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Latin American Journal of Clinical Sciences and Medical Tecnology
Monday November 29th, 2021
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Original Article

Herlinda Reyes-Péreza; Alan Ricardo Quiroz Moguelb; Luis Velásquez Jonesa; Ana María Hernándeza; Pilar García-Roca (0000-0002-3106-773X)a; Lorena Medina-Aymerich (0000-0002-4967-6744)b; Mara Medeiros Domingo (0000-0002-6848-8933)c; Gilberto Castañeda-Hernández (0000-0001-9149-885X)b; Rodrigo González-Ramírez (0000-0002-9824-6679)d.
aDepartamento de Nefrología, Hospital Infantil de México "Federico Gómez", Ciudad de México, México; bCentro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, México; cUnidad de Investigación y Diagnóstico en Nefrología y Metabolismo Mineral Óseo, Hospital Infantil de México "Federico Gómez", Departamento de Farmacología, Facultad de Medicina UNAM, Ciudad de México, México; dConsultor en Farmacología y Farmacocinética, Ciudad de México, México.
Corresponding Author: , . Tel: ; e-mail: xrxr26@hotmail.com

Citation: Reyes Pérez H, Quiroz Moguel A, Velásquez Jones L, Hernández AM, García Roca P, Medina Aymerich L, et al. Comparison between enzyme-multiplied immunoassay technique (EMIT) and high-performance liquid chromatography with ultraviolet detection (HPLC-UV) for the therapeutic drug monitoring of mycophenolic acid in Mexican pediatric patients with renal transplantation.
Lat Am J Clin Sci Med Technol. 2021 Sep; 3: 128-134.
Received: October 14th, 2020.
Accepted: August 10th, 2021.
Published: September 3rd, 2021.
Views: 36
Downloads: 13
ABSTRACT

Introduction. Mycophenolic acid (MPA) is an immunosuppressant; thus, monitoring of plasma levels is recommended. The most popular analytic methods used for the MPA quantification are the enzyme-multiplied immunoassay technique (EMIT) and the high-performance liquid chromatography with ultraviolet detection (HPLC-UV). The purpose of the present study was to compare both methods performances for the therapeutic drug monitoring of MPA in Mexican pediatric patients with renal transplantation. Material and Methods. A prospective cross‐sectional study was carried out, 25 patients with kidney transplantation were included. Mycophenolate mofetil was administered and blood samples were drawn at 0, 0.5, 1, 2, 3, 4, 6, 8, and 12 h after medication. Plasma samples were obtained and divided into two aliquots for further quantification by both methodologies. Each concentration determined by EMIT was compared with the corresponding quantification by HLPC-UV. Bias and precision were estimated as previously described by Sheiner and Beal. Results. EMIT overestimated MPA concentrations with a positive bias of 59.25% and a precision of 54.85%. AUC0-12, the recommended parameter for therapeutic drug monitoring of MPA, was significantly overestimated by EMIT in more than 50%. Discussion. Overestimation derives from metabolite cross-reactivity in EMIT, which does not occur with HPLC-UV. Hence, HPLC-UV appears to be a more suitable method for MPA therapeutic drug monitoring in Mexican pediatric patients with renal transplantation.

Keywords: therapeutic drug monitoring, mycophenolic acid, renal transplantation, pediatric patient
RESUMEN

