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Home , Immunosuppressive drug, Mycophenolic acid

International Journal of Clinical Pharmacy (2019) 41:776–784 https://doi.org/10.1007/s11096-019-00837-z

RESEARCH ARTICLE

Adverse efects of in renal transplant recipients: gender diferences

Ana Spasić1 · Aleksandra Catić‑Đorđević1 · Radmila Veličković‑Radovanović1,2 · Nikola Stefanović1 · Predrag Džodić1 · Tatjana Cvetković2,3

Received: 22 November 2018 / Accepted: 15 April 2019 / Published online: 26 April 2019 © Springer Nature Switzerland AG 2019

Abstract Background Mycophenolic acid is widely used immunosuppressive , associated with adverse efects which increase patient morbidity and decrease adherence. Objective To evaluate the adverse efects in renal transplant recipi- ents under mycophenolate treatment with respect to gender. Setting University Clinical Centre of Nis, Clinic of Nephrol- ogy, Serbia. Method This research included 96 renal transplant recipients, who received immunosuppressive regimen, based on or cyclosporin A, and mycophenolic acid. The high-performance liquid chromatography method combined with protein precipitation was used for the analysis of mycophelate concentration in human plasma. Drug con- centration and dose-adjusted concentration were determined with respect to the patients’ gender. An adverse efect scoring system developed by nephrologists within the University of Bufalo /Transplant Program was used to monitor adverse efects of therapy. Main outcome measure Individual and scores of adverse efects in relation to the dosing regimen and gender. Results Results showed statistically lower dose and concentrations in men compared to the women in our inves- tigation group. Also, female patients demonstrated higher mean scores (cumulative and subscores) within the same dosing regimens of mycophenolic acid. The gastrointestinal score was signifcantly higher in women who received a dose greater than 720 mg compared to men (0.20 ± 0.12 vs 0.12 ± 0.12). Women demonstrated higher individual adverse efects such as diarrhea and skin changes (41.7 vs 17.0; p = 0.038 and 62.5 vs 30.2; p = 0.037, respectively). Conclusions The results of our research showed that recipients’ gender may play an important role in pharmacokinetic profle of mycophenolic acid, suggesting that women had higher concentration of mycophenolic acid and more serious side efects.

Keywords Adverse efects · Gender · Mycophenolic acid · Renal transplantation

Impacts on practice • It is important to choose the best therapy option for each individual patient and to minimize the adverse efects in order to improve outcomes and immunosuppressive • For mycophenolic acid, which is not routinely monitored, adherence post-transplant. gender diferences in drug pharmacokinetic could be accounted for by adjusting doses and therapy manage- ment. Introduction

A renal transplantation is the chosen treatment option for patients with end-stage failure. Throughout the * Ana Spasić world, the most prescribed immunosuppressive proto- [email protected] col contains inhibitors (CNI)—tacrolimus or cyclosporin A, drug (mycophenolic acid or 1 Department of Pharmacy, Faculty of Medicine, University of Nis, Bulevar dr Zorana Djindjica 81, Nis 18000, Serbia mycophenolate mofetil) and . Mycophenolic acid (MPA) is available either as an ester (mycophe- 2 Clinic of Nephrology, Clinical Centre Nis, Nis, Serbia nolate mofetil, MMF) or as a sodium salt (mycophenolate 3 Institute of Biochemistry, Faculty of Medicine, University sodium, EC-MPS). Following oral administration, MMF of Nis, Nis, Serbia

