Limited Sampling Strategies for the Estimation of Sirolimus Daily Exposure in Kidney Transplant Recipients on a Calcineurin Inhibitor—Free Regimen

Abstract

Sirolimus (SRL) is a novel immunosuppressive agent characterized by a narrow therapeutic index. Monitoring of SRL concentrations is mandatory to optimize drug dosing. The area under the concentration-time curve (AUC) is generally accepted as the best pharmacokinetic marker of daily drug exposure. Assessment of full SRL AUC, however, requires the collection of multiple blood samples, imposing both time and cost constraints. Limited sampling strategies (LSS) may be of clinical relevance to improve the therapeutic drug monitoring of SRL. In this study, stepwise multiple regression analysis is conducted on 30 SRL pharmacokinetic profiles obtained from kidney transplant recipients on a cyclosporine-free regimen, and different LSS equations are identified based on 2 or 3 sampling points collected within the first 6 hours after drug intake. The performance of these equations is tested in a separate validation set (n=30). Most of the proposed algorithms are associated with good correlations with the measured AUC and acceptable bias and imprecision. Two equations--based on 2 time points collected within the first 4 hours after dosing--are identified that reliably predict SRL exposure in routine clinical practice compared with the traditional C0-based approach. These tools provide additional information to optimize SRL therapeutic drug monitoring in renal transplant recipients.

Sirolimus and everolimus in kidney transplantation

“…Trough concentration (C trough ) and AUC correlation appears reasonable [16], although others have reported poorer correlation [52]. By contrast, AUC monitoring is often laborious and patient unfriendly unless limited sampling is applied.…”

Evaluation of Single-Point Sampling Strategies for the Estimation of Moclobemide Exposure in Depressive Patients

“…If the differences within mean ±1.96 × the standard deviation are not clinically important, the 2 methods may be used interchangeably. 1,16,33 All statistical analyses were performed with the use of the Statistical Package for the Social Sciences 13.0 for Windows (SPSS, Chicago, Ill).…”

“…The aim of this study was to evaluate whether single concentrationtime points could adequately predict moclobemide systemic exposure. Pharmacokinetic data (full 7-point pharmacokinetic profiles), obtained from 21 depressive inpatients receiving moclobemide (150 mg 3 times daily), were randomly split into development (n = 18) and validation (n = 16) sets. Correlations between the single concentrationtime points and the area under the concentration-time curve within a 6-hour dosing interval at steady-state (AUC 0-6 ) were assessed by linear regression analyses.…”

“…1 However, a growing number of studies performed with different drugs in specific patient subpopulations have revealed a poor association between C 0 and AUC. [15][16][17][18][19][20][21] Concentrations measured at other time points showed much better correlation with AUC, [21][22][23] and more complicated strategies have been developed that include a limited number of sampling time points within a short time post dose (limited sampling strategies [LSS]). 15 To the best of our knowledge, there have been no previous studies evaluating LSS for MCB.…”

Therapeutic Drug Monitoring in Cancer Chemotherapy

“…The genetic polymorphism of these enzymes and combination of drug therapy can affect plasma concentrations of mTOR and may lead to toxicities or treatment failure [89,90]. Cattaneo et al analyzed 2658 sirolimus trough samples in 495 kidney transplant recipients and found that dose-normalized sirolimus trough concentrations were significantly higher in patients treated with cyclosporine and sirolimus, compared with patients treated with mycophenolate mofetil and sirolimus or with patients treated with steroids and sirolimus [91]. They also showed that mean intra-and interpatient variability was 19 and 47%, respectively.…”