Introducción. El ácido micofenólico (mycophenolic acid, MPA) es un inmunosupresor; por tanto, se recomienda el monitoreo de los niveles plasmáticos. Los métodos analíticos más populares utilizados para la cuantificación de MPA son la técnica de inmunoensayo multiplicado por enzimas (enzyme-multiplied immunoassay technique, EMIT) y la cromatografía líquida de alta resolución con detección ultravioleta (high-performance liquid chromatography with ultraviolet detection, HPLC-UV). El objetivo de este estudio fue comparar el desempeño de ambos métodos en el monitoreo de MPA en pacientes pediátricos mexicanos con trasplante renal. Material y métodos. Se realizó un estudio prospectivo transversal en el que se incluyeron 25 pacientes con trasplante renal. Se administró micofenolato de mofetilo y se extrajeron muestras de sangre a las 0, 0.5, 1, 2, 3, 4, 6, 8 y 12 h después del medicamento. Se obtuvieron muestras de plasma y se dividieron en dos alícuotas para su posterior cuantificación mediante ambas metodologías. Cada concentración determinada por EMIT se comparó con la cuantificación correspondiente por HLPC-UV. El sesgo y la precisión se estimaron según lo descrito previamente por Sheiner y Beal. Resultados. EMIT sobrestimó las concentraciones de MPA con un sesgo positivo de 59.25% y una precisión de 54.85%. El AUC0-12, parámetro recomendado para la monitorización terapéutica del MPA, fue sobrestimado significativamente por EMIT en más del 50%. Discusión. La sobreestimación se debe a la reactividad cruzada de metabolitos en EMIT, que no ocurre con HPLC-UV. Por tanto, la HPLC-UV parece ser un método más adecuado para la monitorización de fármacos terapéuticos con MPA en pacientes pediátricos mexicanos con trasplante renal.

Palabras clave: monitoreo terapéutico de fármacos, ácido micofenólico, trasplante renal, paciente pediátrico

INTRODUCTION

Mycophenolic acid (MPA) is a widely used immunosuppressive agent employed in several organ transplants.1 It is the active mycophenolate mofetil metabolite2 and is most extensively used as an anti-rejection maintenance medication in pediatric renal transplantation.2 Since MPA is hugely irritant for the gastric mucosa, it is administered orally as the inactive prodrug mycophenolate mofetil or an enteric-coated formulation of mycophenolate sodium salt.3,4 MPA pharmacokinetics exhibits an essential interindividual variability. Hence, individualized regimens based on therapeutic drug monitoring have been recommended for both adult and pediatric patients.2,5

There are several methods for measuring mycophenolate concentrations in plasma samples. The most popular ones are the enzyme-multiplied immunoassay technique (EMIT) and the high-performance liquid chromatography with ultraviolet detection (HPLC-UV).6 A chromatographic method is a separation procedure, based on the physicochemical interactions of a biological matrix's components, dissolved in a mobile phase. It interacts with a stationary phase, followed by the detection and identification of the matrix's elements. A fixed quantity of enzyme-bound drug and the anti-drug antibody are added to the biological matrix; then, theposterior absorbance measurement during enzyme immunoassays is carried out. High-performance liquid chromatography methods are considered reference techniques because of their ability to separate metabolites from the drug, which yields highly accurate results. Nevertheless, these methods are time-consuming because of the extraction steps and requirement of experienced technicians.

Enzyme immunoassays, including the EMIT, are less wearisome and time-consuming than chromatographic techniques.7,8 Liquid chromatography-based techniques coupled to tandem mass spectrometry improve sensitivity.5,9 However, these methodologies are too expensive to be used on a routine basis in emerging countries, such as Mexico. Their implementation depends on the resources of the hospital and whether it is a transplantation center.

It has been documented that the agreement between EMIT and HPLC-UV is not satisfactory because the metabolite acyl mycophenolic acid glucuronide (AcMPAG) cross-reacts with the former, but not with the latter method.6 Several studies are comparing EMIT and HPLC-UV performances for MPA determination in samples from adults.6 However, these data cannot be directly extrapolated to pediatric patients.2

Clinical studies comparing EMIT and HPLC-UV performance for MPA monitoring in children are scarce.7,8 To our knowledge, there is no information concerning Mexican pediatric patients. Furthermore, it is worth mentioning that some studies have documented that the pharmacokinetics and metabolism of specific immunosuppressive agents in Mexicans differ from those observed in other populations.10–12 Likewise, the existence of interethnic variability in MPA metabolism has been suggested.13 Hence, the purpose of the present work was to evaluate the EMIT and HPLC-UV performance for the determination and pharmacokinetic implications in monitoring MPA after the oral administration of mycophenolate mofetil in Mexican pediatric patients with renal transplantation.

