Sirolimus pharmacokinetics in pediatric renal transplant recipients receiving calcineurin inhibitor co‐therapy

Abstract

We have previously reported sirolimus (SRL) pharmacokinetics (PK) in pediatric renal transplant recipients on a calcineurin inhibitor (CNI)-free protocol. We now report pediatric SRL PK in pediatric renal transplant patients receiving SRL + CNI. SRL was dosed to achieve target trough levels between 10 and 20 ng/mL. We performed 49 SRL PK profiles in pediatric renal transplant recipients receiving SRL in combination with either cyclosporine (CsA; 25 profiles), or tacrolimus (TCL; 24 profiles). Ten of the SRL + TCL profiles were obtained from children receiving SRL on a b.i.d. dosing regimen. All other SRL profiles were q.d. regimens. We calculated, the maximum concentration (C max ), AUC, apparent clearance (aCL; dose/AUC) for dose in mg/m 2 , and mean residence time (MRT). SRL levels were measured at 6 and 7 time points for b.i.d. and q.d. dosing, respectively. Regression analysis of SRL trough values vs. AUC showed good correlation in the SRL q.d. + CsA, SRL q.d. + TCL, and SRL b.i.d. + TCL groups (r 2 = 0.95, 0.68, and 0.44, respectively). SRL aCL corrected for body surface area was higher in children aged 0-5 yr receiving SRL with either CsA or TCL. SRL dosing schedule should be tailored to each patient. Higher SRL aCL may be present in younger children when administered with CNI. Keywords Patients and methodsAll PK profiles were performed as part of an ongoing multi-center randomized clinical trial to evaluate steroid withdrawal protocols in pediatric renal transplant recipients. All study subjects received induction therapy with basiliximab preoperatively and on postoperative day 4. SRL was administered beginning on postoperative day 1 at a dose of 6 mg/m 2 , and was thereafter adjusted to achieve target trough levels in the range of 10-20 ng/mL. SRL was administered q.d. when given in combination with CsA (25 subjects), and q.d. (10 subjects) or b.i.d. (14 subjects) when given in combination with TCL. CsA doses were initiated at 400 mg/m 2 /day for children younger than six yr of age, and at 10 mg/kg/day for children six yr of age and over. CsA doses were adjusted to whole blood trough TDX monoclonal levels within the range of 175-400 ng/mL for the first two wk, then 175-300 ng/mL for three wk to three months, then 50-250 ng/mL after three months. The study protocol allows for the use of TCL as an alternative to CsA. TCL was given b.i.d. at 0.1 mg/kg/dose, and was adjusted to maintain whole blood trough levels between 10 and 15 ng/mL for the first four postoperative wk, and between 5 and 10 ng/mL thereafter. Methylprednisolone was administered peri-operatively and on postoperative day 1. Full dose prednisone (2 mg/kg/day, maximum of 60 mg/day) was initiated on postoperative day 2, and prednisone tapering began on postoperative day 4. At posttransplant month 7, all patients who had no evidence of sub-clinical rejection as determined by protocol biopsy underwent blinded randomization to undergo either steroid withdrawal via placebo or remain on steroid therapy.SRL PK was performed at post-transplant...

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