Figures
Abstract
In this non-randomized extension study of a randomized controlled trial we converted 87 stable long-term kidney transplant recipients (KTR) from either ciclosporin (CSA, n = 28) or tacrolimus (TAC, n = 59) to TAC modified release (TAC MR4) to study the characteristics of TAC trough levels after conversion with the primary endpoint graft function after 12 months. TAC MR4 consumption was calculated by level-to-dose ([ng/mL]/[mg/d]) and concentration-to-dose ([mg/kg])/d) ratios. Influences of ABCB1 single nucleotide polymorphisms (2677G>T/A, 1236C>T, 3435C>T) on TAC metabolism were studied. Graft function of KTR converted from CSA to TAC MR4 significantly declined over 12 months, and remained unchanged after conversion from TAC to TAC MR4. Conversion from CSA to TAC MR4 resulted in supra therapeutic- and conversion from TAC to TAC MR4 in low trough levels. We could not find associations of ABCB1 genotypes and TAC MR4 trough levels. Adverse events and errors with TAC/TAC MR4 intake were common. In stable long-term KTR conversion from TAC to TAC MR4 is feasible. For conversion from CSA we suggest a rate of 1:40 for a rough estimation of TAC MR4 target doses.
Trial registration
PEP Study: Ethics committee N° 393/2004, EudraCT 2004-004209-98.
PEP-X Study: Ethics committee amendment application N° 154/01/2008.
ClinicalTrials.gov NCT03751332.
Citation: Riegersperger M, Plischke M, Jallitsch-Halper A, Steinhauser C, Födinger M, Winkelmayer WC, et al. (2019) A non-randomized trial of conversion from ciclosporin and tacrolimus to tacrolimus MR4 in stable long-term kidney transplant recipients: Graft function and influences of ABCB1 genotypes. PLoS ONE 14(7): e0218709. https://doi.org/10.1371/journal.pone.0218709
Editor: Kathrin Eller, Medizinische Universitat Graz, AUSTRIA
Received: November 30, 2018; Accepted: June 6, 2019; Published: July 2, 2019
Copyright: © 2019 Riegersperger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All data are available from the fig share database accession numbers DOI 10.6084/m9.figshare.7955993 and DOI 10.6084/m9.figshare.7955990.
Funding: The funder Astellas Pharma Inc. provided support in the form of salaries for author MP, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author is articulated in the ‘author contributions’ section.
Competing interests: This commercial affiliation (in the form of salaries from Astellas Pharma Inc. for MP, research/travel funds for MR, and an unrestricted grant for GSP) does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products.
Introduction
The immunosuppressant tacrolimus (TAC) is a standard medication for the prevention of rejection in organ transplantation. Organ dysfunction, rejection and graft-loss due to non-adherence to immunosuppressive agents are observed in as many as 20% of kidney transplant recipients (KTR) [1]. Modified release tacrolimus (TAC MR4) with once-daily (QD) dosing was introduced to the European market in 2007 with the intention to improve drug adherence. TAC MR4 has a tmax of 2 to 2.5 hours, a similar t1/2, and a reduced cmax compared to TAC twice-daily (BID) [2]. The area under the concentration-time curve (AUC0-24) of TAC MR4 in KTR has conversely been reported to be equal [2] and higher [3]. Higher inter-patient AUC-variability [4] and lower inter-patient C0 levels, as well as a lower intra-patient 24-hour variability of drug exposure after conversion from TAC to TAC MR4 have been observed [5–7]. Conversion with a 1:1 ratio [8, 9] resulted in comparable trough levels, equivalent drug requirements and unchanged graft function in stable KTR [10]. Equivalent safety, efficacy, dosing and trough levels after conversion were suggested in long-term and de novo KTR [11–15]. However, reduced TAC MR4 C0 levels [5, 16–18] and dose increments [19, 20] as well as sustained low C0 levels despite dose increments [21–24] have been observed. Mutations in the multi-drug resistance (MDR) gene 1 (gene symbol ABCB1) have been reported to influence TAC dose-adjusted trough levels [25], level to dose (L/D) [16] and concentration to dose (C/D) ratios [26], mostly observed for the ABCB1 2677G>T/A [26–29], ABCB1 1236C>T [28, 29], and ABCB1 3435C>T [30–34] genotypes.
Data on the impact of ABCB1 genotypes on TAC MR4 metabolism are scarce. We sought to examine TAC MR4 trough levels after conversion from either long-term ciclosporin (CSA) or TAC, to analyze the influence of ABCB1 polymorphisms on L/D and C/D ratios, and to investigate effects of TAC MR4 on graft function in a large cohort of stable long-term KTR in eastern Austria. This study is the first to describe the local distribution of these polymorphisms, and to analyze their influences on TAC MR4 metabolism.
Methods
Study design
This is a non-randomized uncontrolled open-label prospective 12 month cohort extension study of the randomized controlled trial (RCT) “The Vienna Prograf and Endothelial Progenitor Cell (PEP) Study” (local ethics committee N° 393/2004, EudraCT 2004-004209-98). PEP was a RCT to investigate the effects of TAC on endothelial progenitor cells in 148 KTR [35]. The extension study PEP-X was approved by the Ethics Committee of the Medical University of Vienna (MUV) as an amendment to PEP on February 7th 2008 with the application N° 154/01/2008 and registered with the governmental health agency. Since the extended release of studies within international registries conforms with today’s standard, the study was registered post-hoc with ClinicalTrials.gov (NCT03751332) after the study had already been completed. The authors confirm that there are no further studies related to this trial. The study has been conducted according to the “World Medical Associations Declaration of Helsinki Statement of Ethical Principles for Medical Research Involving Human Subjects”, and the “Declaration of Istanbul on Organ Trafficking and Transplant Tourism” [36]. The authors of this manuscript are aware of, and fully comply with, the “Best Practice Guidelines of the Committee on Publication Ethics (COPE)” [37]. We are reporting these findings according to the „Strengthening the reporting of genetic association studies (STREGA)”initiative [38], the „Improving the reporting quality of nonrandomized evaluations of behavioral and public health interventions: the TREND statement” [39], and, since this trial is an extension of an RCT, partly to the “CONSORT 2010 Statement: updated guidelines for reporting parallel group randomized trials” [40], respectively. One hundred forty-one patients completed the PEP trial. Two individuals out of the ITT population of 141 patients from the preceding PEP trial were deemed unsuitable at the investigators discretion, due to issues to properly follow the protocol of PEP. Hence, 139 patients (95 TAC, 44 CSA) who had completed the PEP trial were deemed eligible for inclusion. This study was conducted at the Outpatient Service of the Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna. Recruitment started with March 2008, the first individual was included on March 21st 2008. The last on July 11th 2009, and finished the study on July 7th 2010. Every participant gave verbal and written informed consent prior to inclusion, and was to be converted from either CSA or TAC with or without mycophenolate mofetil (MMF) and prednisolone (PRED) to TAC MR4. Conversion from TAC to TAC MR4 was carried out in a 1:1 ratio, and conversion from CSA to TAC MR4 in a dose of 0.1 mg/kg bodyweight. To achieve maximal absorption rates patients were advised to take TAC MR4 in the morning on an empty stomach, or at least 1 hour before, or 2–3 hours after breakfast [9]. The dose was adjusted to attain TAC MR4 whole blood trough concentrations of 5–8 ng/mL. Study visits were at baseline (BL; time point 0), and in weeks 1, 2, 4, 12 and month 12 after conversion, which was the end of the study (EOS). In-between study visits patients followed the practice pattern of our transplant center, with clinical check-ups roughly every 6 to 12 weeks. The primary endpoint was graft function, as reflected in the estimated glomerular filtration rate (eGFR), after 12 months. The values compiled at visits in weeks 1 to 12 served safety purposes only, since adaptations of TAC MR4 were to be expected after conversion from either CSA or TAC. Also, we collected the eGFR from the last two clinical visits prior to inclusion, which were conducted roughly quarterly (-6 and -3 months). We assessed baseline demographic patient characteristics, serum creatinine, TAC MR4 dose and trough levels, as well as blood pressure, height, weight and adverse events, and observed influences of the ABCB1 2677G>T/A, ABCB1 1236C>T, and ABCB1 3435C>T genotypes. Patient reported outcomes were collected at each visit and at the end of the study by chart review. Known common adverse events of TAC were collected at each visit by standardized questionnaires within the paper case report form.
Laboratory methods
All standard laboratory analyses and genotyping procedures were performed at the Clinical Institute of Laboratory Medicine at the Medical University of Vienna. The eGFR was calculated using the 4-variable modification of diet in renal disease (MDRD) prediction equation [41]. TAC trough levels were analyzed from ethylene-diaminetetra-acetic-acid anticoagulated fresh whole blood samples by chemiluminiscent microparticle immunoassay, Abbott Laboratories, Abbott Park, IL, USA. DNA extraction was performed manually from blood samples with the QIAamp DSP DNA Blood Mini Kit (QIAGEN GmbH, Hilden, Germany). Polymerase chain reaction (PCR) was carried out in the primer systems ABCB1 P 6 F/R and P 11 F/R, and genotyping performed according to published protocols [42].
Statistical methods
Categorical data are presented as frequency (n) and percentage (%), continuous data as mean ± standard deviation (SD) and median and interquartile range (IQR), respectively. To calculate the daily consumption of TAC MR4 after conversion from CSA and TAC we computed the level-to-dose (L/D) ([ng/mL]/[mg/d]) [16] and the concentration-to-dose (C/D) ratio ([mg/kg])/d) [26]. Between-group comparisons were performed by Wilcoxon-Mann-Whitney tests, and Δ eGFR was calculated with the Wilcoxon rank sum test with continuity correction. Friedman tests were used to test for changes within groups over time (baseline to end of study). To test for Hardy-Weinberg Equilibrium (HWE) the Chi-Square (χ2) test was used. Data for the analysis of this study were entered manually in Excel worksheets, Microsoft Corporation, Redmond, WA, USA. Correct data entry was independently verified by two study physicians, and corrected if necessary, before entering the final statistical analyses, performed with SPSS Version 21.0, IBM Corporation, Armonk, NY, USA. A probability (P) value of less than 0.05 was considered statistically significant.
Results
The patient disposition is illustrated in Fig 1. Forty-six declined participation, 93 patients (63 TAC, 30 CSA) gave written informed consent for study participation. Three individuals withdrew the consent before baseline, 3 missed the initial study visit at baseline and could not be included, hence a total of 87 (65 male; 59 TAC, 28 CSA) KTR were converted from CSA or TAC to TAC MR4.
CSA = ciclosporin, TAC = tacrolimus, TAC MR4 = tacrolimus modified release.
Of the 87 KTR, 4 received calcineurin inhibitor (CNI) monotherapy (2 TAC, 2 CSA), 25 CNI (20 TAC, 5 CSA) with MMF, 16 CNI (8 TAC, 8 CSA) with PRED, and 42 CNI (29 TAC, 13 CSA) with MMF and PRED. None of the patients received medication with major effects on CNI trough levels. All 87 individuals who had a single exposure with TAC MR4 were included in the intention to treat (ITT) analysis. The median age was 57.5 (49.8–67.7) years. The median time since transplantation was 9.3 (5.8–15.4) years. In the ITT population, the underlying cause of renal failure was autosomal-dominant polycystic kidney disease in 12, diabetic nephropathy in 6, glomerular disease in 26, tubule-interstitial disease in 10, vascular disease in 8, any other in 5, and unknown in 20 individuals. Six patients had a living unrelated donor, 7 a living related donor-, and 73 a deceased donor graft. Donor-specific documentation was unavailable for 1 patient. Seventy-seven KTR completed the study (2 KTR were re-converted to CSA, 1 was re-converted to TAC, there were 2 deaths and 2 graft-losses, and 3 patients were lost to follow-up). The median eGFR of the ITT population was 47.3 (39.1–60) mL/min per 1.73m2 at baseline and 48.3 (38–59.2) mL/min per 1.73m2 at month 12 (Table 1).
After conversion from CSA to TAC MR4 the eGFR significantly declined over 12 months (43.5 [30.3–56.2] mL/min per 1.73m2 at baseline to 40.5 [33.7–57.3] mL/min per 1.73m2; p = 0.003). After conversion from TAC to TAC MR4 the eGFR remained stable (49.7 [41.7–62.2] mL/min per 1.73m2 at baseline and 51.3 [40.6–53.6] mL/min per 1.73m2 at month 12) (Tables 1 and 2). The change of the renal graft function over the study period in both conversion groups did not show any significant difference (Δ eGFR [median and 1st/3rd quartile] CSA to TAC MR4–2.3 [-6.3/-0.4] mL/min per 1.73m2; TAC to TAC MR4–0.18 [-4.1/-0.8] mL/min per 1.73m2; p = 0.12) (Table 2).
Sixty-six (76%) patients experienced adverse events. Ten (36%) patients converted from CSA and 18 (31%) converted from TAC to TAC MR4 suffered from gastrointestinal symptoms. Pruritus was observed in 6 (21%) patients converted from CSA. Three (11%) patients in the CSA to TAC MR4 and 16 (27%) in the TAC to TAC MR4 group suffered from infections. As reported earlier, errors with TAC/TAC MR4 intake occurred [43]. Almost 10% experienced difficulties to properly follow the prescription (Table 3).
TAC MR4 was confused with TAC, and despite written guidance taken twice daily. Instead of TAC MR4, TAC was taken once daily. One patient was prescribed TAC MR4, but was handed out TAC at the pharmacy. The general practitioner of 1 patient converted from TAC MR4 QD to TAC QD. Two males had to be re-converted to CSA due to unbearable pruritus and gastrointestinal symptoms, which both subsided after re-conversion. One female patient with short bowel syndrome requested to be re-converted to TAC due to severe diarrhea which she thought had worsened after conversion to TAC MR4. However, this severe adverse effect remained. Ten individuals terminated the study prematurely. Of those, 2 men died (1 suffered simultaneous malignancies of lung and urinary bladder 11 months after conversion, 1 died of unknown cause 4 months after conversion). Two suffered a graft loss (1 with membranous-proliferative glomerulonephritis 2 months after conversion, 1 of unknown cause 3 months after conversion), and 3 patients (2 males) were lost to follow-up. One female developed a metastasized urothelial malignancy 6 months after conversion. We performed graft biopsies in 6 patients with acute renal failure and de novo proteinuria, respectively, with 1 case of borderline acute graft rejection, 1 acute vascular graft rejection Banff I, 1 membranous-proliferative glomerulonephritis, and 3 grafts with interstitial fibrosis and tubular atrophy.
As observed previously, the distribution of ABCB1 genotypes strongly depends on the population studied. Neither L/D nor C/D ratios exhibited influences of ABCB1 genotypes on TAC metabolism. The median daily CSA dose at conversion to TAC MR4 was 150 (50–200) mg, and the median daily TAC MR4 dose was 4 (1–10) mg 4 weeks and 3.5 (1–10) mg 12 weeks after conversion, which translates to a conversion rate of roughly 1:40 (1:37.5 and 1:42, respectively). After conversion from CSA to TAC MR4, median TAC MR4 trough levels were 13.8 (7.1–18.9) ng/mL at week 1, 9.5 (8–11.4) ng/mL at week 2, 5.9 (5.4–7.8) ng/mL at week 4, 6.9 (5.6–9.4) ng/mL at month 3 and 5.9 (4.3–6.5) ng/mL at month 12. In patients converted from TAC to TAC MR4 median TAC MR4 trough levels were 4.8 (3.6–6.7) ng/mL at week 1, 5.3 (4.3–6.4) at week 2, 5.2 (4.3–6.6) at week 4, 5.5 (4.6–6.7) ng/mL at month 3 and 5.3 (4.3–6.3) at month 12. In patients converted from CSA to TAC MR4 the median daily dose was 7 (7–9) mg at week 1, 6 (4–7) mg at week 2, 4 (2–7) mg at week 4, 3.5 (2–7) mg at month 3, and 3 (2–5) mg at week 12. In patients converted from TAC to TAC MR4 the median daily dose was 3 (2–5) mg from week 1 to month 12. Figs 2 and 3 illustrate the distribution of TAC trough levels in the first week after conversion in the ITT population, and the median TAC trough levels of all patients who finished the study at 12 months after conversion. In the original PEP study we also could not find influences of ABCB1 genotypes on TAC metabolism except for level to dose ratios in the ABCB1 1236C>T genotype at a single time point (week 2: 0.02599 [CC] vs. 0.05704 [CT] vs. 0.03218 [TT]; p = 0.024), which most likely is of no clinical significance. The observed distribution of genotypes ABCB1 1236C>T, 2677G>T/A and 3435C>T in 87 KTR converted from either TAC or CSA to TAC MR4 was not consistent with the Hardy-Weinberg Equilibrium (χ2 = 83.29, p < 0.0001; χ2 = 21.22, p < 0.0007; χ2 = 64.03, p < 0.0001) (Table 4). Fig 4 shows eGFR trajectories of both conversion groups from -6 months to the end of the study.
1/dark bars = conversion from ciclosporin-based immunosuppression (n = 25; the conversion was performed in 28 individuals, 1 had taken TAC immediately before blood sampling and was excluded from the analysis, 1 failed to appear for the scheduled appointment, and 1 re-converted himself to CSA within the first days of TAC MR4 exposure), 2/light bars = conversion from tacrolimus-based immunosuppression (n = 59). Please note that scale of ordinate and abscissa differs from Fig 3.
1/dark bars = conversion from ciclosporin-based immunosuppression (n = 24), 2/light bars = conversion from tacrolimus-based immunosuppression (n = 53). Please note that scale of ordinate and abscissa differs from Fig 2.
CSA = ciclosporin A, TAC = tacrolimus, TAC MR4 = tacrolimus modified release, eGFR = estimated glomerular filtration rate, m = month, w = week. The upper field depicts the trajectories in the CSA group (median and interquartile range; blue dots and lines), in the lower field these are superimposed on the trajectories in the TAC group (median and interquartile range; black dots and lines). The x-axis denominates the points in time and the number of compiled eGFR-measurements (in weeks 1 and 2 omitted due to shortage of space. Week 1: CSA n = 25, TAC = 55. Week 2: CSA n = 27, TAC n = 57).
Discussion
In this open label prospective extension study of a randomized controlled trial we converted 87 KTR from either CSA or TAC to TAC MR4, with a follow up of up to 12 months. We investigated the influence of TAC MR4 on intermediate- to long-term renal graft function, and side effects. We defined the distribution of ABCB1 genotypes in this population and clarified correlations of ABCB1 1236C>T, ABCB1 2677G>T/A and ABCB1 3435C>T genotypes with indicators of TAC MR4 metabolism. Also, we investigated TAC MR4 dose requirements after conversion from CSA and TAC. We found that in stable long-term KTR, the conversion from CSA to TAC MR4 with 0.1 mg per kg BW of TAC, as suggested by the manufacturer, resulted in supra-therapeutic TAC trough levels in a significant proportion of patients. Despite close monitoring and accurate dose adjustments TAC C0 levels were above target for more than 12 weeks after conversion. KTR converted from TAC to TAC MR4 in a 1:1 ratio established low trough levels, similar to previous findings [10, 44]. Conversely, retrospective data from 55 KTR demonstrated a 30% increase of the daily TAC dose. More importantly, after conversion from TAC to TAC MR4, trough levels were reported to be lower [45–47]. De novo KTR needed as much as 50% more TAC MR4 to attain target trough levels compared to de novo TAC [48]. TAC requirements were shown to increase after conversion to TAC MR4 [19, 49]. A retrospective analysis in de novo KTR converted to TAC MR4 from TAC within the immediate post-transplant period showed that TAC C0 levels remained unchanged in 33%, and doses increased in 47%, and decreased in 20% [50]. The eGFR was reported to remain unchanged after conversion from TAC to TAC MR4 [19, 51], conversely other studies found an increased eGFR with TAC MR4 [44, 52, 53]. A per protocol analysis of the conversion from CSA to TAC MR4 in KTR showed no difference of graft function after 24 weeks [54]. In our study, the graft function of KTR converted from CSA to TAC MR4 declined significantly over 12 months, whereas in KTR converted from TAC to TAC MR4 the graft function remained unchanged. In the preceding PEP study, the eGFR in the CSA-based group was 46.7 (40.1–61.8) mL/min at baseline, and 47.6 (36.3–60.8) mL/min at month 24, and in the TAC-based group 45.8 (37.7–55.5) mL/min at baseline, and 47.6 (38.6–60.8) mL/min at month 24 (no significant differences). At the time of initiation of the extension study and conversion to TAC MR4, the eGFR in the CSA group was already lower compared to the eGFR in the TAC group. This may partially explain the differences between the groups. However, the majority of patients from the CSA group experienced supra-therapeutic trough levels after a bodyweight adapted dosing regimen, and stable doses and trough levels in some were achieved only well after three weeks. Thus, CNI toxicity may have contributed to the decline in GFR, which was not observed in those converted from TAC to TAC MR4. Also, those patients had well adjusted, and rather low, median trough levels.
A retrospective observation in 49 KTR with de novo TAC MR4 reported almost double dose requirements to achieve trough levels comparable with 30 KTR and TAC [55]. By contrast, doses decreased in de novo TAC MR4 KTR [56]. Additional factors may explain the inter-individual variability of TAC metabolism, which is known to be influenced by mutations in the cytochrome-p 450 (CYP) 3A4 [57] and 3A5*1/*3 systems [6, 58], and co-administration of more than 10 mg/d PRED produces a greater demand for TAC/TAC MR4 to achieve target trough levels [59]. Data on the influence of bodyweight on TAC exposure are inconsistent [59, 60]. A model of patient outcomes and treatment costs over a 5-year horizon estimated patient- and graft survival as well as cost-effectiveness favoring TAC MR4 [61] based on the assumption that TAC MR4 would lead to a reduced incidence of acute rejection episodes, thus cutting down expenses for further treatments and consecutive morbidity. This assumption may not hold, however, as acute rejection rates as high as 8% at 6 months and 10% at 12 months after transplantation were observed in patients receiving TAC MR4, compared to 4% and 7.5% in those receiving TAC, respectively, with the necessity for anti-rejection therapy in 18.2% (TAC MR4) and 11.8% (TAC) [11]. Other conversion studies did not observe biopsy proven rejections [56]. The C/D ratios after conversion from TAC to TAC MR4 were observed to remain unchanged, despite a significant reduction of TAC trough levels [16]. ABCB1 single nucleotide polymorphisms influence CNI metabolism and C/D ratios. Therefore, to uncover the potential influences on TAC metabolism, we examined the distribution of ABCB1 genotypes 2677G>T/A, 1236C>T, and 3435C>T among the study cohort. Although there are many studies of the effects of ABCB1 2677G>T/A [26, 27] [28, 29], 1236C>T [28, 29], and 3435C>T [30–34] on CSA and TAC metabolism, there is insufficient data for TAC MR4. No influences of the ABCB1 3435C>T genotype on TAC MR4 levels were demonstrated in Japanese de novo KTR [6]. In this study, as well as in the preceding RCT [35], we could not find clinically relevant associations of ABCB1 1236C>T, 2677G>T/A and 3435C>T genotypes with TAC MR4 trough levels, although these results are limited by the relatively small sample size. Most deviations from the Hardy-Weinberg Equilibrium indicate either methodological or technical errors [62]. For this study we applied a rare quality criterion and confirmed all mutant homozygous genotypes by repeated analysis of DNA samples. Moreover, the accuracy of the PCR-based genotyping assay was confirmed by direct nucleotide sequence analysis of heterozygous samples. Hence, the HWE-deviation observed in this study may be explained by the relatively small sample size and/or patient selection. It has been proposed that non-adherence would be observed less frequently with a once-daily regimen. This might be the case in some patients. Admittedly, skipping one TAC BID dose reduces the exposure by 50%, whereas one skipped TAC MR4 QD dose reduces this by 100% [63]. Non-adherence to the QD regimen was described as high as 62%, and 40% for the BID regimen [64]. We neither systematically surveyed the adherence nor patient satisfaction. However, we frequently asked whether QD was preferred over BID. Patients with little medication tended to appreciate QD rather than BID, whereas patients who were prescribed large amounts of medication tended to have a neutral position. Many KTR suffer from gastrointestinal symptoms, mostly attributable to chronic renal insufficiency, CNI- and MMF therapy. Conversion to TAC MR4 has been demonstrated to reduce gastrointestinal side effects [65]. We found that adverse events were common, especially gastrointestinal symptoms occurred. A third of those converted from CSA/TAC to TAC MR4 experienced diarrhea, and 3 patients requested to be re-converted to TAC and CSA, respectively, due to intolerable gastrointestinal symptoms. Infections occurred almost three times more often after conversion from TAC to TAC MR4, compared to conversion from CSA. Pruritus was only observed in those converted from CSA. Erroneous intake occurred more frequently in those converted from TAC to TAC MR4. However, incidents and errors with intake or prescriptions were quite common. Major limitations of this study certainly are the non-randomized character of an extension study, as well as the lack of a control group. However, this is somehow counterbalanced by the fact that the original trial was a RCT. Secondly, the study population represents a convenience sample without formal power analyses. Therefore, these results cannot be generalized. Also, there is no information on graft biopsy prior to enrolment with main histologic findings, presence or occurrence of anti-HLA antibodies. We did not conduct surveillance biopsies.
Conclusions
We found, that in stable long-term kidney transplant recipients, conversion from twice daily TAC to once daily TAC is feasible. We observed supra-therapeutic TAC concentrations in a large portion of KTR after conversion from CSA to once TAC MR4, despite closely monitored TAC trough levels and frequent dose adaptations. If a conversion from CSA to TAC MR4 is considered, we suggest a conversion rate of 1:40 for a rough estimation of TAC MR4 target doses to avoid accidental overdoses.
Supporting information
S1 File. Amendment to the ethics commission of the medical university of Vienna (german).
Amendment to the Ethics Commission of the Medical University of Vienna to extend the original randomized controlled trial PEP as PEP-X. Original version (german).
https://doi.org/10.1371/journal.pone.0218709.s001
(DOC)
S2 File. English translation of the amendment to the ethics commission of the medical university of Vienna drafted in german language.
Amendment to the Ethics Commission of the Medical University of Vienna to extend the original randomized controlled trial PEP as PEP-X. Translated version (english).
https://doi.org/10.1371/journal.pone.0218709.s002
(DOCX)
S3 File. TREND statement.
Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) statement checklist.
https://doi.org/10.1371/journal.pone.0218709.s003
(PDF)
References
- 1. Weng FL, Israni AK, Joffe MM, Hoy T, Gaughan CA, Newman M, et al. Race and electronically measured adherence to immunosuppressive medications after deceased donor renal transplantation. J Am Soc Nephrol. 2005;16(6):1839–48. pmid:15800121.
