than what has been reported for adults, due to rapid metabolism. We conclude that children require SRL dosing every 12 h, higher doses and frequent drug monitoring to achieve target SRL concentrations.

Figures

Fig. 1

Median (IQR) and mean (s.d.) SRL PK profiles at month 1 and month 3 following renal transplantation in pediatric renal transplant recipients.

Fig. 2

Half-life (T1/2) and terminal T1/2 stratified by month 1 and month 3 following renal transplantation (a), (b); subject age under or over 6 yr (c), (d); and SRL liquid vs. tablet formulation (e), (f). SRL terminal T1/2 is statistically significantly lower in the younger age group (p < 0.05).

Fig. 3

Correlation of subject age with SRL T1/2 [(a), r2 = 0.03, p = 0.4] and SRL terminal T1/2 [(b), r2 = 0.14, p = 0.07].

Fig. 4

Correlation of SRL trough levels with AUC (r2 = 0.84, p < 0.001).

Fig. 5

SRL AUC (ng h/mL) stratified by month 1 and month 3 following renal transplantation (a), subject age under or over 6 yr (b), and SRL liquid vs. tablet formulation (c). SRL AUC is significantly higher at month 1 vs. month 3, corresponding to protocol dosing targets.

Fig. 6

Lipid profiles in 13 pediatric and adolescent renal transplant recipients.

Fig. 7

MPA AUC (mcg h/mL) stratified by month 1 and month 3 following renal transplantation (a) and by subject age under or over 6 yr (b).