Liquid chromatography-tandem mass spectrometry outperforms fluorescence polarization immunoassay in monitoring everolimus therapy in renal transplantation.
BACKGROUND
There is a need to monitor everolimus blood concentrations in renal transplant recipients as a result of its high pharmacokinetic variability and narrow therapeutic window. However, analytical methods to determine blood concentrations often differ in performance. Therefore, we investigated whether two commonly used therapeutic drug monitoring methods for everolimus were in agreement and to what extent their differences could lead to differences in dosage advice.


METHODS
Six hundred twelve whole blood samples were obtained from 28 adult renal transplant recipients receiving everolimus and prednisolone therapy. These samples included 286 everolimus trough concentrations. The remaining samples were obtained up to 6 hours post everolimus intake and allowed calculation of 84 AUCs0-12h. All samples were analyzed with fluorescence polarization immunoassay (FPIA) on an Abbott TDxFLx analyzer and liquid chromatography-tandem mass spectrometry (LC-MS/MS).


RESULTS
Everolimus blood concentrations measured with FPIA and LC-MS/MS were not in agreement. Concentrations determined by FPIA were, on average, 23% higher than concentrations quantified by LC-MS/MS. Moreover, concentrations lower than 15 mug/L or AUC0-12h determined with FPIA could be twofold higher than with LC-MS/MS. This variability can lead to clinically relevant differences in dose adjustment of up to 1.25 mg everolimus despite using a correction factor of 23%. Finally, when trough concentrations were measured with FPIA, higher intrapatient variability was observed compared with the use of LC-MS/MS.


CONCLUSIONS
LC-MS/MS outperforms FPIA for clinical drug monitoring and intervention of everolimus therapy in adult renal transplant recipients on dual therapy with prednisolone. Specifically, the use of FPIA can lead to clinically relevant differences in everolimus dosage advice and higher intrapatient variability.
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. D.J.A.R.Moes@lumc.nl
Dirk Jan A R
DJ
Moes
Rogier R
RR
Press
Johan W
JW
de Fijter
Henk-Jan
HJ
Guchelaar
Jan
J
den Hartigh
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D016903:Drug Monitoring / Q000379:methods; D000068338:Everolimus; D005260:Female; D016231:Fluorescence Polarization Immunoassay; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood*; D016030:Kidney Transplantation / Q000276:immunology* / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D011786:Quality Control; D015203:Reproducibility of Results; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D053719:Tandem Mass Spectrometry
D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus