ORIGINAL ARTICLE
Similar MPA Exposure on Modified Release and Regular Tacrolimus Guido Filler, MD, PhD, FRCPC,*† Alexander A. Vinks, PharmD, PhD, FCP,‡§ Shih-Han S. Huang, MD, FRCPC,* Anthony Jevnikar, MD, FRCPC, MSc,* and Norman Muirhead, MD, FRCPC, FRCP*
Abstract: Concomitant immunosuppression may affect the mycophenolate mofetil exposure. Astellas developed a once-daily modified release formulation of tacrolimus (TacMR) with the potential to reduce the likelihood of nonadherence. It is unknown whether mycophenolic acid (MPA) area under the concentration– time curve (AUC) differs between the 2 tacrolimus (Tac) formulations. In a 2-by-2 crossover design, 20 stable renal transplant recipients on twice-daily Tac either continued their usual Tac therapy (n = 10, group 1) or switched to TacMR for a 12-week period (n = 10, group 2), after which the patients crossed over to the other formulation for another 12-week period. Pharmacokinetic profiles using limited sampling strategies were obtained before randomization (visit 1), and at 12 (visit 2) and 24 weeks (visit 3) at steady state. MPA AUC was calculated using the Pawinski formula. When analyzing visits on Tac, TacMR, and back on Tac combined, the MPA AUC for all 20 patients at baseline was 42.24 (16.98), 37.18 (13.75), and 40.09 (16.69) mg$h$L21, respectively, which was not statistically significant using repeated measures (P = 0.1327, R2 = 0.1109). We conclude that MPA pharmacokinetic profiles are not altered when converting patients from Tac to TacMR. Key Words: tacrolimus formulations, mycophenolate mofetil, mycophenolic acid, mycophenolate acid glucuronide, equivalence (Ther Drug Monit 2014;36:353–357)
Received for publication August 7, 2013; accepted September 29, 2013. From the Departments of *Medicine, Division of Nephrology; and †Pediatrics, Division of Pediatric Nephrology, Children’s Hospital, London Health Science Centre and Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada; and ‡Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati; and §Department of Pediatrics, College of Medicine, University of Cincinnati, Ohio. The authors declare no conflict of interest. G. Filler and N. Muirhead attended a scientific advisory board meeting organized by Astellas, Inc. Supported by Astellas, Inc. (N. Muirhead). Correspondence: Guido Filler, MD, PhD, FRCPC, Department of Pediatrics, Division of Pediatric Nephrology, Children’s Hospital, London Health Sciences Centre, University of Western Ontario, 800 Commissioners Rd East, Rm B1-436, London, ON N6A 5W9, Canada (e-mail: guido. fi[email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
Ther Drug Monit Volume 36, Number 3, June 2014
INTRODUCTION Nonadherence with immunosuppressive medications is a critical issue in organ transplantation.1 Recently, Astellas developed a once-daily modified release formulation of tacrolimus (TacMR) that has the potential to reduce the likelihood of nonadherence. To date, most of the published data relating to the use of TacMR originate from industry-sponsored clinical trials. These have shown that conversion from tacrolimus (Tac) to TacMR on a milligram to milligram basis in both stable and de novo kidney and liver transplant recipients yields lower peak concentrations but equivalent overall drug exposure [area under the concentration–time curve (AUC)] and trough concentrations.2 Tac is often given in combination with mycophenolate mofetil (MMF), the inactive morpholinoethyl ester prodrug of mycophenolic acid (MPA), or the enteric-coated mycophenolate sodium (EC-MPS). MPA is a potent immunosuppressant that reduces rejection after renal transplantation. There is level 2 evidence from the APOMYGRE trial that a minimum MPA exposure (measured as AUC) is required to prevent rejection,3 and pharmacokinetic monitoring of MPA is recommended.4 The target AUC of 30–60 mg$h$L21 has been defined through an international consensus conference5–7 and is also accepted for liver transplantation.8 The clinical pharmacokinetics of MPA are characterized by high between-subject and within-subject variability.9 Coadministration of other immunosuppressive may influence MPA exposure.10,11 Significantly higher doses of MMF are needed to achieve the same exposure on cyclosporine, whereas concomitant Tac augments the bioavailability of MPA, at least in vitro.12 Other studies revealed that MPA exposure without a concomitant calcineurin inhibitor was in the middle between that on concomitant Tac or cyclosporine.11,13 One of the main reasons for the drug–drug interaction is the inhibition of multidrug resistance protein 2–mediated transport in the presence of the main MPA metabolite, 7-O-MPA-glucuronide (MPAG).9 Other explanations include gene polymorphisms in the enzymes that metabolize MPA, especially the UGT1A9-275T.A/-2152C.T polymorphisms.14,15 High dosages of corticosteroids may induce expression of UGT, reducing exposure to MPA. Exposure to MPA when MMF is given in combination with cyclosporine is approximately 30%–40% lower than when given alone or with Tac or sirolimus.9 There is also data suggesting that there is increased MPA exposure in stable kidney transplant recipients on Tac as compared with after conversion to sirolimus, which may have an interaction
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between Tac and MMF at the level of their intestinal absorption.16 It is unknown whether and to what degree TacMR affects the pharmacokinetics of MPA. There are also only very few studies on the within-subject variability of MPA exposure parameters, but 1 preliminary study suggests a mean intraindividual coefficient of variation (CV) of 30%–47% (range, 18%– 80%).17 To assure stable graft function when switching between the 2 different Tac formulations, we wanted to determine that the exposure was unaffected by the conversion. As pharmacokinetics of Tac and MPA may change over time,1 we designed a crossover randomized trial to assess this question.
METHODS Twenty adult renal transplant recipients were recruited into a prospective crossover design cohort study. Patients had to be transplanted at least 12 months before enrollment, had to have stable allograft function with a serum creatinine ,180 mmol/L, an epidermal growth factor receptor of .30 mL/min, no increase/decrease of .10% in creatinine in the previous 3 months, were targeted to a Tac trough level of 5–8 ng/mL, and were stable within that target range in the previous 3 months. Patients also had to be treated with concomitant MMF. The institutional review board approved the study. After obtaining informed consent, baseline data including demographics, serum urea, creatinine, electrolytes, fasting lipids and fasting glucose, trough Tac level, sparse sampling MPA pharmacokinetic profile, concurrent medication profile, and physical examination were collected. Eligible patients were then randomized to a 3-month period to either continue on Tac (group 2) or an equivalent dose of TacMR (group 1) and crossed over after 3 months. Tac levels were adjusted if the levels were outside of the desired range, but MMF doses were left unchanged. Patients underwent PK monitoring using a limited sampling strategy (LSS).18 MPA plasma concentrations were measured at 3 time points: before (predose concentration), and 30 and 120 minutes after oral MMF administration.18,19 The MPA abbreviated AUC from 0 to 12 hours (AUC0–12 h) was calculated from these 3 MPA concentrations using a validated algorithm from adult patients on Tac. The formula reads AUC0–12 h = 7.75 + 6.49c (0 h) + 0.76c (0.5 h) + 2.43c (2 h), where “c” is the MPA concentration at the specific time point.18 On 2 occasions, the 0.5-h concentration was missing. We extrapolated the missing points using the same percentiles from 156 unpublished full 12-point pharmacokinetic profiles that were closest to the 2-hour concentrations. Dose adjustment of MMF therapy was discouraged and did not occur during the 24-week study period. Each patient underwent 3 LSS measurements, that is at baseline (visit 1), week 12 (visit 2), and week 24 (visit 3) on both standard Tac and TacMR therapy. MPA AUC was calculated at each time point. MPA and MPAG concentrations were measured at the laboratory at Cincinnati Children’s Hospital as previously described.15
STATISTICS Continuous data were tested for normal distribution using the Shapiro–Wilk test. For normally distributed data,
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parametric methods were used; otherwise nonparametric tests were used. Wherever possible, simple descriptive statistics were used. Normally distributed data were expressed as mean (SD). CV calculations were performed as per clinical chemistry laboratory guidelines. No adjustments were made for missing values (two 30-minute MPA concentrations were missing).
RESULTS The demographics of the patients are summarized in Table 1. There were 9 male and 11 female subjects enrolled into the study. A total of 14 patients were recipients of deceased donor renal transplants (second transplant in 2), whereas the remainder had received living donor transplants. The 20 renal transplant recipients underwent a total of 60 abbreviated pharmacokinetic profiles with measures of a morning trough level and 30 and 120 minutes after oral intake of either Tac or TacMR. MPA levels were not normally distributed. Therefore, data were presented as median and interquartile range (Table 2). At baseline visit and thereafter, Tac trough levels were normally distributed. There were no significant differences between the trough Tac levels at visits 1, 2, and 3 (Table 3). We also compared the Tac trough levels during TacMR and Tac treatment and found no significant differences with a mean of 5.07 (1.17) ng/mL on TacMR and 5.08 (1.21) ng/mL on Tac (P = 0.9616, paired t test). MMF dose per kilograms per day was normally distributed. For the entire group, the baseline MMF dose per kilogram body weight was 14.84 (4.81) mg/kg, and at the end of the TacMR 12-week period, the mean MMF dose was 14.82 (4.90) mg/kg; the mean MMF dose at the end of the Tac 12-week period was 14.85 (4.99) mg/kg. This of course was not statistically significant (P = 0.9007, R2 = 0.1009, repeated-measures analysis of variance). When analyzing
TABLE 1. Patient Demographics
All (N = 20) Age, yr Time post-transplant, mo Baseline Tac dose, mg/d Baseline eGFR, mL/min/1.73 m2 Group 1 (n = 10) Age, yr Time post-transplant, mo Baseline Tac dose, mg/d Baseline eGFR, mL/min/1.73 m2 Group 2 (n = 10) Age, yr Time post-transplant, mo Baseline Tac dose, mg/d Baseline eGFR, mL/min/1.73 m2
Mean (P, If Applicable)
SD
Range
56.6 78 2.35 55.05
12.6 38.5 1 13.4
35–79 18–147 1–5 38–79
53.7 92.3 2.28 54.3 54.3 59.0 (0.227) 55.5 (0.03) 2.32 (0.841) 55.2 (0.841)
12.6 43.8 1.29 13.5 13.5 11.9 38.5 0.86 13.4
35–77 17–142 1–5 38–79 38–89 44–79 29–96 1–4 39–78
Baseline eGFR was calculated using the MDRD formula (http://www.kidney.org/ professionals/kdoqi/gfr_calculator.cfm). eGFR, epidermal growth factor receptor.
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Similar MPA Exposure on Modified Release Tac
TABLE 2. MPA Levels (mg/L) in the Pharmacokinetic Profiles as Morning Trough Levels, and 30 and 120 Minutes After Intake Number of values Minimum 25% percentile Median 75% percentile Maximum
0 min
30 min
120 min
60 0.0900 1.040 1.860 3.035 6.290
58 0.1000 3.410 5.840 10.99 35.10
60 0.1000 2.910 4.195 6.125 13.10
visits on Tac, TacMR, and back on Tac combined, the MPA AUC for all 20 patients at baseline was 42.24 (16.98), 37.18 (13.75), and 40.09 (16/69) mg$h$L21, respectively, which was not statistically significant using repeated measures (P = 0,1327, R2 = 0.1109). Ten patients were randomized to receive TacMR, followed by Tac (group 1), and the other 10 patients received Tac and then TacMR (group 2). MPA AUC was tested for normal distribution using the Kolmogorov–Smirnov normality test, the D’Agostino and Pearson omnibus normality test, and the Shapiro–Wilks test for normality, and all tests revealed a normal distribution. Therefore, data were expressed as mean (6SD). Mean MPA doses were not statistical significantly different between both groups: at baseline, these were 13.14 (3.60) mg$kg21$d21 in group 1 and 16.53 (5.16, P = 0.117) mg$kg21$d21 in group 2 (unpaired t test). After 12 weeks of TacMR, mean MMF dose was 12.97 (3.92) mg$kg21$d21 in group 1 and 16.66 (5.27) mg$kg21$d21 in group 2 (P = 0.0926, unpaired t test), and after 12 weeks of Tac, mean MMF dose was 13.00 (3.39) mg$kg21$d21 in group 1 and 16.70 (5.29) mg$kg21$d21 in group 2 (P = 0.0910, unpaired t test). However, mean MPA AUC at the beginning of the study was 34.31 (9.71) mg$h$L21 in group 1, whereas it was 50.18 (19.35) mg$h$L21 in group 2, which was significantly different (P = 0.0324, unpaired t test). Within both group 1 and 2, there was no significant difference between visits 1 and 2, visits 1 and 3, and visits 2 and 3 (paired t test). There was, therefore, no effect of the Tac formulation on the MPA AUC (Fig. 1). We also examined the comparison of MPA AUC between TacMR and Tac in the combined group. Mean MPA AUC on TacMR was 37.18 (13.75) mg$h$L21, not significantly different from the MPA AUC on Tac, which
FIGURE 1. MPA AUCs in both group 1 (Tac-TacMR-Tac) and group 2 (Tac-Tac-TacMR). A significant number of AUCs were both above and below the target range of 30–60 mg$h$L21. The bars show the mean (SD) of the MPA AUC.
was 40.09 (16.69) mg$h$L21 (P = 0.2628, paired t test, Fig. 2). We were also able to compare the MPA AUC over time on Tac in all 20 patients. At visit 1 (all patients on Tac), the MPA AUC was 42.24 (16.98) mg$h$L21, not significantly different from the last time point on Tac (6 months in half of the patients and 3 in the other half), when the MPA AUC was 40.09 (16.69) mg$h$L21 (Fig. 2). There was, therefore, no difference in the MPA exposure between periods of treatment with Tac or TacMR. We also performed repeated measures 1-way analysis of variance to assess for changes over time and found no significant changes (P = 0.2524) nor did we find evidence in the post-test for linear trend (slope = 21.623, R2 = 0.0072; P = 0.2024). We also measured the main metabolite, the glucuronide MPAG. MPAG trough levels were 42.9 (21.58) mg/L at
TABLE 3. Tac Trough Levels (ng/mL) at Baseline, at 12 Weeks, and 24 Weeks After Randomization Number of values Minimum 25% percentile Median 75% percentile Maximum Mean SD Standard error
0 min
30 min
120 min
20 2.000 3.850 4.800 6.075 9.600 5.170 1.881 0.4206
20 2.600 4.625 5.000 5.700 8.300 5.165 1.243 0.2780
20 3.400 3.950 5.100 5.475 7.500 4.985 1.123 0.2511
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FIGURE 2. Comparison of the MPA AUC on Tac versus TacMR. Although the MPA AUC was 10% higher on Tac, this did not reach statistical significance.
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visit 1, 39.25 (19.64) at visit 2, and 40.25 (23.84) at visit 3. There was no change over time. Similar to the MPA, there was no difference in MPAG trough levels between the different formulations of Tac. Not unexpectedly, there was a weak but significant correlation between the serum creatinine and the MPAG trough level (R2 = 0.07818, P = 0.0320), given that MPAG accumulates in chronic kidney disease. We also studied the relationship between the Tac trough level and MPA AUC. As both MPA AUC and Tac trough levels were normally distributed, we used linear regression analysis. We found no evidence for a correlation between MPA AUC and Tac trough levels (R2 = 0.02644; P = 0.2145). We then calculated the CV of the morning trough levels for MPA as well as for the concentrations at 30 and 120 minutes after intake and the CV for the MPA AUC. The MPA trough level had a much higher CV (0.667). The 30-minute post-dose MPA level had a CV of 0.825 and the 120-minute level had a CV of 0.558, whereas the MPA AUC level had a lower CV of 0.395. The CV of the MPA AUC on TacMR was slightly lower (0.369) when compared with Tac (0.416). Finally, we calculated the CV of the morning trough levels for Tac (0.280).
DISCUSSION The main objective of this study was the evaluation of the equivalence of the MPA exposure in stable renal transplant recipients who were converted from regular formulation to modified release Tac formulation. Based on the wellestablished drug–drug interaction between Tac and MMF12,20 and the differing pharmacokinetics of the 2 formulations,1 we hypothesized that MPA exposure may vary among the 2 formulations. However, we found no significant difference in the MPA exposure among both formulations and concluded that it is unnecessary to adjust dosing of MMF or EC-MPS after conversion to once-daily TacMR Tac formulation. However, we found substantial variability in the MPA exposure in the 20 patients. Eighteen of the 58 MPA AUCs (2 could not be calculated due to missing 30-minute concentrations) were below the proposed effective exposure level of 30 mg$h$L21. The study confirms the previously reported high interindividual variability of MPA exposure.3,5,21–23 In the consensus documents, the need to exceed an AUC of 30 mg$h$L21 to prevent rejection was stressed.5–7 The data presented here suggest that PK monitoring should be used to prevent underexposure of MMF or EC-MPS. At this point in time, pharmacokinetic monitoring of MMF/EC-MPS therapy in North America is usually the only standard among pediatric transplant centers. Even if pharmacokinetic monitoring is used, physicians often fail to comply with the recommended dose changes.24,25 There is much less certainty about the safe upper limit of the MPA AUC, but 60 mg$h$L21 is considered a safe upper limit.5,7 Our data also suggest that MMF/EC-MPS dosing can be reduced in some of the patients. This may reduce the cancer risk and the risk for viral infections. This study has several strengths. Tac exposure was kept constant throughout. The crossover design reduces the potential confounding effect of changes over time.1 We also
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had a significant spread in the MPA exposure allowing for an assessment of low and high exposure, and patients with high MPA exposures behaved similarly to patients with low exposure without variability based on the Tac formulation (data not shown). Based on the careful design, the study is adequately powered. Limitations of the study include the lack of a complete pharmacokinetic profile with the inevitable variability of the assessment of the true exposure,26 the lack of full PK profiles for Tac. The study with within-subject design may also be subject to a carryover effect because having been tested under 1 condition may affect how participants behave in another condition; however, we feel that a practice effect, a fatigue effect, assimilation, or “catching-on” effects have been relevant here. Furthermore, there are growing concerns that the trough level may not be ideal for monitoring the oncedaily formulation of Tac.1 The data also only apply to patient with relatively good renal function. As patients with more advanced chronic kidney disease were excluded, we cannot comment on the effect of accumulation of MPAG in patients with renal impairment.27 The data also do not apply to children where there is ontogeny (age dependency) of drug disposition of MMF in children with this combination.28 Nonetheless, this study addresses the knowledge gap about the potential impact of the various Tac formulations on the MPA pharmacokinetics. Based on this study, we can eliminate any concerns that the conversion from Tac to TacMR will negatively affect MPA exposure.
SUMMARY We do not have sufficient evidence to reject the hypothesis that conversion from Tac to TacMR may affect the MPA exposure. Patients had identical Tac (measured as trough level) and MPA exposure (measured as abbreviated AUC using the Pawinski LSS). However, there was wide interindividual and intraindividual variability of MPA exposure with approximately half the patients had overexposure and underexposure. There was a slight trend toward lower MPA exposure over time, although this did not reach statistical significance. Not unexpectedly, there was a significant correlation between the MPAG trough level and the serum creatinine, which over time may lead to enhanced MPA exposure with worsening kidney function. This trend warrants repeated measurement of MPA exposure over time. Taken together, our study suggests that equivalence of MPA exposure is maintained when converting patients to the modified release Tac. However, given the evidence for an MPA AUC exceeding 30 mg$h$L21 and the high prevalence of underexposure, repeated MPA exposure measurements are recommended. REFERENCES 1. Hougardy JM, de Jonge H, Kuypers D, et al. The once-daily formulation of tacrolimus: a step forward in kidney transplantation? Transplantation. 2012;93:241–243. 2. Barraclough KA, Isbel NM, Johnson DW, et al. Once- versus twicedaily tacrolimus: are the formulations truly equivalent? Drugs. 2011; 71:1561–1577. 3. Le Meur Y, Buchler M, Thierry A, et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant. 2007;7:2496–2503.
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4. van Gelder T, Le Meur Y, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit. 2006;28:145–154. 5. Tonshoff B, David-Neto E, Ettenger R, et al. Pediatric aspects of therapeutic drug monitoring of mycophenolic acid in renal transplantation. Transplant Rev (Orlando). 2011;25:78–89. 6. Kuypers DR, Le Meur Y, Cantarovich M, et al. Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation. Clin J Am Soc Nephrol. 2010;5:341–358. 7. Le Meur Y, Borrows R, Pescovitz MD, et al. Therapeutic drug monitoring of mycophenolates in kidney transplantation: report of The Transplantation Society consensus meeting. Transplant Rev (Orlando). 2011; 25:58–64. 8. Brunet M, Cirera I, Martorell J, et al. Sequential determination of pharmacokinetics and pharmacodynamics of mycophenolic acid in liver transplant patients treated with mycophenolate mofetil. Transplantation. 2006;81:541–546. 9. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet. 2007;46:13–58. 10. Grinyo JM, Ekberg H, Mamelok RD, et al. The pharmacokinetics of mycophenolate mofetil in renal transplant recipients receiving standarddose or low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus: the Symphony pharmacokinetic substudy. Nephrol Dial Transplant. 2009; 24:2269–2276. 11. Filler G, Zimmering M, Mai I. Pharmacokinetics of mycophenolate mofetil are influenced by concomitant immunosuppression. Pediatr Nephrol. 2000; 14:100–104. 12. Zucker K, Tsaroucha A, Olson L, et al. Evidence that tacrolimus augments the bioavailability of mycophenolate mofetil through the inhibition of mycophenolic acid glucuronidation. Ther Drug Monit. 1999;21:35–43. 13. Filler G, Hansen M, LeBlanc C, et al. Pharmacokinetics of mycophenolate mofetil for autoimmune disease in children. Pediatr Nephrol. 2003; 18:445–449. 14. van Schaik RH, van Agteren M, de Fijter JW, et al. UGT1A9 -275T.A/2152C.T polymorphisms correlate with low MPA exposure and acute rejection in MMF/tacrolimus-treated kidney transplant patients. Clin Pharmacol Ther. 2009;86:319–327. 15. Fukuda T, Goebel J, Cox S, et al. UGT1A9, UGT2B7, and MRP2 Genotypes can Predict mycophenolic acid pharmacokinetic variability in pediatric kidney transplant recipients. Ther Drug Monit. 2012;34:671–679.
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Similar MPA Exposure on Modified Release Tac
16. Braun F, Schocklmann H, Ziegler E, et al. Increased mycophenolic acid exposure in stable kidney transplant recipients on tacrolimus as compared with those on sirolimus: implications for pharmacokinetics. Clin Pharmacol Ther. 2009;86:411–415. 17. Shaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: report of a roundtable discussion. Ther Drug Monit. 2001;23:305–315. 18. Pawinski T, Hale M, Korecka M, et al. Limited sampling strategy for the estimation of mycophenolic acid area under the curve in adult renal transplant patients treated with concomitant tacrolimus. Clin Chem. 2002;48:1497–1504. 19. Filler G, Mai I. Limited sampling strategy for mycophenolic acid area under the curve. Ther Drug Monit. 2000;22:169–173. 20. Ekberg H, van Gelder T, Kaplan B, et al. Relationship of tacrolimus exposure and mycophenolate mofetil dose with renal function after renal transplantation. Transplantation. 2011;92:82–87. 21. Filler G. Value of therapeutic drug monitoring of MMF therapy in pediatric transplantation. Pediatr Transplant. 2006;10:707–711. 22. Filler G, Feber J. The transplanted child: New immunosuppressive agents and the need for pharmacokinetic monitoring. Paediatr Child Health. 2002;7:525–532. 23. Filler G, Lepage N, Delisle B, et al. Effect of cyclosporine on mycophenolic acid area under the concentration-time curve in pediatric kidney transplant recipients. Ther Drug Monit. 2001;23:514–519. 24. van Gelder T, Silva HT, de Fijter JW, et al. Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial. Transplantation. 2008;86:1043–1051. 25. Hocker B, van Gelder T, Martin-Govantes J, et al. Comparison of MMF efficacy and safety in paediatric vs. adult renal transplantation: subgroup analysis of the randomised, multicentre FDCC trial. Nephrol Dial Transplant. 2011;26:1073–1079. 26. Filler G. Abbreviated mycophenolic acid AUC from C0, C1, C2, and C4 is preferable in children after renal transplantation on mycophenolate mofetil and tacrolimus therapy. Transpl Int. 2004;17:120–125. 27. Kaminska J, Glyda M, Sobiak J, et al. Pharmacokinetics of mycophenolic acid and its phenyl glucuronide metabolite in kidney transplant recipients with renal impairment. Arch Med Sci. 2012;8:88–96. 28. Filler G, Foster J, Berard R, et al. Age-dependency of mycophenolate mofetil dosing in combination with tacrolimus after pediatric renal transplantation. Transplant Proc. 2004;36:1327–1331.
