ORIGINAL ARTICLE        Diminished Mycophenolic Acid Exposure Caused by              Omeprazole May Be Clinically Relevant...
David-Neto et al                                                            Ther Drug Monit  Volume 34, Number 3, June 201...
Ther Drug Monit  Volume 34, Number 3, June 2012                                                                      MPA P...
David-Neto et al                                                         Ther Drug Monit  Volume 34, Number 3, June 2012  ...
Ther Drug Monit  Volume 34, Number 3, June 2012                                                MPA Pharmacokinetics and PP...
David-Neto et al                                                                       Ther Drug Monit  Volume 34, Number ...
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Mmf omeprazole

  1. 1. ORIGINAL ARTICLE Diminished Mycophenolic Acid Exposure Caused by Omeprazole May Be Clinically Relevant in the First Week Posttransplantation Elias David-Neto, MD,* Kelly M. Takaki, BS,* Fabiana Agena, MSc,* Paschoalina Romano, MSc,† Nairo M. Sumita, MD,† Maria E. Mendes, MD,† Leticia Aparecida Lopes Neri, MSc,† and William C. Nahas, MD* Key Words: renal transplantation, mycophenolic acid, pharmacoki-Background: Some studies have reported a decreased absorption netic, proton-pump inhibitor, immunosuppressionof mycophenolic acid (MPA) from mycophenolate mofetil (MMF)in renal transplanted (RTx) patients under proton-pump inhibitors (Ther Drug Monit 2012;34:331–336)(PPIs). There is still a lack of information regarding (1) whetherthis effect occurs when MMF is administered with either tacroli-mus or cyclosporine A [calcineurin inhibitors (CNIs)], (2) whether INTRODUCTIONthe effect has the same amplitude during the first year after RTx, Mycophenolate mofetil (MMF) has replaced azathioprineand finally (3) whether this decrease in exposure is clinically as the antiproliferative immunosuppressant in organ trans-relevant. plantation. Adequate exposure to mycophenolic acid (MPA)Methods: We retrospectively analyzed the omeprazole effect in is associated with a decreased rate of acute rejection.1,2348 12-hour pharmacokinetic samplings [area under the curve After oral administration, MMF is absorbed in the(AUC)0–12h] performed on days 7, 14, 30, 60, 180, and 360 after stomach and metabolized to its active metabolite MPA byRTx in 77 patients who participated in previous trials. plasma and tissues esterases.3,4 The MPA peak concentration occurs within 1–2 hours after MMF administration.5 It hasResults: For all periods, the groups with and without PPI did not been suggested that a higher pH level in the stomach candiffer in all variables. By mixed-model analysis of variance, PPI impair MMF metabolism and therefore decrease its absorp-reduced the MPA AUC0–12h (P , 0.0008) in the patients under tion.3,6 Proton-pump inhibitors (PPIs) are often prescribed toboth CNIs mainly due to decreased absorption (P = 0.049). In the transplant recipients to prevent gastrointestinal complications,tacrolimus group, a lower exposure seemed also due to a decreased which are common and cause significant morbidity and mor-MPA reabsorption at 10–12 hours. The PPI effect remains throug- tality post transplant.4,6,7 At our center, omeprazole was thehout the first year but was clinically more important on day 7. By most used PPI during the early 2000s. Based on the meanCox analysis, the use of PPI was associated with a 25% less 24-hour gastric pH, the relative potencies of the most usedchance of being adequately exposed to MPA (95% confidence PPIs as compared with omeprazole is 0.23 and, 0.90 for pan-interval 0.58–0.99, P = 0.04). Similarly, the number of patients toprazole, lansoprazole, and 1.60 and 1.82 for esomeprazole,underexposed to MPA (AUC , 30 ng$h/mL) was higher at most and rabeprazole, respectively.8periods in the PPI group but again not statistically significant. Studies have demonstrated that comedication of PPIs with MMF decreases MMF absorption, thereby decreasingConclusions: These data indicate that PPI decreases the MPA both MPA and MPAG exposure.3,4,6,9,10 Nevertheless, theseexposure when associated with both CNIs but particularly in the first studies were performed either in the first week after trans-week after RTx. In this period, the MMF dose should be increased. plantation or many years afterward with a single calcineurinThis effect lasts throughout the first year but does not seem to be inhibitor (CNI) in heart transplant recipients or in healthyclinically relevant after the