Vol:.(1234567890)1 3 International Journal of Clinical Pharmacy (2019) 41:776–784 777 undergoes rapid and extensive presystemic elimination by . This research proposes a new approach into clini- deesterifcation, creating its active metabolite—MPA. Pre- cal of mycophenolic acid and indicates the vious studies and clinical experience showed that pharma- importance of the gender on the adverse efects during its cotherapy protocol including MMF or EC-MPS along with treatment. and CNI have signifcantly decreased the incidence of acute rejection and improved patient and renal Aim of the study allograft survival [1, 2]. MPA is primarily glucuronidated to a pharmacologically inactive glucuronide metabolite The aim of this study was the evaluation of adverse events (MPAG) by UDP-glucuronosyltransferases (UGT) in the within renal transplant recipients under MPA treatment with intestine and , which is in turn transported into the bile respect to gender. by the multidrug resistance-associated protein 2 (MRP2) and possibly other efux transporters that have yet to be Ethics approval elucidated [3]. Immunosuppressive drugs are associated with signif- Patients gave written informed consent and all investiga- cant adverse efects which increase patient morbidity and tions were approved by the Ethical committee (Faculty of decrease medication adherence [4–6]. Frequent mild to mod- Medicine, University of Nis). erate adverse efects, as a result of overexposure to MPA, lead to increased patient non-adherence and therefore afect patients’ quality of life. On the other hand, underexposure to Method MPA may be associated with the risk of graft rejection and long-term allograft survival post-transplant [7, 8]. This research was performed in 96 Serbian renal transplant Previous studies suggested diferent target therapeutic recipients. The patients were routinely monitored and treated ranges of MPA concentration with respect to chosen CNI, in the Clinic of Nephrology (University Clinical Centre tacrolimus (TAC) or cyclosporin A [9, 10]. Miura et al. [11, of Nis, Serbia) during 2017. All patients enrolled in this 12] reported that monitoring of the trough level is insuf- cross-sectional study were in the late post-transplant period cient for therapeutic drug monitoring because there is wide (> 12 months), median 69.5 months (interquartile range inter-patient and intra-patient variability in MPA pharma- 41–105 months). Data were collected during 12 months. cokinetics. It was shown that renal and hepatic impairment, Renal transplant recipients received oral MMF dialysis, gender, food, ethnicity, co-morbidities, time after (Cellcept­ ®, Roche) or enteric-coated MPA (Myfortic­ ®, transplantation, hyperbilirubinaemia, hypoalbuminaemia, Pharma) as a part of a triple immunosuppressive pharmacogenetics and drug–drug interactions seemed to regimen, which also included prednisone (PRE) and tac- have an infuence on the variability of MPA pharmacoki- rolimus (Tac) or cyclosporin A (CyA). The dose of MPA netics [13, 14]. and MMF varied from 0.72 to 1.44 g/day and from 1.00 to Authors reported that recipients’ gender may be a sig- 2.00 g/day, respectively. It was administered in two divided nifcant factor in MPA exposure variability and adverse doses, every 12 h. In order to make comparable doses of efects following MMF/MPA therapy [15, 16]. Meaningful MMF and MPA levels in both groups, doses of MMF gender-based diferences in drug disposition pathways could and MPA were converted to the equivalent of MPA by mul- result in corresponding diferences in dosage requirements tiplying the MMF dose by 0.72. The choice of MMF or the between men and women. Sex infuences were observed in MPA was driven according the physicians’ habits. During glucuronidation with more rapid MPA clearance, body mass the follow-up period, there was no switch from MMF to index normalized clearance and lower dose normalized MPA MPA (or MPA to MMF). There was an initial unique dose area under the concentration versus time curve (AUC) in for each patient (1440 mg, expressed as MPA dose), then males compared to females [15, 17]. These clinical fndings adjusted overtime according to BMI and already present were confrmed by experimental evidence in rats and in vitro leucopenia. Based on clinical experience, in stable renal studies, in which gender diferences in UGT activity were recipients, the dose was reduced to half after 12 months. reported [18, 19]. In order to avoid gastrointestinal adverse effects of Previous studies have suggested that implementation immunosuppressive treatment and to provide a satisfactory of MPA monitoring in clinical practice may provide more patient’s adherence, proton pump inhibitor (PPI) in 20 mg adjusted dosage regimens and optimal drug exposure, which daily dose was administered to 80.52% patients, whereas can lead to overall improvement of clinical outcomes [20, other patients (19.48%) received ranitidine. The PPI is pre- 21]. ferred for treating gastrointestinal adverse efects in renal This article is a result of our continuous work within a transplant recipients, but 19.48% received ranitidine because feld of pharmacokinetic variability of immunosuppressive of other drugs in therapy and their interactions with PPI.

