Development and validation of an analytical method using UPLC–MS/MS to quantify everolimus in dried blood spots in the oncology setting

Knapen, Lotte M.; Beer, Yvo de; Brüggemann, Roger J. M.; Stolk, L. M. L.; Vries, Frank de; Tjan‐Heijnen, Vivianne C. G.; Erp, Nielka P. van; Croes, Sander

doi:10.1016/j.jpba.2017.10.039

Cited by 25 publications

(15 citation statements)

References 27 publications

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“…The predictive performance of the DBS analytical method was established using the method described by Sheiner and Beal [35]. In short, DBS concentrations were used to predict WB concentrations.…”

Section: Discussionmentioning

confidence: 99%

Clinical application of a dried blood spot assay for sirolimus and everolimus in transplant patients

Veenhof

Koster²,

Alffenaar

et al. 2019

Clinical Chemistry and Laboratory Medicine (CCLM)

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Background Monitoring of immunosuppressive drugs such as everolimus and sirolimus is important in allograft rejection prevention in transplant patients. Dried blood spots (DBS) sampling gives patients the opportunity to sample a drop of blood from a fingerprick at home, which can be sent to the laboratory by mail. Methods A total of 39 sirolimus and 44 everolimus paired fingerprick DBS and whole blood (WB) samples were obtained from 60 adult transplant patients for method comparison using Passing-Bablok regression. Bias was assessed using Bland-Altman. Two validation limits were pre-defined: limits of analytical acceptance were set at >67% of all paired samples within 20% of the mean of both samples and limits of clinical relevance were set in a multidisciplinary team at >80% of all paired samples within 15% of the mean of both samples. Results For both sirolimus and everolimus, Passing-Bablok regression showed no differences between WB and DBS with slopes of 0.86 (95% CI slope, 0.72–1.02) and 0.96 (95% CI 0.84–1.06), respectively. Only everolimus showed a significant constant bias of 4%. For both sirolimus and everolimus, limits of analytical acceptance were met (76.9% and 81.8%, respectively), but limits or clinical relevance were not met (77.3% and 61.5%, respectively). Conclusions Because pre-defined limits of clinical relevance were not met, this DBS sampling method for sirolimus and everolimus cannot replace WB sampling in our center at this time. However, if the clinical setting is compatible with less strict limits for clinical relevance, this DBS method is suitable for clinical application.

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Section: Discussionmentioning

confidence: 99%

Clinical application of a dried blood spot assay for sirolimus and everolimus in transplant patients

Veenhof

Koster²,

Alffenaar

et al. 2019

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…Bioanalysis of the WB, DBS, and DBS wb samples was performed using two validated ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods. One method was used for the analysis of WB samples and another method was used to analyze the DBS and DBS wb samples [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

Clinical validation study of dried blood spot for determining everolimus concentration in patients with cancer

Willemsen¹,

Knapen

Beer

et al. 2017

Eur J Clin Pharmacol

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PurposeEverolimus treatment is seriously hampered by its toxicity profile. As a relationship between everolimus exposure and effectiveness and toxicity has been established, early and ongoing concentration measurement can be key to individualize the dose and optimize treatment outcomes. Dried blood spot (DBS) facilitates sampling at a patients’ home and thereby eases dose individualization. The aim of this study is to determine the agreement and predictive performance of DBS compared to whole blood (WB) to measure everolimus concentrations in cancer patients.MethodsPaired DBS and WB samples were collected in 22 cancer patients treated with everolimus and analyzed using UPLC-MS/MS. Bland-Altman and Passing-Bablok analysis were used to determine method agreement. Limits of clinical relevance were set at a difference of ± 25%, as this would lead to a different dosing advice. Using DBS concentration and Passing-Bablok regression analysis, WB concentrations were predicted.ResultsSamples of 20 patients were suitable for analysis. Bland-Altman analysis showed a mean ratio of everolimus WB to DBS concentrations of 0.90, with 95% of data points within limits of clinical relevance. Passing-Bablok regression of DBS compared to WB revealed no constant bias (intercept 0.02; 95% CI 0.93–1.35) and a small proportional bias (slope 0.89; 95% CI 0.76–0.99). Predicted concentrations showed low bias and imprecision and 90% of samples had an absolute percentage prediction error of < 20%.ConclusionsDBS is a valid method to determine everolimus concentrations in cancer patients. This can especially be of value for early recognition of over- or underexposure to enable dose adaptations.Electronic supplementary materialThe online version of this article (10.1007/s00228-017-2394-0) contains supplementary material, which is available to authorized users.

