Predictive value of pretransplantation cyclosporine pharmacokinetic studies on initial post‐transplantation dosing in pediatric kidney allograft recipients

Abstract

Despite the introduction of a variety of new immunosuppressive agents, cyclosporine A (CsA) has maintained a strong position in pediatric transplantation (Tx). Post-Tx dosing with CsA is a challenging task because of the narrow therapeutic window of the drug, the great individual variability of metabolism and the lack of consensus about the optimal dosage and targeted blood concentration. Sufficient administration of CsA may be protective against acute rejections and other early complications after Tx, which is crucial for the long-term survival of the graft. Individual doses based on pre-Tx pharmacokinetic studies might be helpful in achieving optimal early concentrations of CsA. To asses the usefulness of pharmacokinetic studies, we retrospectively compared the post-Tx doses administered with the individually predicted doses between 1988 and 1998. Multiple regression of data on 65 de novo renal transplant recipients, 1.1-15.5 yr old, was used to analyze the significance of the predicted dose, trough blood concentration of CsA (B-CsA), serum creatinine and age at the time of Tx in explaining the doses used during the first three post-Tx weeks. Patients were grouped according to age (<2, 2-8 and >8 yr), according to the predicted dose (within or outside +/-25% of age-group average), and according to the oral formulation of CsA. Standard dosing scheme was simulated by using age-specific average doses in the place of the individual predicted doses. Administered doses of CsA were high [averaging 22.6 (504), 20.7 (484), and 12.4 mg/kg/d (329 mg/m2/d) for patients <2, 2-8, and >8 yr old] but the average B-CsA remained in the target range of 250-450 microg/L. The predicted dose and age were significant parameters in explaining the administered doses during the first 3 wk after Tx. B-CsA and S-creatinine were non-significant. The predicted doses were used to initiate the dosing of CsA after Tx (R2 = 0.70) and adjustments to dosing were made during the next weeks (R2 = 0.59, 0.52). Multiple regression model showed better fit for 60% of our patients, who had atypical predicted doses (R2 = 0.74, 0.60, 0.64 for first, second and third post-Tx weeks, respectively), most remarkably in patients <2 yr of age, than for the study population as a whole. A simulated standard dose was not able to explain the administered doses of CsA. In conclusion, pre-Tx pharmacokinetic studies are valuable for determining individual post-Tx starting doses, especially for those patients who need high or low doses of CsA. Individual dosing led to relatively high initial CsA doses, which could be significant for the long-term survival of the graft.

Long‐Term Changes in Cyclosporine Pharmacokinetics After Renal Transplantation in Children: Evidence for Saturable Presystemic Metabolism and Effect of NR1I2 Polymorphism

“…In our center, we have conducted a pretransplantation pharmacokinetic study to identify patients with an exceptionally large or small dose requirement of cyclosporine 52 . In our study, the allometrically scaled systemic clearance immediately after transplantation correlated strongly with the pretransplantation clearance ( r 2 = 0.69), as opposed to the bioavailability, which correlated poorly with its pretransplantation value ( r 2 < 0.01).…”

Better renal function with enhanced immunosuppression and protocol biopsies after kidney transplantation in children

“…All patients were on triple immunosuppression consisting of AZA, MP, and CsA (20). Only the microemulsion formulation of oral cyclosporine (Neoral®) was used.…”

“…Only the microemulsion formulation of oral cyclosporine (Neoral®) was used. CsA was started with pharmacokinetically determined individual doses (20, 21) three times a day in children under 8 yr of age because of their faster elimination (22) and in two doses in the older children, aiming at a trough blood concentration of 300 μ g/L (specific monoclonal radioimmunoassay). By 3 months after Tx B‐CsA was targeted at 150–200 μ g/L, after 6 months at 150 μ g/L and after 12 months at the maintenance level of 100 μ g/L.…”

Pretransplantation Pharmacokinetic Assessments to Predict Posttransplantation Dosing Requirements in renal Transplant Recipients: What Is Known?

“…In our opinion, the broad clinical implementation of pretransplantation assessment of CYP3A4 activity with midazolam as a drug probe or pretransplantation tacrolimus pharmacokinetics is not a promising approach because several studies have previously demonstrated clear discrepancies between pre‐ and posttransplantation pharmacokinetics of oral calcineurin inhibitors (CNIs) ( Table 1 ). If pediatric transplant recipients 2 and patients with combination antiretroviral therapy 3 are disregarded, all studies addressing pretransplantation pharmacokinetic assessments with oral CNIs have shown either a poor correlation between pre‐ and posttransplantation pharmacokinetics and dose requirements in “a general” adult kidney transplant recipient population, or that oral CNIs were not superior to standard dosing regimens, or both. Pharmacokinetically, this poor correlation is probably caused by a high within‐patient variability of peritransplant bioavailability of CNIs, 4 but the CNI metabolism will also be affected by the concomitant administration of interacting drugs.…”