- 2. van Hooff J, Van der Walt I, Kallmeyer J, Miller D, Dawood S, Moosa MR, et al. Pharmakokinetics in stable kidney transplant recipients after conversion from twice-daily to once-daily tacrolimus formulations. Ther Drug Monit. 2012;34(1):46–52. pmid:22249344
- 3. Hardinger KL, Park JM, Schnitzler MA, Koch MJ, Miller BW, Brennan DC. Pharmacokinetics of tacrolimus in kidney transplant recipients: twice daily versus once daily dosing. Am J Transplant. 2004;4(4):621–5. pmid:15023155.
- 4. Saint-Marcoux F, Debord J, Undre N, Rousseau A, Marquet P. Pharmacokinetic modeling and development of Bayesian estimators in kidney transplant patients receiving the tacrolimus once-daily formulation. Ther Drug Monit. 2010;32(2):129–35. pmid:20110850.
- 5. Wu MJ, Cheng CY, Chen CH, Wu WP, Cheng CH, Yu DM, et al. Lower variability of tacrolimus trough concentration after conversion from prograf to advagraf in stable kidney transplant recipients. Transplantation. 2011;92(6):648–52. pmid:21912349.
- 6. Niioka T, Satoh S, Kagaya H, Numakura K, Inoue T, Saito M, et al. Comparison of pharmakokinetics and pharmacogenetics of once- and twice-daily tacrolimus in the early stage after renal transplantation. Transplantation. 2012;94(10):1013–9. pmid:23073468
- 7. Stifft F, Stolk LM, Undre N, van Hooff JP, Christiaans MH. Lower variability in 24-hour exposure during once-daily compared to twice-daily tacrolimus formulation in kidney transplantation. Transplantation. 2014;97(7):775–80. pmid:24686426
- 8. First MR, Fitzsimmons WE. New drugs to improve transplant outcomes. Transplantation. 2004;77(9 Suppl):S88–92. pmid:15201693.
- 9. Agency EM. EPAR Advagraf. 2008.
- 10. Alloway R, Steinberg S, Khalil K, Gourishankar S, Miller J, Norman D, et al. Conversion of stable kidney transplant recipients from a twice daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen. Transplant Proc. 2005;37(2):867–70. pmid:15848559.
- 11. First MR. First clinical experience with the new once-daily formulation of tacrolimus. Ther Drug Monit. 2008;30(2):159–66. pmid:18367975
- 12. Wente MN, Sauer P, Mehrabi A, Weitz J, Büchler MW, Schmidt J, et al. Review of the clinical experience with a modified release form of tacrolimus (FK 506E (MR4)) in transplantation. Clin Transplant. 2006;20(Suppl. 17):80–4.
- 13. Cross SA, Perry CM. Tacrolimus once-daily formulation: in the prophylaxis of transplant rejection in renal or liver allograft recipients. Drugs. 2007;67(13):1931–43. pmid:17722962.
- 14. Silva HT Jr., Yang HC, Abouljoud M, Kuo PC, Wisemandle K, Bhattacharya P, et al. One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. Am J Transplant. 2007;7(3):595–608. pmid:17217442.
- 15. Takahashi K, Abe R, Usuki S, So M. Safety and efficacy of once-daily modified-release tacrolimus in kidney transplant recipients: interim analysis of multicenter postmarketing surveillance in Japan. Transplant Proc. 2014;46(2):406–10. pmid:24655975
- 16. Mecule A, Tinti F, Poli L, Bachetoni A, Umbro I, Nofroni I, et al. Tacrolimus trough levels and level-to-dose ratio in stable renal transplant patients converted to a once-daily regimen. Transplant Proc. 2011;43(4):1024–7. pmid:21620042.
- 17. Umbro I, Tinti F, Mecule A, Bachetoni A, Poli L, Pignatelli A, et al. Long-term interleukin-2 assessment after conversion from a twice-daily to once-daily tacrolimus regimen in stable kidney recipients. Transplant Proc. 2012;44(7):1907–9. pmid:22974867.
- 18. Bäckman L, Persson CA. An observational study evaluating tacrolimus dose, exposure, and medication adherence after conversion from twice- to once-daily tacrolimus in liver and kidney transplant recipients. Ann Transplant. 2014;19:138–44. pmid:24637379
- 19. Guirado L, Cantarell C, Franco A, Huertas EG, Fructuoso AS, Fernandez A, et al. Efficacy and safety of conversion from twice-daily to once-daily tacrolimus in a large cohort of stable kidney transplant recipients. Am J Transplant. 2011;11(9):1965–71. pmid:21668633.
- 20. Glick L, Shamy F, Nash M, Sokwala A, Malavade T, Prasad GR, et al. A prospective cohort conversion study of twice-daily to once-daily extended-release tacrolimus: role of ethnicity. Transplant Res. 2014;3(1):1–5.
- 21. Tinti F, Mecule A, Poli L, Bachetoni A, Umbro I, Brunini F, et al. Improvement of graft function after conversion to once daily tacrolimus of stable kidney transplant patients. Transplant Proc. 2010;42(10):4047–8. pmid:21168623.
- 22. de Jonge H, Kyupers DR, Verbeke K, Vanrenterghem Y. Reduced C0 concentrations and increase dose requirements in renal allograft recipients converted to the novel once-daily tacrolimus formulation. Transplantation. 2010;90(5):523–9. pmid:20592652
- 23. Kramer BK, Charpentier B, Backman L, Silva HT Jr., Mondragon-Ramirez G, E Cassuto-Viguier, et al. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. Am J Transplant. 2010;10(12):2632–43. pmid:20840480.