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Similar MPA Exposure on Modified Release and Regular Tacrolimus Guido Filler, MD, PhD, FRCPC,*† Alexander A. Vinks, PharmD, PhD, FCP,‡§ Shih-Han S. Huang, MD, FRCPC,* Anthony Jevnikar, MD, FRCPC, MSc,* and Norman Muirhead, MD, FRCPC, FRCP*
Abstract: Concomitant immunosuppression may affect the mycophenolate mofetil exposure. Astellas developed a once-daily modified release formulation of tacrolimus (TacMR) with the potential to reduce the likelihood of nonadherence. It is unknown whether mycophenolic acid (MPA) area under the concentration– time curve (AUC) differs between the 2 tacrolimus (Tac) formulations. In a 2-by-2 crossover design, 20 stable renal transplant recipients on twice-daily Tac either continued their usual Tac therapy (n = 10, group 1) or switched to TacMR for a 12-week period (n = 10, group 2), after which the patients crossed over to the other formulation for another 12-week period. Pharmacokinetic profiles using limited sampling strategies were obtained before randomization (visit 1), and at 12 (visit 2) and 24 weeks (visit 3) at steady state. MPA AUC was calculated using the Pawinski formula. When analyzing visits on Tac, TacMR, and back on Tac combined, the MPA AUC for all 20 patients at baseline was 42.24 (16.98), 37.18 (13.75), and 40.09 (16.69) mg$h$L21, respectively, which was not statistically significant using repeated measures (P = 0.1327, R2 = 0.1109). We conclude that MPA pharmacokinetic profiles are not altered when converting patients from Tac to TacMR. Key Words: tacrolimus formulations, mycophenolate mofetil, mycophenolic acid, mycophenolate acid glucuronide, equivalence (Ther Drug Monit 2014;36:353–357)
Received for publication August 7, 2013; accepted September 29, 2013. From the Departments of *Medicine, Division of Nephrology; and †Pediatrics, Division of Pediatric Nephrology, Children’s Hospital, London Health Science Centre and Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada; and ‡Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati; and §Department of Pediatrics, College of Medicine, University of Cincinnati, Ohio. The authors declare no conflict of interest. G. Filler and N. Muirhead attended a scientific advisory board meeting organized by Astellas, Inc. Supported by Astellas, Inc. (N. Muirhead). Correspondence: Guido Filler, MD, PhD, FRCPC, Department of Pediatrics, Division of Pediatric Nephrology, Children’s Hospital, London Health Sciences Centre, University of Western Ontario, 800 Commissioners Rd East, Rm B1-436, London, ON N6A 5W9, Canada (e-mail: guido. fi[email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
Ther Drug Monit Volume 36, Number 3, June 2014
INTRODUCTION Nonadherence with immunosuppressive medications is a critical issue in organ transplantation.1 Recently, Astellas developed a once-daily modified release formulation of tacrolimus (TacMR) that has the potential to reduce the likelihood of nonadherence. To date, most of the published data relating to the use of TacMR originate from industry-sponsored clinical trials. These have shown that conversion from tacrolimus (Tac) to TacMR on a milligram to milligram basis in both stable and de novo kidney and liver transplant recipients yields lower peak concentrations but equivalent overall drug exposure [area under the concentration–time curve (AUC)] and trough concentrations.2 Tac is often given in combination with mycophenolate mofetil (MMF), the inactive morpholinoethyl ester prodrug of mycophenolic acid (MPA), or the enteric-coated mycophenolate sodium (EC-MPS). MPA is a potent immunosuppressant that reduces rejection after renal transplantation. There is level 2 evidence from the APOMYGRE trial that a minimum MPA exposure (measured as AUC) is required to prevent rejection,3 and pharmacokinetic monitoring of MPA is recommended.4 The target AUC of 30–60 mg$h$L21 has been defined through an international consensus conference5–7 and is also accepted for liver transplantation.8 The clinical pharmacokinetics of MPA are characterized by high between-subject and within-subject variability.9 Coadministration of other immunosuppressive may influence MPA exposure.10,11 Significantly higher doses of MMF are needed to achieve the same exposure on cyclosporine, whereas concomitant Tac augments the bioavailability of MPA, at least in vitro.12 Other studies revealed that MPA exposure without a concomitant calcineurin inhibitor was in the middle between that on concomitant Tac or cyclosporine.11,13 One of the main reasons for the drug–drug interaction is the inhibition of multidrug resistance protein 2–mediated transport in the presence of the main MPA metabolite, 7-O-MPA-glucuronide (MPAG).9 Other explanations include gene polymorphisms in the enzymes that metabolize MPA, especially the UGT1A9-275T.A/-2152C.T polymorphisms.14,15 High dosages of corticosteroids may induce expression of UGT, reducing exposure to MPA. Exposure to MPA when MMF is given in combination with cyclosporine is approximately 30%–40% lower than when given alone or with Tac or sirolimus.9 There is also data suggesting that there is increased MPA exposure in stable kidney transplant recipients on Tac as compared with after conversion to sirolimus, which may have an interaction
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between Tac and MMF at the level of their intestinal absorption.16 It is unknown whether and to what degree TacMR affects the pharmacokinetics of MPA. There are also only very few studies on the within-subject variability of MPA exposure parameters, but 1 preliminary study suggests a mean intraindividual coefficient of variation (CV) of 30%–47% (range, 18%– 80%).17 To assure stable graft function when switching between the 2 different Tac formulations, we wanted to determine that the exposure was unaffected by the conversion. As pharmacokinetics of Tac and MPA may change over time,1 we designed a crossover randomized trial to assess this question.