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Renal transplant recipients had stabilized graft func- Statistical analysis tion and received the same immunosuppressive regimen (CyA or Tac based immunosuppressive protocol) with the Statistical analysis was performed using the statistical pack- unchanged dose of MPA for at least 3 months prior the age SPSS software version 20. Clinical and biochemical data research. Patients with acute rejection episodes, or who were compared using the t test for normally distributed data were switched to another immunosuppressive regimen (expressed as mean ± SD) and Mann–Whitney U test for (CyA to Tac) during the follow-up period or those with data that were not normally distributed. One way analysis creatinine clearance lower than 15 mL/min were excluded of variances (ANOVA) test and Kruskal–Wallis test for not from the study. normally distributed data was used for comparison with Gender, age, time after transplantation, the presence of three or more groups. Chi square test was performed for diabetes mellitus, organ source (living or deceased donor) categorical variables. The diference in the compared data and immunosuppressive co-medication were recorded for was considered statistically signifcant when the p value was all patients. less than 5% (p < 0.05). Hematological and routine biochemical parameters, such as number of erythrocyte (RBC), leucocytes (WBC) and (PLT), level of hemoglobin (HGB), haematocrit (%), serum albumin (ALB), urea (URE), creatinine (CRE) Results levels were measured in Clinical Chemistry Laboratory in the Clinic of Nephrology using automated random access The conducted research included 96 patients who clinical chemistry analyzer (ERBA XL-600, ERBA Diag- underwent renal transplantation: 60 (62.57%) men nostics Mannheim GmbH, Mannheim, Germany). The and 36 (37.5%) women, with an average age of about estimated glomerular fltration rate (e-GFR) was calculated 44.33 ± 11.45 years. The mean post-transplantation time using the 4-factor MDRD equation [22]. was 79.31 ± 53.49 months. Seventy-one (74.0%) patients A fasting blood sample was taken from each patient dur- received living donor and 25 (26.0%) deceased donor grafts. ing routine control at the Clinic at 8.00 h, before the next The demographic characteristics of patients, their biochemi- dose of the drug administration. The MPA trough concentra- cal and haematological parameters are shown in Table 1. tion in human plasma was determinated by validated high- The median value of MPA and prednisone daily dose was performance liquid chromatography (HPLC) method [23]. 884.57 mg and 8.03 mg, respectively. Nineteen patients did not have any form of MPA in therapy. The results showed that gender was a statistically sig- Adverse efect scoring system nifcant determinant of pharmacokinetic variability. The obtained data showed that women had a statistically higher Patients’ gender may be a signifcant factor in MPA expo- dose of MPA and plasma trough concentration of MPA com- sure variability and may be associated with adverse efects pared to men with a transplanted kidney (p < 0.05), while following MPA therapy. Previous fndings suggest gender there was no diference in dose-adjusted plasma trough con- should be considered during MPA [15]. centration of MPA (Table 2). In order to monitor adverse efects of therapy, we used an All analyzed scores did not show a statistically signif- adverse efect scoring system developed by nephrologists cant diference as to whether patients receive MPA: GIT within the University of Bufalo Nephrology/Transplant score (Z = 0.914; p = 0.361), aesthetic score (Z = 0.113; Program [24]. p = 0.910), CNS score (Z = 0.714; p = 0.475) and cumula- The scoring system focused on 18 common non-renal tive score (Z = 1.163; p = 0.245) (Table 3). adverse efects associated with immunosuppressive regi- In addition, female patients demonstrated higher mean mens. Patients were asked to estimate the severity of any scores (cumulative and subscores) within the same MPA adverse efect (i.e. 0 → no adverse efect; 1 + → mild to dosing regimens. The results of the conducted study showed 3 + → severe manifestations). Adverse efect scores [gastro- that the GIT score is signifcantly lower in men who received intestinal (GIT), central (CNS), aesthetic] a dose greater than 720 mg compared to women. Men who were formed to estimate the organ system specifc adverse received a lower dose had a greater aesthetic, CNS, and efects. The cumulative score was calculated as the quotient cumulative score compared to men who received a higher of each patient’s total score divided by the maximum score dose of MPA (Table 4). of all possible symptoms. This cumulative score showed Table 5 shows the distribution and overall frequency of the number of adverse efects with a appropriate severity individual immunosuppressive adverse efects based on rating [24]. All patients flled out the questionnaire at least patients’ gender. Women demonstrated a higher total score 6 months after transplantation. than men and this was particularly evident for the occurrence

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Table 1 Characteristics of the patients of diarrhea and skin changes (41.7 vs 17.0; p = 0.038 and p Male Female p 62.5 vs 30.2; = 0 .037, respectively). (n = 60) (n = 36) The frequency of individual side efects in both genders with diferent dose regimens of MPA is shown in Fig. 1. Age (years) 45.05 ± 10.59 43.61 ± 12.79 NS Female patients demonstrated higher individual adverse Time post-transplant 81.97 ± 53.33 76.67 ± 54.06 NS efects within the same MPA dosing regimens. There was a (months) signifcant diference in myopathy between men and women Donor type who received an MPA dose of 720 mg. Results suggested Living 42 (70.0%) 29 (80.6%) NS that skin changes were statistically more common in women Deceased 18 (30.0%) 7 (19.4%) compared to men who received a higher dose of MPA. Number of drugs in therapy < 5 6 (10.0%) 4 (11.1%) NS ≥ 5 54 (90.0%) 32 (88.9%) Discussion MPA dose Without MPA 7 (11.7%) 12 (33.3%) 0.010* Mycophenolic acid is a part of the most prescribed immu- 720 mg 37 (61.7%) 12 (33.3%) nosuppressive protocols in the world. Although, it does > 720 mg 16 (26.7%) 12 (33.3%) not have as narrow therapeutic index as TAC, its adverse Prednisone dose efects may still complicate post-transplantation period in < 10 mg 42 (70.0%) 24 (66.7%) NS renal transplant recipients. The previous researches showed ≥ 10 mg 18 (30.0%) 12 (33.3%) large intra- and inter-individual variability in plasma con- CNI centration and exposure of MPA after renal transplantation Tacrolimus 51 (85.0%) 30 (83.3%) NS [25, 26]. Cyclosporine 9 (15.0%) 6 (16.7%) It has been shown so far that gender and drug–drug inter- Hematocrit actions may infuence the of tacrolimus Low level 15 (25.0%) 14 (38.9%) NS and others CNI, and also MPA [27–29]. The obtained results Normal level 45 (75.0%) 20 (55.6%) showed that women had higher plasma trough concentration High level 0 (0.0%) 2 (5.6%) of MPA compared to men. This fnding is in accordance with Albumin (g/L) 41.75 ± 0.25 41.95 ± 0.27 NS WBC (cells/mm3) 8.3 ± 1.67 7.0 ± 1.88 NS previous research, which showed that females have slower Serum creatinine (µmol/L) 132.55 ± 19.35 126.78 ± 23.69 NS MPA clearance [15]. The same study showed race-depend- eGFR (mL/min/1.73 m2) 55.09 ± 11.37 49.95 ± 10.45 NS ent pharmacokinetics of MPA. Our research did not analyze the infuence of race, due to all of the patients enrolled in MPA mycophenolic acid, CNI calcineurin inhibitors, WBC leuco- this study had the Caucasian origin. Conversely, Pescovitz cytes, eGFR estimated glomerular fltration rate, NS non signifcant, et al. [30] did not fnd any association between gender and Normal level of hematocrit for male: 42–54%, for female: 38–46% pharmacokinetic parameters of MPA. Show et al. [31] dem- *p < 0.05 onstrated that ethnicity and gender do not signifcantly afect the primary pharmacokinetic parameters of MPA. In con- trast to our study, this research was conducted in the early post-transplantation period. This suggests that gender may

Table 2 Dose, concentration Gender of the patients Z p and dose-adjusted concentration of MPA in relation to gender Male (n = 53) Female (n = 24)