- 24. Jelassi ML, Lefeuvre S, Karras A, Moulonguet L, Billaud EM. Therapeutic drug monitoring in de novo kidney transplant receiving the modified-release once-daily tacrolimus. Transplant Proc. 2011;43(2):491–4. pmid:21440742.
- 25. Tsuchiya N, Satoh S, Tada H, Li Z, Ohyama C, Sato K, et al. Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation. 2004;78(8):1182–7. pmid:15502717.
- 26. Anglicheau D, Verstuyft C, Laurent-Puig P, Becquemont L, Schlageter MH, Cassinat B, et al. Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. J Am Soc Nephrol. 2003;14(7):1889–96. pmid:12819250.
- 27. Anglicheau D, Legendre C, Thervet E. Pharmacogenetics in solid organ transplantation: present knowledge and future perspectives. Transplantation. 2004;78(3):311–5. pmid:15316356.
- 28. Mourad M, Mourad G, Wallemacq P, Garrigue V, Van Bellingen C, Van Kerckhove V, et al. Sirolimus and tacrolimus trough concentrations and dose requirements after kidney transplantation in relation to CYP3A5 and MDR1 polymorphisms and steroids. Transplantation. 2005;80(7):977–84. pmid:16249748.
- 29. Mendes J, Martinho A, Simoes O, Mota A, Breitenfeld L, Pais L. Genetic polymorphisms in CYP3A5 and MDR1 genes and their correlations with plasma levels of tacrolimus and cyclosporine in renal transplant recipients. Transplant Proc. 2009;41(3):840–2. WOS:000265504300015. pmid:19376366
- 30. Akbas SH, Bilgen T, Keser I, Tuncer M, Yucetin L, Tosun O, et al. The effect of MDR1 (ABCB1) polymorphism on the pharmacokinetic of tacrolimus in Turkish renal transplant recipients. Transplant Proc. 2006;38(5):1290–2. pmid:16797284.
- 31. Loh PT, Lou HX, Zhao Y, Chin YM, Vathsala A. Significant impact of gene polymorphisms on tacrolimus but not cyclosporine dosing in Asian renal transplant recipients. Transplant Proc. 2008;40(5):1690–5. pmid:18589174.
- 32. Kotrych K, Sulikowski T, Domanski L, Bialecka M, Drozdzik M. Polymorphism in the P-glycoprotein drug transporter MDR1 gene in renal transplant patients treated with cyclosporin A in a Polish population. Pharmacol Rep. 2007;59(2):199–205. pmid:17556798.
- 33. Ashavaid T, Raje H, Shalia K, Shah B. Effect of gene polymorphisms on the levels of calcineurin inhibitors in Indian renal transplant recipients. Indian J Nephrol. 2010;20(3):146–51. pmid:21072155; PubMed Central PMCID: PMC2966981.
- 34. Wu P, Ni X, Wang M, Xu X, Luo G, Jiang Y. Polymorphisms in CYP3A5*3 and MDR1, and haplotype, modulate response to plasma levels of tacrolimus in Chinese renal transplant recipients. Ann Transplant. 2011;16(1):54–60. pmid:21436775
- 35. Riegersperger M, Plischke M, Steiner S, Seidinger D, Sengoelge G, Winkelmayer WC, et al. Effect of conversion from ciclosporin to tacrolimus on endothelial progenitor cells in stable long-term kidney transplant recipients. Transplantation. 2013;95(11):1338–45. pmid:23594858.
- 36. Trafficking ISoTTaO. The Declaration of Istanbul on Organ Trafficking and Transplant Tourism. Clin J Am Soc Nephrol. 2008;3(5):1227–31. pmid:18701611
- 37.
Ethics CoP. The COPE Report 1999. BMJ Books. 1999:43–7. http://dx.doi.org/10.1136/oem.57.8.506.
- 38. Little J, Higgins JPT, Ioannidis JPA, Moher D, Gagnon F, van Elm E, et al. STrengthening the REporting of Genetic Association studies (STREGA)—an extension of the STROBE statement. Eur J Clin Invest. 2009;39(4):247–66. pmid:19297801
- 39. Des Jarlais DC, Lyles C, Crepaz N. Improving the reporting quality of nonrandomized evaluations of behavioral and public health interventions: the TREND statement. Am J Public Health. 2004;94(3):361–6. pmid:14998794
- 40. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340.
- 41. Levey AS. Clinical practice. Nondiabetic kidney disease. N Engl J Med. 2002;347(19):1505–11. pmid:12421894.
- 42. Sunder-Plassmann R, Rieger S, Endler G, Brunner M, Müller M, Mannhalter C. Simultaneous analysis of MDR1 C3435T, G2677T/A, and C1236T genotypes by multiplexed mutagenically separated PCR. Clin Chem Lab Med. 2005;43(2):192–4. pmid:15843215.
- 43. Prograf ISMP C. and Mix-up Advagraf. Can J Hosp Pharm. 2009;62(5):417–8.