METHODS Twenty adult renal transplant recipients were recruited into a prospective crossover design cohort study. Patients had to be transplanted at least 12 months before enrollment, had to have stable allograft function with a serum creatinine ,180 mmol/L, an epidermal growth factor receptor of .30 mL/min, no increase/decrease of .10% in creatinine in the previous 3 months, were targeted to a Tac trough level of 5–8 ng/mL, and were stable within that target range in the previous 3 months. Patients also had to be treated with concomitant MMF. The institutional review board approved the study. After obtaining informed consent, baseline data including demographics, serum urea, creatinine, electrolytes, fasting lipids and fasting glucose, trough Tac level, sparse sampling MPA pharmacokinetic profile, concurrent medication profile, and physical examination were collected. Eligible patients were then randomized to a 3-month period to either continue on Tac (group 2) or an equivalent dose of TacMR (group 1) and crossed over after 3 months. Tac levels were adjusted if the levels were outside of the desired range, but MMF doses were left unchanged. Patients underwent PK monitoring using a limited sampling strategy (LSS).18 MPA plasma concentrations were measured at 3 time points: before (predose concentration), and 30 and 120 minutes after oral MMF administration.18,19 The MPA abbreviated AUC from 0 to 12 hours (AUC0–12 h) was calculated from these 3 MPA concentrations using a validated algorithm from adult patients on Tac. The formula reads AUC0–12 h = 7.75 + 6.49c (0 h) + 0.76c (0.5 h) + 2.43c (2 h), where “c” is the MPA concentration at the specific time point.18 On 2 occasions, the 0.5-h concentration was missing. We extrapolated the missing points using the same percentiles from 156 unpublished full 12-point pharmacokinetic profiles that were closest to the 2-hour concentrations. Dose adjustment of MMF therapy was discouraged and did not occur during the 24-week study period. Each patient underwent 3 LSS measurements, that is at baseline (visit 1), week 12 (visit 2), and week 24 (visit 3) on both standard Tac and TacMR therapy. MPA AUC was calculated at each time point. MPA and MPAG concentrations were measured at the laboratory at Cincinnati Children’s Hospital as previously described.15
STATISTICS Continuous data were tested for normal distribution using the Shapiro–Wilk test. For normally distributed data,
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parametric methods were used; otherwise nonparametric tests were used. Wherever possible, simple descriptive statistics were used. Normally distributed data were expressed as mean (SD). CV calculations were performed as per clinical chemistry laboratory guidelines. No adjustments were made for missing values (two 30-minute MPA concentrations were missing).
RESULTS The demographics of the patients are summarized in Table 1. There were 9 male and 11 female subjects enrolled into the study. A total of 14 patients were recipients of deceased donor renal transplants (second transplant in 2), whereas the remainder had received living donor transplants. The 20 renal transplant recipients underwent a total of 60 abbreviated pharmacokinetic profiles with measures of a morning trough level and 30 and 120 minutes after oral intake of either Tac or TacMR. MPA levels were not normally distributed. Therefore, data were presented as median and interquartile range (Table 2). At baseline visit and thereafter, Tac trough levels were normally distributed. There were no significant differences between the trough Tac levels at visits 1, 2, and 3 (Table 3). We also compared the Tac trough levels during TacMR and Tac treatment and found no significant differences with a mean of 5.07 (1.17) ng/mL on TacMR and 5.08 (1.21) ng/mL on Tac (P = 0.9616, paired t test). MMF dose per kilograms per day was normally distributed. For the entire group, the baseline MMF dose per kilogram body weight was 14.84 (4.81) mg/kg, and at the end of the TacMR 12-week period, the mean MMF dose was 14.82 (4.90) mg/kg; the mean MMF dose at the end of the Tac 12-week period was 14.85 (4.99) mg/kg. This of course was not statistically significant (P = 0.9007, R2 = 0.1009, repeated-measures analysis of variance). When analyzing
TABLE 1. Patient Demographics
All (N = 20) Age, yr Time post-transplant, mo Baseline Tac dose, mg/d Baseline eGFR, mL/min/1.73 m2 Group 1 (n = 10) Age, yr Time post-transplant, mo Baseline Tac dose, mg/d Baseline eGFR, mL/min/1.73 m2 Group 2 (n = 10) Age, yr Time post-transplant, mo Baseline Tac dose, mg/d Baseline eGFR, mL/min/1.73 m2
Mean (P, If Applicable)
SD
Range
56.6 78 2.35 55.05
12.6 38.5 1 13.4
35–79 18–147 1–5 38–79
53.7 92.3 2.28 54.3 54.3 59.0 (0.227) 55.5 (0.03) 2.32 (0.841) 55.2 (0.841)
12.6 43.8 1.29 13.5 13.5 11.9 38.5 0.86 13.4
35–77 17–142 1–5 38–79 38–89 44–79 29–96 1–4 39–78
Baseline eGFR was calculated using the MDRD formula (http://www.kidney.org/ professionals/kdoqi/gfr_calculator.cfm). eGFR, epidermal growth factor receptor.
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Similar MPA Exposure on Modified Release Tac
TABLE 2. MPA Levels (mg/L) in the Pharmacokinetic Profiles as Morning Trough Levels, and 30 and 120 Minutes After Intake Number of values Minimum 25% percentile Median 75% percentile Maximum
0 min
30 min
120 min
60 0.0900 1.040 1.860 3.035 6.290
58 0.1000 3.410 5.840 10.99 35.10
60 0.1000 2.910 4.195 6.125 13.10
visits on Tac, TacMR, and back on Tac combined, the MPA AUC for all 20 patients at baseline was 42.24 (16.98), 37.18 (13.75), and 40.09 (16/69) mg$h$L21, respectively, which was not statistically significant using repeated measures (P = 0,1327, R2 = 0.1109). Ten patients were randomized to receive TacMR, followed by Tac (group 1), and the other 10 patients received Tac and then TacMR (group 2). MPA AUC was tested for normal distribution using the Kolmogorov–Smirnov normality test, the D’Agostino and Pearson omnibus normality test, and the Shapiro–Wilks test for normality, and all tests revealed a normal distribution. Therefore, data were expressed as mean (6SD). Mean MPA doses were not statistical significantly different between both groups: at baseline, these were 13.14 (3.60) mg$kg21$d21 in group 1 and 16.53 (5.16, P = 0.117) mg$kg21$d21 in group 2 (unpaired t test). After 12 weeks of TacMR, mean MMF dose was 12.97 (3.92) mg$kg21$d21 in group 1 and 16.66 (5.27) mg$kg21$d21 in group 2 (P = 0.0926, unpaired t test), and after 12 weeks of Tac, mean MMF dose was 13.00 (3.39) mg$kg21$d21 in group 1 and 16.70 (5.29) mg$kg21$d21 in group 2 (P = 0.0910, unpaired t test). However, mean MPA AUC at the beginning of the study was 34.31 (9.71) mg$h$L21 in group 1, whereas it was 50.18 (19.35) mg$h$L21 in group 2, which was significantly different (P = 0.0324, unpaired t test). Within both group 1 and 2, there was no significant difference between visits 1 and 2, visits 1 and 3, and visits 2 and 3 (paired t test). There was, therefore, no effect of the Tac formulation on the MPA AUC (Fig. 1). We also examined the comparison of MPA AUC between TacMR and Tac in the combined group. Mean MPA AUC on TacMR was 37.18 (13.75) mg$h$L21, not significantly different from the MPA AUC on Tac, which
FIGURE 1. MPA AUCs in both group 1 (Tac-TacMR-Tac) and group 2 (Tac-Tac-TacMR). A significant number of AUCs were both above and below the target range of 30–60 mg$h$L21. The bars show the mean (SD) of the MPA AUC.