MATERIAL AND METHODS

Patients and Study Design

A prospective cross‐sectional study. Patients' eligibility was established based on the total of patients participating in an alternative pharmacokinetic (PK) study within the transplantation program at Departmento de Nefrología from Hospital Infantil de México "Federico Gómez".

A total of 25 patients with kidney transplantation were assessed for eligibility (see demographic data in Table 3). Parental written informed consent was obtained in all cases (older than 12 years). Patients were excluded due to incomplete PK profile to perform proper non-compartmental analysis and non‐adherence to the treatment. Patients received maintenance immunosuppressive therapy with tacrolimus, mycophenolate mofetil (every 12 h at the dose established by the clinical staff), and prednisone. All patients were at a steady state at the time of the study. The patients included in the study received different MPA formulations: 32% (n=8) Myfortic®, 32% (n=8) Celprot®, 16% (n=4) Lanfetil®, 12% (n=3) Cellcept®, and 8% (n=2) Kofetil®.

The study was conducted according to the principles of the World Medical Association's Declaration of Helsinki 2008, and it was approved by the Institutional Internal Review Boards and Ethics Committees from the Hospital.

Patients arrived at the clinical facilities in the morning of the study day, under fasting conditions. An indwelling cannula was inserted in a suitable forearm vein. Then, mycophenolate mofetil's corresponding oral dose was administered and blood samples were drawn at 0, 0.5, 1, 2, 3, 4, 6, 8, and 12 h after medication. Plasma was obtained by centrifugation, and the plasma samples were divided into two aliquots and stored at -70°C until analysis. MPA in plasma was quantitated by two analytical methods, EMIT and HPLC-UV.

MPA Quantification

In one of the aliquots in each plasma sample, MPA quantification was performed by EMIT employing the commercially available SIEMENS platform with MPA EMIT 2000 reagents (Siemens Healthcare Diagnostics, Mexico City) (Table 1) according to the manufacturer’s instructions. The reported quantification range is 0.1 to 15 μg/ml. Samples with concentrations above this range were diluted before quantification.

Tabla 1. Precision and recovery reported for EMIT method
Test LevelMean (μg/ml)Within run precision (%)Total precision (%)Recovery (%)
Low13.46.199

Medium7.53.64.5103

High124.96.5102

In the remainder aliquot in each plasma sample, MPA was quantified by HPLC-UV detection, following a procedure previously described14, with several modifications. Briefly, analyses were performed on a LaChrom Elite chromatography coupled to a UV-L-2400 detector (Hitachi, Tokyo, Japan).

The stationary phase was a ZORBAX Eclipse Plus C18 4.6 x 150 mm column (particle size 3.5 µm) (Agilent Technologies, Santa Clara, CA, USA). The column was eluted with a mixture of methanol/phosphate buffer 0.04M, pH 6 (54/46 v/v) at a flow rate of 1.6 ml/min at a temperature of 40°C. UV detection was carried out at a wavelength of 215 nm. Diclofenac was employed as an internal standard at a concentration of 200 μg/mL. The MPA quantification range was 0.5 to 50 µg/ml. According to Norma Oficial Mexicana, the method was validated (Table 2, Figure 1).15

Table 2. Precision and accuracy of HPLC-UV method
NominalIntra-dayInter-day
concentration ±
(µg/ml)
Recovered concentration
± D.E (µg/ml)
CV
(%)
D
(%)
Recovered concentration
± D.E (µg/ml)
CV
(%)
D
(%)
LLOQ 0.50.57 ± 0.025.014.020.49 ± 0.0817.20.28