first week. volunteers in cross-sectional studies addressed to look at this effect.3,4,6,9,10 Exposure to MPA seems to be lower in patients treatedReceived for publication November 24, 2011; accepted January 28, 2012. with omeprazole during the first year, but this reduction inFrom the *Division of Urology, Renal Transplantation Service, University of exposure seems to be clinically important in the first week Sao Paulo; and †Division of Central Laboratory, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil. after transplantation.Elias David-Neto has received research grants from Novartis, Pfizer and In the real world of renal transplantation, patients are Bristol-Meirs-Squibb. Otherwise, the authors declare no funding or administered PPIs during variable periods of time, have conflicts of interest. a wide range of renal function that may affect the renalCorrespondence: Elias David-Neto, MD, Renal Transplantation Service, Hospital das Clinicas, University of Sao Paulo, Sao Paulo 03127-030, excretion of the metabolite glucoronide MPA (MPAG), and Brazil (e-mail: elias.david.neto@attglobal.net). may use both kinds of CNIs, which may change the effect ofCopyright © 2012 by Lippincott Williams & Wilkins PPIs on MPA pharmacokinetics (PK). The use of tacrolimusTher Drug Monit Volume 34, Number 3, June 2012 331
  2. 2. David-Neto et al Ther Drug Monit Volume 34, Number 3, June 2012(TAC), associated with MMF, leads to an increased exposure 180, and 360 days (periods) posttransplant and were admittedto MPA particularly due to intestinal reabsorption of the on the evening before the PK study to ensure that medicationMPAG between 6 and 12 hours after the oral dose.11,12 On the was administered exactly at 8 PM on that the day. After aother hand, this intestinal reabsorption does not occur or 12-hour overnight fast, blood was drawn at 8 AM (C0), andoccurs in much smaller amounts when Cyclosporin A the patients were given the drugs. Blood samples were then(CyA) is used with MMF. collected at 1, 2, 3, 4, 6, 8, 10, and 12 hours postdose, and the Also, there is no substantial information regarding patients were discharged after the last sample had beenwhether the observed effect of PPIs on MPA absorption lasts drawn. Blood samples were stored in ethylenediaminetetra-over time. For example, the absorption of MPA presents acetic acid tubes. The total MPA concentration was deter-a time-dependent increase in exposure.13,14 It could be that mined by MPA–enzyme multiplied immunoassay techniquethis increase in bioavailability over time could make the PPI (EMIT) 2000 assay, with an EMIT 2000 (Dade-Behring,effect on MPA absorption clinically irrelevant after a certain United States). Total blood TAC levels were measured byperiod of time. the Abbott IMx and CyA by TDx. The MPA-EMIT 2000 Therefore, there are many aspects of the effect of PPIs assay measures the total MPA and the acyl-metaboliteon MPA absorption that need to be addressed. AcMPA and gives results 6%–8% higher than those obtained The aim of this study was to analyze the influence of using high-performance liquid chromatography. All PKomeprazole on MPA-PK throughout the first year after parameters were analyzed, including area under the curvetransplantation in a large number of PK samplings performed (AUC)0–12h, maximum concentration (Cmax), trough levelin renal transplant recipients, using both CNIs along with (C0), and MPA concentrations at 1, 2, 3, 4, 6, 8, 10, and 12MMF, in a cross-sectional retrospective analysis of MPA-PKs hours postdose (C1, C2, C3, C4, C6, C8, C10, and C12, respec-obtained at sequential periods of time after transplantation. tively). To take into account the confounding factor of MMF drug dose changes, MPA-PK parameters were analyzed both unadjusted and adjusted for the respective MMF dose (milli- METHODS AND PATIENTS grams per kilogram per dose) at each time point. The unad- justed AUC0–12h was analyzed to verify whether or notStudy Design and Patients patients were exposed to the MPA therapeutic window during The studies from which the data were derived were each period after transplantation.approved by the Hospital das Clinicas of the University ofSao Paulo School of Medicine Committee on ethics in Statistical Analysesresearch (CAPPesq). Additionally, this retrospective analysis For statistical data analysis, the SPSS software packagereceived approval by the same committee (0564/11). was used (SPSS 16.0 for Windows; SPSS Inc, Chicago, IL). This analysis included patients who had participated in Values of