Exploring sirolimus pharmacokinetic variability using data available from the routine clinical care of renal transplant patients – population pharmacokinetic approach

Abstract

Summary Background Due to wide intra- and inter-individual pharmacokinetic variability and narrow therapeutic index of sirolimus, the therapeutic drug monitoring (TDM) of sirolimus with detailed biochemical and clinical monitoring is necessary for dose individualization in kidney transplant patients. The purpose of the study was to explore and identify factors that contribute to pharmacokinetic variability by developing and validating a population model using routine TDM data and routinely monitored biochemical and clinical parameters. Methods The data obtained by routine monitoring of 38 patients over a period of one year from the sirolimus treatment initiation, were collected from patients’ records. Population analysis was performed using the software NONMEM®. The validity of the model was tested by the internal and external validation techniques. Results The pharmacokinetic variability was partially explained with patient’s age and liver function. CL/F was found to decrease with age. According to the developed model, sirolimus CL/F decreases by, in average, 37% in patients with aspartate aminotransferase (AST) greater than 37 IU/L. The internal and external validation confirmed the satisfactory prediction of the developed model. Conclusions The population modeling of routinely monitored data allowed quantification of the age and liver function influence on sirolimus CL/F. According to the final model, patients with compromised liver function expressed via AST values require careful monitoring and dosing adjustments. Proven good predictive performance makes this model a useful tool in everyday clinical practice.

Concept and utility of population pharmacokinetic and pharmacokinetic/pharmacodynamic models in drug development and clinical practice

“…Similarly, the utility of population PK approach could be observed in characterising immunosuppressive drugs' PK. Golubovic et al developed population PK models based on TDM data of sirolimus and tacrolimus from adult kidney transplant patients (67,68). Moreover, the published population models and intrinsic and extrinsic factors contributing to variability for specific therapeutic groups are summarised in review articles (69,70).…”

Prior information for population pharmacokinetic and pharmacokinetic/pharmacodynamic analysis: overview and guidance with a focus on the NONMEM PRIOR subroutine

“…Most articles reviewed validated the models built with priors using simulation-based diagnostics (i.e. VPC [5, 6, 9, 11-14, 17-24, 28, 30-34], pcVPC [8,10,16,29], and NPDE [9,25,29]). Some used bootstrap [4, 5, 9, 11-14, 16-18, 20, 23-25, 27, 32, 34], SIR [28] and external validation [30,33,34].…”

Sirolimus Pharmacokinetics Variability Points to the Relevance of Therapeutic Drug Monitoring in Pediatric Oncology

“…In transplantation, trough concentration is highly correlated with sirolimus exposure, its efficacy, and toxicity [ 20 , 21 , 24 ]. Therapeutic targets of sirolimus associated with cyclosporine are generally between 5 and 15 µg/L, while trough sirolimus concentrations greater than 15 µg/L are correlated with increased toxicity and less than 5 µg/L with decreased efficacy [ 21 ].…”