was 40.09 (16.69) mg$h$L21 (P = 0.2628, paired t test, Fig. 2). We were also able to compare the MPA AUC over time on Tac in all 20 patients. At visit 1 (all patients on Tac), the MPA AUC was 42.24 (16.98) mg$h$L21, not significantly different from the last time point on Tac (6 months in half of the patients and 3 in the other half), when the MPA AUC was 40.09 (16.69) mg$h$L21 (Fig. 2). There was, therefore, no difference in the MPA exposure between periods of treatment with Tac or TacMR. We also performed repeated measures 1-way analysis of variance to assess for changes over time and found no significant changes (P = 0.2524) nor did we find evidence in the post-test for linear trend (slope = 21.623, R2 = 0.0072; P = 0.2024). We also measured the main metabolite, the glucuronide MPAG. MPAG trough levels were 42.9 (21.58) mg/L at
TABLE 3. Tac Trough Levels (ng/mL) at Baseline, at 12 Weeks, and 24 Weeks After Randomization Number of values Minimum 25% percentile Median 75% percentile Maximum Mean SD Standard error
0 min
30 min
120 min
20 2.000 3.850 4.800 6.075 9.600 5.170 1.881 0.4206
20 2.600 4.625 5.000 5.700 8.300 5.165 1.243 0.2780
20 3.400 3.950 5.100 5.475 7.500 4.985 1.123 0.2511
Ó 2014 Lippincott Williams & Wilkins
FIGURE 2. Comparison of the MPA AUC on Tac versus TacMR. Although the MPA AUC was 10% higher on Tac, this did not reach statistical significance.
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visit 1, 39.25 (19.64) at visit 2, and 40.25 (23.84) at visit 3. There was no change over time. Similar to the MPA, there was no difference in MPAG trough levels between the different formulations of Tac. Not unexpectedly, there was a weak but significant correlation between the serum creatinine and the MPAG trough level (R2 = 0.07818, P = 0.0320), given that MPAG accumulates in chronic kidney disease. We also studied the relationship between the Tac trough level and MPA AUC. As both MPA AUC and Tac trough levels were normally distributed, we used linear regression analysis. We found no evidence for a correlation between MPA AUC and Tac trough levels (R2 = 0.02644; P = 0.2145). We then calculated the CV of the morning trough levels for MPA as well as for the concentrations at 30 and 120 minutes after intake and the CV for the MPA AUC. The MPA trough level had a much higher CV (0.667). The 30-minute post-dose MPA level had a CV of 0.825 and the 120-minute level had a CV of 0.558, whereas the MPA AUC level had a lower CV of 0.395. The CV of the MPA AUC on TacMR was slightly lower (0.369) when compared with Tac (0.416). Finally, we calculated the CV of the morning trough levels for Tac (0.280).
DISCUSSION The main objective of this study was the evaluation of the equivalence of the MPA exposure in stable renal transplant recipients who were converted from regular formulation to modified release Tac formulation. Based on the wellestablished drug–drug interaction between Tac and MMF12,20 and the differing pharmacokinetics of the 2 formulations,1 we hypothesized that MPA exposure may vary among the 2 formulations. However, we found no significant difference in the MPA exposure among both formulations and concluded that it is unnecessary to adjust dosing of MMF or EC-MPS after conversion to once-daily TacMR Tac formulation. However, we found substantial variability in the MPA exposure in the 20 patients. Eighteen of the 58 MPA AUCs (2 could not be calculated due to missing 30-minute concentrations) were below the proposed effective exposure level of 30 mg$h$L21. The study confirms the previously reported high interindividual variability of MPA exposure.3,5,21–23 In the consensus documents, the need to exceed an AUC of 30 mg$h$L21 to prevent rejection was stressed.5–7 The data presented here suggest that PK monitoring should be used to prevent underexposure of MMF or EC-MPS. At this point in time, pharmacokinetic monitoring of MMF/EC-MPS therapy in North America is usually the only standard among pediatric transplant centers. Even if pharmacokinetic monitoring is used, physicians often fail to comply with the recommended dose changes.24,25 There is much less certainty about the safe upper limit of the MPA AUC, but 60 mg$h$L21 is considered a safe upper limit.5,7 Our data also suggest that MMF/EC-MPS dosing can be reduced in some of the patients. This may reduce the cancer risk and the risk for viral infections. This study has several strengths. Tac exposure was kept constant throughout. The crossover design reduces the potential confounding effect of changes over time.1 We also
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had a significant spread in the MPA exposure allowing for an assessment of low and high exposure, and patients with high MPA exposures behaved similarly to patients with low exposure without variability based on the Tac formulation (data not shown). Based on the careful design, the study is adequately powered. Limitations of the study include the lack of a complete pharmacokinetic profile with the inevitable variability of the assessment of the true exposure,26 the lack of full PK profiles for Tac. The study with within-subject design may also be subject to a carryover effect because having been tested under 1 condition may affect how participants behave in another condition; however, we feel that a practice effect, a fatigue effect, assimilation, or “catching-on” effects have been relevant here. Furthermore, there are growing concerns that the trough level may not be ideal for monitoring the oncedaily formulation of Tac.1 The data also only apply to patient with relatively good renal function. As patients with more advanced chronic kidney disease were excluded, we cannot comment on the effect of accumulation of MPAG in patients with renal impairment.27 The data also do not apply to children where there is ontogeny (age dependency) of drug disposition of MMF in children with this combination.28 Nonetheless, this study addresses the knowledge gap about the potential impact of the various Tac formulations on the MPA pharmacokinetics. Based on this study, we can eliminate any concerns that the conversion from Tac to TacMR will negatively affect MPA exposure.