LQC 0.80.81 ± 0.045.01.940.77 ± 0.067.83.17

MQC 7.57.52 ± 0.070.90.367.51 ± 0.030.40.19

HQC 3534.89 ± 0.531.50.2934.73 ± 0.361.00.77

CV: coefficient of variation; D: deviation; LLOQ: lower limit of quantification; LQC: lower quality control; MQC: medium quality control

Pharmacokinetic and Statistical Analysis

Plasma concentration against time curves was constructed for each patient and each analytical method. Peak (Cmax) and trough (predose C0 and postdose C12) plasma concentrations of MPA, as well as the time to reach the peak (Tmax), were directly determined from these plots. The area under the curve was estimated by the trapezoidal rule, as previously described.14

Each concentration determined by EMIT was compared with the corresponding quantification by HLPC-UV; the latter was considered the reference method. The agreement between the concentration data obtained with EMIT (CEMIT) and HPLC-UV (CHPLC) was assessed by linear regression.16 Bias and precision were determined as described by Sheiner and Beal.17 Bias was determined by the mean prediction error (MPE; Eq. 1) and MPE percentage (%MPE; Eq. 2). Precision was estimated by the mean squared prediction error (MSPE; Eq. 3) and the root‐mean‐squared prediction error (RMSE; Eq. 4).

Normality was assessed by the Shapiro-Wilk test for all the estimated PK parameters. Values of Cmax, C0, C12, and AUC0-12 determined by either EMIT or HPLC-UV were statistically compared by Student t-test, while Mann-Whitney U test constrasted Tmax values. Statistical analysis was performed using GraphPad Prism® version 5.3 for Windows (GraphPad Software, San Diego, CA, USA). Differences were considered to achieve statistical significance when P < 0.05.

RESULTS

Twenty-five pediatric patients (9 females, 16 males) participated in the study. Table 3 shows the demographic and clinical characteristics. All patients were receiving tacrolimus in addition to mycophenolate mofetil. Tacrolimus trough levels were determined as part of patients' routine management with a kidney transplant in the hospital. Median tacrolimus through blood concentration was 6.1 ng/mL (Table 3).

Table 3. Demographic and clinical data of the pediatric patients with kidney transplantation participating in the study

n
Demographic
25
Gender (female / male)(9 / 16)

Weight (kg)36.38 ± 14.59

Age (years)15 (4 - 17)

Cr (mg / dL)0.97 (0.23 – 1.78)

C0 Tac (ng / mL)7.064 ± 4.536

Hb (mg / dL)11.6 ± 1.837

Leucocytes ( x109 L)6.2 (4.0 – 10.2)

Cr: serum creatinine; C0 Tac: tacrolimus trough levels; Hb: hemoglobin. Values are expressed as mean ± SD; median and range. All the patients under tacrolimus, mycophenolate mofetil, and prednisone regimen.

MPA concentrations were determined in 225 plasma samples. Figure 2 depicts the comparison between the values obtained using EMIT and HPLC-UV. It was noticeable that a good agreement was not achieved. When the two methods were contrasted by linear regression, the Pearson's correlation coefficient (r2) amounted to only 0.673. A significant positive bias was estimated as an MPE value of 1.96 µg/ml (95% CI; 1.27 - 2.62 µg/ml), while %MPE was 59.25%. Precision indicators, MSPE and RMSE, were 30.04 (95% CI; 20.44 – 39.65) and 54.85%, respectively.

Pharmacokinetic parameters were estimated with both EMIT and HPLC-UV for the 25 patients included in the study (Table 4). AUC0-12 was significantly overestimated, by more than 50%, by EMIT concerning HPLC-UV. Nonetheless, differences between the two analytical methods in other parameters did not reach statistical significance. According to the variation coefficients for all the determined pharmacokinetic parameters, interindividual variability was high. Variability was significant for C0, being higher than that observed for C12, although similar values were expected as both predose C0 and postdose C12 correspond to trough concentrations once a steady state is achieved.2

DISCUSSION

The present work's purposes were to evaluate EMIT and HPLC-UV for the therapeutic drug monitoring of MPA in Mexican pediatric patients with renal transplantation and contrast the PK implications in the monitoring of MPA.

