Dose-adjusted and dose/kg-adjusted concentrations of mycophenolic acid precursors reflect metabolic ratios of their metabolites in contrast with tacrolimus and cyclosporine.

Ewa Hryniewiecka,Dorota Żochowska,Sławomir Nazarewski,Emilia Samborowska,Maciej Kosieradzki,Leszek Pączek,Jolanta Żegarska,Radosław Jaźwiec,Michał Dadlez

doi:10.1042/bsr20182031

Abstract

Background and purpose: Therapeutic drug monitoring is a valuable tool supporting immunosuppressive therapy. Significant variation of immunosuppressive drug (ISD) concentrations during their use at similar doses is the basis of dose-normalization strategy. The strategy of dose-adjustment is proposed to identify variability in the rate of ISD metabolism. While the parent drug-to-metabolite ratio (metabolic ratio, MR) represents the rate of formation of individual metabolites. The present study was aimed at evaluation of associations between ISDs’ metabolism rate expressed as dose-adjusted concentrations (C/D) and dose/kg-adjusted concentrations (C/D/kg) and MRs of individual metabolites of tacrolimus, cyclosporine A and MPA precursors.Experimental approach: 506 patients have participated: 284 males (56.13%) and 222 females (43.87%); 318 after kidney (62.85%) and 188 after liver transplantation; median age was 51.34 (39.32-59.95) years and median time after transplantation 78.92 (33.87-138.4) months.Key results: Generally, we have not observed significant relationships between dose-adjusted and dose/kg-adjusted concentrations and MRs of cyclosporine and tacrolimus. Significant correlations were found for: AM9/CsA and dMC-CsA/CsA in kidney transplant recipients and MIII/Tac, AM1/CsA and AM4N/CsA in liver transplant recipients. In contrast, MRs of mycophenolic acid (MPA) metabolites correlated significantly with MPA C/D and C/D/kg both in kidney and liver transplant recipients.Conclusion and implications: In conclusion, easily available and easy to use in clinical practice C/D and C/D/kg ratios cannot be considered as parameters directly reflecting the rate of generation of major metabolites of cyclosporine and tacrolimus both in liver and kidney transplant recipients.

Highlights

Therapeutic drug monitoring (TDM) is a valuable tool that supports usage of medicinal products with narrow therapeutic window and high inter- and intraindividual variability of dose/exposure relationship
A total of 506 patients have participated in the study: 284 males (56.13%) and 222 females (43.87%); 318 patients were kidney recipients (62.85%) and 188 patients were liver recipients (37.15%); steroids were taken by 369 patients (72.93%); precursors of mycophenolic acid (pMPA) were taken by 314 patients (62.06%); Tac was taken by 308 patients (60.87%) and Cyclosporine A (CsA) was taken 157 patients (31.03%)
Since the determination of concentrations of individual immunosuppressive drug (ISD) metabolites or polymorphisms of genes encoding enzymes engaged in the metabolism of immunosuppressants are not widely available, dose-adjusted concentration (C/D) and dose/kg-adjusted concentration (C/D/kg) evaluation seems to be a very promising strategy [6,7]

Summary

Introduction

Therapeutic drug monitoring (TDM) is a valuable tool that supports usage of medicinal products with narrow therapeutic window and high inter- and intraindividual variability of dose/exposure relationship. Significant variation of immunosuppressive drug concentrations during their use at similar doses was the basis of dose-normalization strategy. Higher drug concentration/dose ratios are indicative of lower activity of complex processes leading to ISD clearance from patients’ blood, including slower metabolism, whereas higher metabolite concentration/dose ratios indicate increased rate of these processes. Significant variation of immunosuppressive drug (ISD) concentrations during their use at similar doses is the basis of dose-normalization strategy. The present study was aimed at evaluation of associations between ISDs’ metabolism rate expressed as dose-adjusted concentrations (C/D) and dose/kg-adjusted concentrations (C/D/kg) and MRs of individual metabolites of tacrolimus, cyclosporine A and MPA precursors. Conclusion and implications: In conclusion, available and easy to use in clinical practice C/D and C/D/kg ratios cannot be considered as parameters directly reflecting the rate of generation of major metabolites of cyclosporine and tacrolimus both in liver and kidney transplant recipients

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Results

Conclusion