Therapeutic Drug Monitoring, Electronic Health Records, and Pharmacokinetic Modeling to Evaluate Sirolimus Drug Exposure–Response Relationships in Renal Transplant Patients

Abstract

Background Sirolimus, an immunosuppressant agent used in renal transplantation, can prevent allograft rejection. Identification of the therapeutic index (ratio of minimum toxic concentration to minimum therapeutic concentration) for immunosuppresants is necessary to optimize the care of patients and set standards for bioequivalence evaluation of sirolimus products. However, the therapeutic index for sirolimus has been inconsistently defined, potentially due to inconsistencies in sirolimus exposure-response relationships. Methods The authors used retrospective therapeutic drug monitoring data from the electronic health records of patients treated in a tertiary healthcare system from 2008 to 2014, to: 1) develop a population pharmacokinetic model, 2) use the model to simulate sirolimus concentrations, and 3) characterize the exposure-response relationship. Using Wilcoxon rank-sum and Fisher’s exact tests, the authors determined relationships between sirolimus exposure and adverse events (anemia, leukopenia, thrombocytopenia, hyperlipidemia, decline in renal function) and the composite efficacy endpoint of graft loss or rejection. Results The developed 2-compartment population pharmacokinetic model showed appropriate goodness of fit. In a late-phase (>12 months), post-renal transplant population of 27 inpatients, the authors identified statistically significant relationships between 83 simulated peak and trough sirolimus concentrations and outcomes: graft loss or rejection (p=0.018), and decline in renal function (p=0.006), respectively. Conclusions Use of therapeutic drug monitoring results and pharmacokinetic modeling permitted correlation of sirolimus concentrations with graft loss or rejection, and decline in renal function. However, the method was limited in its assessment of other adverse events. To better evaluate sirolimus exposure-response relationships, the method should be applied to a larger sample of newly-transplanted patients with a higher propensity toward adverse events or efficacy failure.

Clinical implementation of pharmacogenetics and model‐informed precision dosing to improve patient care

“…To date, a number of population PK/PD modelling studies have been published for sirolimus, mostly in patients after renal transplantation. [33][34][35][36][37][38][39][40][41] As part of these studies several predictors of clearance were identified, including body size (ie body weight), hematocrit and CYP3A5 genotype. 33,35,38 Djebli et al developed a Bayesian estimator as part of sirolimus dose individualization using a practical three-time point limited sampling strategy with samples at pre dose, 1 and 3 hours post dose.…”

“…These studies are not only the investigations using a pharmacometrics approach to characterize sirolimus PK/PD. To date, a number of population PK/PD modelling studies have been published for sirolimus, mostly in patients after renal transplantation 33–41 . As part of these studies several predictors of clearance were identified, including body size (ie body weight), hematocrit and CYP3A5 genotype 33,35,38 .…”

A gold-based immunochromatographic strip for the detection of sirolimus in human whole blood

“…However, sirolimus has a long half-life, a narrow therapeutic window, and large individual variations in the pharmacokinetics 8 and therefore, its improper use may cause adverse reactions, such as immune rejection, thrombocytopenia, leucopenia, or hyperlipidemia. 9,10 Immunosuppressive drugs in the body are usually measured once or twice a day before the patient is given a new dosage 11 and it is, therefore, important to monitor their blood levels for the duration of any treatment. In addition, a rapid and efficient monitoring method for sirolimus should allow its quantification in human whole blood, because it is mainly distributed in erythrocytes.…”

Population Pharmacokinetic Analysis and Dosing Optimization of Sirolimus in Children With Tuberous Sclerosis Complex

“…Although several studies have described the population pharmacokinetic (PopPK) characteristics of sirolimus in pediatric patients, [9][10][11][12] pharmacokinetic data for children with TSC are still limited. 13,14 In addition, the therapeutic range for oral sirolimus is narrow, and the apparent clearance and apparent volume of distribution (V d ) are highly variable in pediatric patients, 9 which might lead to treatment failure or increased drugrelated toxicity.…”