SUMMARY We do not have sufficient evidence to reject the hypothesis that conversion from Tac to TacMR may affect the MPA exposure. Patients had identical Tac (measured as trough level) and MPA exposure (measured as abbreviated AUC using the Pawinski LSS). However, there was wide interindividual and intraindividual variability of MPA exposure with approximately half the patients had overexposure and underexposure. There was a slight trend toward lower MPA exposure over time, although this did not reach statistical significance. Not unexpectedly, there was a significant correlation between the MPAG trough level and the serum creatinine, which over time may lead to enhanced MPA exposure with worsening kidney function. This trend warrants repeated measurement of MPA exposure over time. Taken together, our study suggests that equivalence of MPA exposure is maintained when converting patients to the modified release Tac. However, given the evidence for an MPA AUC exceeding 30 mg$h$L21 and the high prevalence of underexposure, repeated MPA exposure measurements are recommended. REFERENCES 1. Hougardy JM, de Jonge H, Kuypers D, et al. The once-daily formulation of tacrolimus: a step forward in kidney transplantation? Transplantation. 2012;93:241–243. 2. Barraclough KA, Isbel NM, Johnson DW, et al. Once- versus twicedaily tacrolimus: are the formulations truly equivalent? Drugs. 2011; 71:1561–1577. 3. Le Meur Y, Buchler M, Thierry A, et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant. 2007;7:2496–2503.
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4. van Gelder T, Le Meur Y, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit. 2006;28:145–154. 5. Tonshoff B, David-Neto E, Ettenger R, et al. Pediatric aspects of therapeutic drug monitoring of mycophenolic acid in renal transplantation. Transplant Rev (Orlando). 2011;25:78–89. 6. Kuypers DR, Le Meur Y, Cantarovich M, et al. Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation. Clin J Am Soc Nephrol. 2010;5:341–358. 7. Le Meur Y, Borrows R, Pescovitz MD, et al. Therapeutic drug monitoring of mycophenolates in kidney transplantation: report of The Transplantation Society consensus meeting. Transplant Rev (Orlando). 2011; 25:58–64. 8. Brunet M, Cirera I, Martorell J, et al. Sequential determination of pharmacokinetics and pharmacodynamics of mycophenolic acid in liver transplant patients treated with mycophenolate mofetil. Transplantation. 2006;81:541–546. 9. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet. 2007;46:13–58. 10. Grinyo JM, Ekberg H, Mamelok RD, et al. The pharmacokinetics of mycophenolate mofetil in renal transplant recipients receiving standarddose or low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus: the Symphony pharmacokinetic substudy. Nephrol Dial Transplant. 2009; 24:2269–2276. 11. Filler G, Zimmering M, Mai I. Pharmacokinetics of mycophenolate mofetil are influenced by concomitant immunosuppression. Pediatr Nephrol. 2000; 14:100–104. 12. Zucker K, Tsaroucha A, Olson L, et al. Evidence that tacrolimus augments the bioavailability of mycophenolate mofetil through the inhibition of mycophenolic acid glucuronidation. Ther Drug Monit. 1999;21:35–43. 13. Filler G, Hansen M, LeBlanc C, et al. Pharmacokinetics of mycophenolate mofetil for autoimmune disease in children. Pediatr Nephrol. 2003; 18:445–449. 14. van Schaik RH, van Agteren M, de Fijter JW, et al. UGT1A9 -275T.A/2152C.T polymorphisms correlate with low MPA exposure and acute rejection in MMF/tacrolimus-treated kidney transplant patients. Clin Pharmacol Ther. 2009;86:319–327. 15. Fukuda T, Goebel J, Cox S, et al. UGT1A9, UGT2B7, and MRP2 Genotypes can Predict mycophenolic acid pharmacokinetic variability in pediatric kidney transplant recipients. Ther Drug Monit. 2012;34:671–679.
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16. Braun F, Schocklmann H, Ziegler E, et al. Increased mycophenolic acid exposure in stable kidney transplant recipients on tacrolimus as compared with those on sirolimus: implications for pharmacokinetics. Clin Pharmacol Ther. 2009;86:411–415. 17. Shaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: report of a roundtable discussion. Ther Drug Monit. 2001;23:305–315. 18. Pawinski T, Hale M, Korecka M, et al. Limited sampling strategy for the estimation of mycophenolic acid area under the curve in adult renal transplant patients treated with concomitant tacrolimus. Clin Chem. 2002;48:1497–1504. 19. Filler G, Mai I. Limited sampling strategy for mycophenolic acid area under the curve. Ther Drug Monit. 2000;22:169–173. 20. Ekberg H, van Gelder T, Kaplan B, et al. Relationship of tacrolimus exposure and mycophenolate mofetil dose with renal function after renal transplantation. Transplantation. 2011;92:82–87. 21. Filler G. Value of therapeutic drug monitoring of MMF therapy in pediatric transplantation. Pediatr Transplant. 2006;10:707–711. 22. Filler G, Feber J. The transplanted child: New immunosuppressive agents and the need for pharmacokinetic monitoring. Paediatr Child Health. 2002;7:525–532. 23. Filler G, Lepage N, Delisle B, et al. Effect of cyclosporine on mycophenolic acid area under the concentration-time curve in pediatric kidney transplant recipients. Ther Drug Monit. 2001;23:514–519. 24. van Gelder T, Silva HT, de Fijter JW, et al. Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial. Transplantation. 2008;86:1043–1051. 25. Hocker B, van Gelder T, Martin-Govantes J, et al. Comparison of MMF efficacy and safety in paediatric vs. adult renal transplantation: subgroup analysis of the randomised, multicentre FDCC trial. Nephrol Dial Transplant. 2011;26:1073–1079. 26. Filler G. Abbreviated mycophenolic acid AUC from C0, C1, C2, and C4 is preferable in children after renal transplantation on mycophenolate mofetil and tacrolimus therapy. Transpl Int. 2004;17:120–125. 27. Kaminska J, Glyda M, Sobiak J, et al. Pharmacokinetics of mycophenolic acid and its phenyl glucuronide metabolite in kidney transplant recipients with renal impairment. Arch Med Sci. 2012;8:88–96. 28. Filler G, Foster J, Berard R, et al. Age-dependency of mycophenolate mofetil dosing in combination with tacrolimus after pediatric renal transplantation. Transplant Proc. 2004;36:1327–1331.
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