Dose of MPA (mg)a 849.06 ± 212.91 990 ± 304.92 − 2.014 0.044* 720 (720–1440) 900 (720–1440) Concentration of MPA (µg mL−1) 2.71 ± 2.26 4.31 ± 3.19 − 2.082 0.037* 2.10 (0.08–12.33) 3.05 (1.36–11.21) Dose-adjusted concentration of 0.0032 ± 0.0025 0.0046 ± 0.004 − 1.454 0.146 −1 MPA (µg mL /mg) 0.0027 (0.0–0.11) 0.0034 (0.001–0.016)

Data are shown as mean ± standard deviation and median (range) Z Mann–Whitney U test *p < 0.05 a MMF dose was calculated as MPA equivalent

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Table 3 Scores of adverse efects, depending on the therapy of MPA infuence MPA pharmacokinetics in the late period after Without MPA With MPA Z p transplantation, contributing to its variability and long-term (n = 19) (n = 77) adverse efects associated with MPA exposure. This study has shown that 57% of stable renal transplant Gastrointestinal 0.13 ± 0.09 0.17 ± 0.14 0.914 0.361 recipients experienced gastrointestinal symptoms, even when Aesthetic 0.12 ± 0.11 0.13 ± 0.13 0.113 0.910 they received a proton pump inhibitor (PPI) or histamine 2 CNS 0.18 ± 0.18 0.21 ± 0.18 0.714 0.475 (H2) antagonist—ranitidine. Similar results have Cumulative 0.22 ± 0.16 0.18 ± 0.17 1.163 0.245 been reported in other studies [16, 32], although reported MPA mycophenolic acid, CNS central nervous system, Z Mann–Whit- frequencies of gastrointestinal adverse efects were generally ney U test

Table 4 Scores of adverse Scores of adverse efects Dose of MPA efects in relation to the MPA dosing regimen in both genders 720 mg > 720 mg Male Female Male Female (n = 37) (n = 12) (n = 16) (n = 12)

Concentration of MPA (µg ­mL−1) 2.37 ± 1.65 4.12 ± 3.63 3.51 ± 3.24 4.17 ± 2.83 Gastrointestinal 0.17 ± 0.15 0.21 ± 0.17 0.12 ± 0.12c 0.20 ± 0.12 Aesthetic 0.16 ± 0.15a 0.20 ± 0.10 0.06 ± 0.11 0.10 ± 0.11 CNS 0.23 ± 0.17b 0.30 ± 0.18 0.12 ± 0.15 0.18 ± 0.19 Cumulative 0.19 ± 0.12a 0.24 ± 0.12 0.10 ± 0.07 0.16 ± 0.11

MPA mycophenolic acid, CNS central nervous system a Male (720 mg) versus Male (> 720 mg), p < 0.01 b Male (720 mg) versus Male (> 720 mg), p < 0.05 c Male (> 720 mg) versus Female (> 720 mg), p < 0.05

Table 5 The frequency Adverse efects 0 1+ 2+ 3+ Overall fre- p of severity scores for quency (%) immunosuppressive adverse efects M/F M/F M/F M/F M/F Vomiting 48/21 5/3 0/0 NA 9.4/12.5 NS Diarrhea 44/14 9/9 0/1 NA 17.0/41.7 0.038 Dyspepsia 44/16 6/6 2/1 1/1 17.0/33.3 NS Acid suppressive therapy 10/5 39/18 4/1 NA 81.1/79.2 NS Acne 37/19 6/4 8/1 2/0 30.2/20.8 NS Skin changes 37/9 12/10 4/4 0/1 30.2/62.5 0.037 Hirsutism 47/23 4/1 2/0 0/0 11.3/4.2 NS Moon facies 31/12 18/8 3/4 1/0 41.5/50.0 NS Gingival hyperplasia 37/16 13/4 3/4 NA 30.2/33.3 NS Bufalo hump 50/24 3/0 NA NA 5.7/0.0 NS Tremor 31/10 17/11 4/2 1/1 41.5/58.3 NS Headache 38/16 15/8 NA NA 28.3/33.3 NS Insomnia 31/13 16/8 5/3 1/0 41.5/45.8 NS Myopathy 31/13 17/5 5/6 0/0 41.5/45.8 NS Ophthalmic changes 49/23 4/1 NA NA 7.5/4.2 NS Mania/excitable behavior 29/11 19/12 5/1 NA 45.3/54.2 NS Depression 35/14 17/9 1/1 0/0 34.0/41.7 NS Post-transplant diabetes mellitus 44/21 9/3 NA NA 17.0/12.5 NS