Table 4. MPA pharmacokinetic parameters in the pediatric patients with kidney transplantation participating in the study derived from plasma concentration against time curves constructed with data obtained using EMI of HPLC-UV
MethodologyMeanSDMedian (range)CV (%)P value
AUC0_12 (μg*h / mL)EMIT79.2329.5180.95 (18.48 - 146.24)37.24*p = 0.0111

HPLC60.0936.3152.72 (8.10 - 117.19)60.44

C0 (μg / mL)EMIT6.196.93.58 (0.62 - 27.72)111.56p = 0.3941

HPLC4.576.362.04 (0.0 - 26.00)139.13

C12 (μg / mL)EMIT4.372.043.91 (1.0 - 8.52)46.62p = 0.9765

HPLC4.382.334.10 (0.87 - 10.60)53.13

Cmax (μg / mL)EMIT26.1511.1926.76 (3.88 - 49.68)42.79p = 0.1080

HPLC21.458.9621.63 (5.6 - 49.94)41.79

Tmax (h)EMIT1.380.951.00 (0.00 - 3.100)68.49p = 0.4026

HPLC1.180.751.00 (0.00 - 3.00)63.58

* Denotes a statistical significant difference between EMIT and HPLC-UV, P < 0.005

Filler and colleagues have clearly stated the need for MPA therapeutic drug monitoring in pediatric patients with renal transplantation, as there is strong evidence that MPA monitoring affects clinical outcomes.2

Mycophenolate mofetil has been extensively used as an anti-rejection maintenance medication in pediatric renal transplantation, but it is not beneficial for some patients due to unusual individual PK profiles.18 The results confirm an important interindividual variability in MPA pharmacokinetics (Figure 3, Table 4); thus, the role of therapeutic drug monitoring in pediatric patients with renal transplantation is crucial. It must be highlighted that patients change formulation frequently and the recommendation is to perform MPA monitoring at least each time the formulation has changed and when patients show adverse events associated with MPA administration.

A) MPA plasma concentration against time curves obtained with EMIT and HPLC-UV in 25 pediatric patients with renal transplantation (mean ± SEM). B) Area under the plasma concentration against time curve (mean, whiskers at 5-95 % percentiles. Dashed lines represent the therapeutic range: 30-60 μg*h / mL).

MPA therapeutic drug monitoring can be carried out by measuring trough concentrations (either predose C0 or postdose C12) or by estimation of AUC0-12. In pediatric patients, it has been stated that AUC0-12 should be the preferred parameter for MPA therapeutic drug monitoring.2 Our results are consistent with this assumption. The coefficient of variation for trough concentrations, particularly for predose C0, was higher than those observed for AUC0-12 (Table 4). Moreover, the coefficient of variations observed for C0 and C12 were not consistent, even though both values represent trough concentrations at a steady state.

MPA is submitted to enterohepatic circulation; thus, it exhibits high intraindividual and interindividual variability. Hence, trough concentration may show wide fluctuations even within the same individual.3,18,19 On the other hand, AUC is considered the paramount marker of drug exposure.16,20 Moreover, a lack of correlation between MPA AUC0-12 and either C0 or C12 in pediatric patients has been observed. Thus, trough concentrations for therapeutic drug monitoring are not recommended.2

These methodologies comparison has been performed previously in pediatric patients. However, inconsistent results and the lack of concordance of results7,8 allow continuing to explore differences in population and metabolic differences, as well as sampling times after transplantation.21

EMIT and HPLC-UV procedures are widely used for MPA therapeutic drug monitoring. It has been reported that EMIT overestimates the results concerning HPLC-UV due to cross-reactivity of the metabolite AcMPAG.6,22 That was also the case in the present study. When EMIT performances were compared to HPLC-UV, there was a positive bias amounting to 59.25%, with a precision of 54.85% and a Pearson correlation coefficient (r2) of 0.673. These results are far from ideal.