- 44. Spagnoletti G, Gargiulo A, Salerno MP, Favi E, Pedroso JA, Calia R, et al. Conversion from Prograf to Advagraf in stable kidney transplant recipients: better renal function after 3-year follow-up. Transplant Proc. 2014;46(7):2224–7. pmid:25242756
- 45. Nakamura Y, Hama K, Katayama H, Soga A, Toraishi T, Yokoyama T, et al. Safety and efficacy of conversion from twice-daily tacrolimus (Prograf) to once-daily prolonged-release tacrolimus (Graceptor) in stable kidney transplant recipients. Transplant Proc. 2012;44(1):124–7. pmid:22310595
- 46. Tran D, Vallée M, Collette S, Senécal L, Lafrance JP, Dandavino R, et al. Conversion from twice-daily to once-daily extended-release tacrolimus in renal transplant recipients: 2-year results and review of the literature. Exp Clin Transplant. 2014;12(4):323–7. pmid:24844288
- 47. Hougardy JM, Broeders N, Kianda M, Massart A, Madhoun P, Le Moine A, et al. Conversion from Prograf to Advagraf among kidney transplant recipients results in sustained decrease in tacrolimus exposure. Transplantation. 2011;91(5):566–9. WOS:000287474300014. pmid:21192316
- 48. Crespo M, Mir M, Marin M, Hurtado S, Estadella C, Guri X, et al. De novo kidney transplant recipients need higher doses of Advagraf compared with Prograf to get therapeutic levels. Transplant Proc. 2009;41(6):2115–7. pmid:19715848.
- 49. Lauzurica R, Morales JM, van Hooff J. Renal function and safety in stable kidney transplant recipients converted from immediate-release to prolongued-release tacrolimus. Transplant Int. 2012;25:48–55.
- 50. Jannot M, Masson I, Alamartine E, Mariat C. Early conversion from twice-daily tacrolimus to once-daily extended formulation in renal transplant patients before hospital discharge. Ann Transplant. 2014;19:320–4. pmid:24999809
- 51. Oh CK, Huh KH, Lee JS, Cho HR, Kim YS. Safety and efficacy of conversion from twice-daily tacrolimus to once-daily tacrolimus one month after transplantation: randomized controlled trial in adult renal transplantation. Yonsei Med J. 2014;55(5):1341–7. pmid:25048494
- 52. Kolonko A, Chudek J, Wiecek A. Improved kidney graft function after conversion from twice daily tacrolimus to a once daily prolonged-release formulation. Transplant Proc. 2011;43(8):2950–3. pmid:21996198.
- 53. Sessa A, Esposito A, Iavicoli G, Lettieri E, Ragosta G, Rossano R, et al. Cardiovascular risk factors in renal transplant patients after switch from standard tacrolimus to prolonged-release tacrolimus. Transplant Proc. 2012;44(7):1901–6. pmid:22974866.
- 54. Rostaing L, Sanchez-Fructuoso A, Franco A, Glyda M, Kuypers DR, Jaray J. Conversion to tacrolimus once-daily from ciclosporin in stable kidney transplant recipients: a multicenter study. Transpl Int. 2012;25(4):391–400. pmid:22211928.
- 55. Andres A, Delgado-Arranz M, Morales E, Dipalma T, Polanco N, Gutierrez-Solis E, et al. Extendend-release tacrolimus therapy in de novo kidney transplant recipients: a single-center experience. Transplant Proc. 2010;42(8):3034–7. pmid:20970602
- 56. van Hooff JP, Alloway RR, Trunecka P, Mourad M. Four-year experience with tacrolimus once-daily prolonged release in patients from phase II conversion and de novo kidney, liver, and heart studies. Clin Transplant. 2011;25:1–12.
- 57. Li CJ, Li L, Lin L, Jiang HX, Zhong ZY, Li WM, et al. Impact of the CYP3A5, CYP3A4, COMT, IL-10 and POR genetic polymorphisms on tacrolimus metabolism in chinese renal transplant recipients. PLoS ONE. 2014;9(1):e86206. pmid:24465960
- 58. Lunde I, Bremer S, Midvedt K, Mohebi B, Dahl M, Bergan S, et al. The influence of CYP3A, PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients. Eur J Clin Pharmacol. 2014;70(6):685–93. pmid:24658827
- 59. Zhao W, Fakhoury M, Baudouin V, Storme T, Maisin A, Deschenes G, et al. Population pharmacokinetics and pharmacogenetics of once daily prolonged-release formulation of tacrolimus in pediatric and adolsecent kidney transplant recipients. Eur J Clin Pharmacol. 2013;69:189–95. pmid:22706623
- 60. Press RR, Ploeger BA, den Hartigh J, van der Straaten T, van Pelt J, Danhof M, et al. Explaining variability in tacrolimus pharmacokinetics to optimize early exposure in adult kidney transplant recipients. Ther Drug Monit. 2009;31(2):187–97. pmid:19258929.
- 61. Abecassis MM, Seifeldin R, Riordan ME. Patient outcomes and economics of once-daily tacrolimus in renal transplant patients: results of a modeling analysis. Transplant Proc. 2008;40(5):1443–5. pmid:18589126.
- 62. Hosking L, Lumsden S, Lewis K, Yeo A, McCarthy L, Bansal A, et al. Detection of genotyping errors by Hardy-Weinberg equilibrium testing. Eur J Hum Genet. 2004;12(5):395–9. pmid:14872201
- 63. Hougardy JM, de Jonge H, Kuypers D, Abramowicz D. The once-daily formulation of tacrolimus: a step forward in kidney transplantation? Transplantation. 2012;93(3):241–3. pmid:22234346.
- 64. Kuypers DRJ, Peeters PC, Sennesael JJ, Kianda MN, Vrijens B, Kristanto P, et al. Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring. Transplantation. 2013;95(2):333–40. WOS:000313722500018. pmid:23263559
- 65. Veroux M, Grosso G, Ekser B, Corona D, Giaquinta A, Veroux P. Impact of conversion to a once daily tacrolimus-based regimen in kidney transplant recipients with gastrointestinal complications. Transplantation. 2012;93(9):895–9. pmid:22298033.