M/F male/female, NA not applicable, NS non signifcant

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Fig. 1 Individual adverse efects in relation to the MPA dosing regimen and gender higher. This variation may be related to the methodology is a frequently prescribed PPI against gastro- used for the estimation of gastrointestinal symptoms in dif- intestinal side efects in renal transplant patients, such as ferent researches, because such symptoms are often under- heartburn and nausea [33]. estimated by both patients and physicians. In addition, our Female recipients demonstrated more severe symptoms, patients received PPI (usually pantoprazole) or ranitidine in particularly evident in the occurrence of diarrhea. Addi- order to reduce the gastrointestinal side efects that are com- tionally, they had a statistically higher dose of MPA and mon under immunosuppressive therapy with mycophenolate. plasma trough concentration of MPA compared to men.

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This is consistent with fndings from other studies [34–36]. Potential limitations of this study are related to con- The potential mechanism through which MMF causes the comitant with overlapping adverse efects intestinal symptoms is the inhibition of and profles and inability to distinguish causative relationships the induction of at the level of the colonic crypts to individual medications. In addition, the patients flled through an immune-mediated mechanism, as well as the out the questionnaire for renal transplant recipients which loss of villous, normal structure of duodenum [37]. Fol- didn’t include doctor verifcation. Consequently, objec- lowing our fndings, women demonstrated a higher gastro- tive immunosuppressive monitoring can be limited with intestinal score than men, with statistic signifcation in the routine clinical application of these patient rating scales. group that received a dose greater than 720 mg compared In conclusion, women had statistically higher MPA to men with the same dose of MPA. Morissette et al. [38] dose and concentrations compared to the men and dem- studied gender diferences in MMF pharmacokinetics in onstrated higher mean scores (cumulative and subscores) 100 renal transplant patients using the MPAG/MPA con- within the same MPA dosing regimens. The GIT score centration ratio as a measure of overall glucuronidation. was signifcantly higher in women who received a dose The nearly two-fold diference in the rate and extent of greater than 720 mg compared to men. Women demon- UGT-mediated glucuronidation, indicated that males strated higher individual adverse efects such as diarrhea have increased glucuronidation as compared to females and skin changes. For MPA, which is not routinely moni- (p < 0.0001), thus impacting mycophenolate dosing [38]. tored, gender diferences in drug pharmacokinetic could be Although females demonstrated higher mean subscores accounted for by adjusting doses and therapy management. (GIT, aesthetic, CNS) and cumulative score compared Therefore, it is important to choose the best therapy option with male patients, these diferences were not statisti- for each individual patient and to minimize the adverse cally signifcant. All of the analyzed scores were higher efects in order to improve graft outcomes and immuno- in patients who received a 720 mg MPA dose compared suppressive adherence post-transplant. to a higher dose of MPA. Vanhove et al. [34] found that gastrointestinal side efects and hematologic toxicity were Acknowledgements The authors would like to thank Dr. Rocco Venuto, who gave us the support to apply the immunosuppressive the main reason for the dose reduction of MMF in the frst adverse efects scoring system to our patients. post-transplant year. Bunnapradist et al. [39] confrmed that gastrointestinal side efects are dose dependent in Funding This study was supported by a grant from the Ministry of patients treated with MPA. On the other hand, Zhang et al. Education, Science and Technological Development of the Republic [40] investigated the efcacy and safety of intensifed EC- of Serbia—Project Nos. 41018 and 172044. MPS protocol in renal transplant recipients. This regimen Conflicts of interest The authors report no conficts of interest. did not increase the incidence of adverse efects, includ- ing diarrhea and leucopenia. 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