Moreover, the present study's bias was higher concerning a previously reported %MPE value of 46% determined in Caucasian adult patients' samples.6 As the metabolite interference explains the discrepancy between EMIT and HPLC-UV, this difference in bias may respond to variations in MPA biotransformation in children, compared to adults (as suggested by Filler and colleagues2) and/or to interethnic variability in MPA metabolism (as proposed by Li et al.).13 We have demonstrated an interethnic variability, particularly between Mexicans and Caucasians, in the disposition of other immunosuppressive agents.10-12

Unfortunately, our results cannot be contrasted with previous studies comparing EMIT and HPLC-UV for MPA therapeutic drug monitoring in pediatric patients, as bias and precision were not reported. However, these studies also yielded an overestimation by the former method.7,8 Nonetheless, the authors concluded that both methods are adequate to predict graft rejection. We disagree, at least in the case of Mexican children with renal transplantation. Our results show a significant overestimation (more than 50%) in AUC0-12, the most suitable parameter for pediatric patients' decision-making. Considering that target values2 for AUC0-12 should be between 30 and 60 μg*h/ml, that is only a factor out of two between the lower and higher limits of the therapeutic window. The difference between methods appears to be relevant. Hence, therapeutic window values observed for MPA in pediatric patients measured by HPLC-UV, or other specific chromatographic methods5,7, cannot be directly extrapolated to results yielded by EMIT.

CONCLUSIONS

After mycophenolate mofetil oral administration in Mexican pediatric patients with renal transplantation, MPA plasma concentrations exhibit a large interindividual variability. Therefore, therapeutic drug monitoring is justified.

MPA concentrations in plasma samples determined by EMIT and HPLC-UV are not in good agreement. EMIT overestimates concerning HPLC-UV. Hence, HPLC-UV should be the preferred method for therapeutic drug monitoring of MPA in Mexican pediatric patients with renal transplantation treated with mycophenolate mofetil.

ACKNOWLEDGMENTS

Alan Quiroz-Moguel and Lorena Medina-Aymerich are fellows of CONACyT. Funding sources: Protocolo HIM 2011/013.

CONFLICT OF INTEREST

The authors declare there is no conflict of interest.

REFERENCES

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Latin American Journal of Clinical Sciences and Medical Technology, Año 1, No. 1, octubre, 2019 es una publicación contínua editada por Vesalio S.C.; http://www.lajclinsci.com/    Editor responsable: Gilberto Castañeda Hernández.    Reserva de Derechos al Uso Exclusivo: 04-2019-062013242000-203; ISSN: 2683-2291; ambos otorgados por el Instituto Nacional del Derecho de Autor.    Responsable de la última actualización de este número, Web Master Hunahpú Velázquez Martínez, calle San Luis Potosí # 182-1, Col. Roma, Alcaldía Cuauhtémoc, C.P. 06700, Ciudad de México; teléfono: 55 64 40 41    Fecha de última modificación, 30 de marzo de 2020.
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All Rights Reserved® 2019

Latin American Journal of Clinical Sciences and Medical Technology, Año 1, No. 1, octubre, 2019 es una publicación contínua editada por Vesalio S.C.; http://www.lajclinsci.com/    Editor responsable: Gilberto Castañeda Hernández.    Reserva de Derechos al Uso Exclusivo: 04-2019-062013242000-203; ISSN: 2683-2291; ambos otorgados por el Instituto Nacional del Derecho de Autor.    Responsable de la última actualización de este número, Web Master Hunahpú Velázquez Martínez, calle San Luis Potosí # 182-1, Col. Roma, Alcaldía Cuauhtémoc, C.P. 06700, Ciudad de México; teléfono: 55 64 40 41    Fecha de última modificación, 30 de marzo de 2020.