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“…TAC and other related immunosuppressant drugs, like sirolimus, everolimus, and cyclosporine A, must be constantly evaluated in blood samples to allow characterization of their pharmacokinetics and optimization of medicine use and formulations. − For this reason, a great number of immunoassays and mass spectrometry methods have been developed. − Different ionizing agents including Ca 2+ can be used, and it has been shown that TAC complexation by calcium and other cations affects ion fragmentation in mass spectrometry analysis and is relevant for TAC quantitation and identification. , …”

Section: Introductionmentioning

confidence: 99%

Evaluation of Ca²⁺ Binding Sites in Tacrolimus by Infrared Multiple Photon Dissociation Spectroscopy

et al. 2018

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Tacrolimus (TAC) is an efficient immunosuppressant used in organ transplantation procedures. There is an intrinsic correlation between TAC and Ca because of the dependence of its action mechanism on calcium and calcineurin, and the role of ion coordination on TAC identification and quantitation. To depict the Ca binding sites in TAC, this work carried out gas-phase vibrational infrared multiple photon dissociation spectroscopy of [Ca(TAC)] and of three other TAC mimetic molecules (probes 1-3). Density functional theory (DFT) and Monte Carlo (MC) simulations were also used to support the experimental data assignment, and natural bond orbital (NBO) analysis was carried out to depict the coordination sphere. PM3 and B3LYP/6-31G(d) levels of theory displayed similar trends during the MC simulations, suggesting that PM3 is a viable alternative to more expensive DFT calculations, at least during the conformational analysis step. Infrared spectroscopy of the [Ca(probe X)] and [Ca(probe X)] ( X = 1-3) complexes allowed for a useful guide for building guess geometries and for the band assignment of the [Ca(TAC)] complex. Nevertheless, the MC approach was particularly useful for exploring the potential energy surface. The lowest energy conformation for [Ca(TAC)] was found by MC simulations and is 32.92 kJ mol lower in energy than the one found by comparing the results obtained for Ca coordination in probes, despite the calculated spectra being virtually identical. Both approaches are good ways to depict the coordination sites, and these results suggest that using small molecules as models is a reliable approach to depict the geometry or coordination sites of extensive ions, yielding a robust correlation between experimental and theoretical spectra. Furthermore, MC survey produced a lower energy conformation with a good match to the experimental results. Both methods depict the Ca coordination sphere as a hexacoordinated environment where the main coordination centers are carbonyl groups.

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Development and validation of an analytical method using UPLC–MS/MS to quantify everolimus in dried blood spots in the oncology setting

Cited by 25 publications

References 27 publications

Clinical application of a dried blood spot assay for sirolimus and everolimus in transplant patients

Clinical application of a dried blood spot assay for sirolimus and everolimus in transplant patients

Clinical validation study of dried blood spot for determining everolimus concentration in patients with cancer

Evaluation of Ca²⁺ Binding Sites in Tacrolimus by Infrared Multiple Photon Dissociation Spectroscopy

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Development and validation of an analytical method using UPLC–MS/MS to quantify everolimus in dried blood spots in the oncology setting

Cited by 25 publications

References 27 publications

Clinical application of a dried blood spot assay for sirolimus and everolimus in transplant patients

Clinical application of a dried blood spot assay for sirolimus and everolimus in transplant patients

Clinical validation study of dried blood spot for determining everolimus concentration in patients with cancer

Evaluation of Ca2+ Binding Sites in Tacrolimus by Infrared Multiple Photon Dissociation Spectroscopy

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Evaluation of Ca²⁺ Binding Sites in Tacrolimus by Infrared Multiple Photon Dissociation Spectroscopy