continuous variables are expressed as the mean ±the previous studies13,15,16 from our group regarding MPA-PK SD. The chi-square test was used to test differences in ratesand had at least 1 complete 12-hour PK. To summarize the and proportions. One-way analysis of variance (ANOVA)population of the 2 trials, male and female patients aged was used to compare differences among continuous variables18–65 years, recipients of a non-HLA identical kidney allo- between groups. Differences were considered statistically sig-graft who presented panel reactive antibodies ,50% were nificant at P , 0.05. Because not all the patients performedconsidered to be eligible for the trials. Women should use all the PKs and due to differences in the frequency of usingeffective contraception, and those of childbearing age should the 2 calcineurin inhibitors, mixed-model ANOVA usinghave a negative pregnancy test before enrolment. The subjects SAS version 9 (SAS Institute Inc Cary, NC) was used towere excluded if they received a nonrenal organ, had a history analyze the PKs considering 3 concurrent variables: PPI,of alcohol or illicit drug abuse, and/or had liver enzymes period after transplantation, and TAC or CyA..2 times the upper normal limit. A search in the electronic database was performed tofind patients who were administered PPIs at each PK study. RESULTSOnly patients who used PPIs for at least 3 days before each Seventy-seven patients underwent 348 MPA-PKPK sampling were considered as “with PPI” to ascertain sta- assessments during the analyzed period. The demographicsble PPI levels. Assumption was made that oral drugs take at of those who performed the MPA-PK on day 7 (n = 72) underleast 4 times the half life to reach steady-state concentration in PPI or not are given in Table 1. These patients representedplasma. The control patients were derived from the same a sample of our transplanted population, with the exceptionstudies but did not received PPIs during the PK study. PPI that our current practice was to use TAC with all the patientsdoses refer to those used on the day of the PK study. with a few exceptions. The mean age of this study population At each period after RTx, the patients were divided into was 41.7 ± 12.5 years, and most patients were white by origin2 groups according to the administration of PPI: a control (69.4%). Most patients’ immunosuppression consisted ofgroup (without PPI) and a study group (with PPI). TAC and MMF (63.9%), and there were more organs trans- planted from deceased donors (61.1%) than live donors.Pharmacokinetics Omeprazole was the only PPI prescribed to this The patients received MMF twice a day. They were population. Single doses were taken in the morning andsubmitted to a 12-hour MPA-PK on visits of 7, 14, 30, 60, twice-a-day doses in the morning and at night. Table 2 shows332 Ó 2012 Lippincott Williams Wilkins
  3. 3. Ther Drug Monit Volume 34, Number 3, June 2012 MPA Pharmacokinetics and PPIs TAC (n = 224) and CyA (n = 124) patients, analyzed togetherTABLE 1. Demographic Data of 72 Kidney Transplant in all the periods.Recipients With and Without PPIs Medication on Day 7 AfterTransplantation By the mixed-model ANOVA, the PPI group had a lower AUC0–12h (P = 0.0008) and lower Cmax (P = Demographics PPI (%) No PPI (%) Total (%) 0.049), and these differences were not changed by the CNIsGender used either TAC or CyA and remain during the first year. Female 23 (42.6) 10 (55.6) 33 (45.8) In the TAC group, the AUC0–12h and Cmax (adjusted by Male 31 (57.4) 8 (44.4) 39 (54.2) dose) were 17.3% and 14.1% lower in the omeprazole group, Age (yrs) 41.7 ± 12.5 41.8 ± 12.5 41.7 ± 12.5 respectively. There was also a lower MPA level at C10 (20%)Race to C12 (22%) in the PPI group, the period of time when reab- Oriental 1 (1.8) 1 (1.4) sorption of MPA from MPAG occurs. In the CyA group, the White 36 (66.7) 14 (77.8) 50 (69.4) AUC0–12h and Cmax (adjusted by dose) were 17.9% and 22% African Brazilian 17 (31.5) 4 (22.2) 21 (29.2) lower in the omeprazole group, respectively. Figures 2A–FBaseline immunosuppression show the 12-hour unadjusted PKs at all visits. The AUC0–12h Cyclosporine/MMF 22 (40.7) 4 (22.2) 26 (36.1) was lower in the PPI group compared with that in the non-PPI TAC/MMF 32 (59.3) 14 (77.8) 46 (63.9) group at all visits. Similarly, the Cmax was lower at all the visitsDonor with the exception of days 14 and 360. By mixed-model Deceased 34 (63.0) 10 (55.6) 44 (61.1) ANOVA, the effect of diminished exposure to MPA in the Live 20 (37.0) 8 (44.4) 28 (38.9) PPI group remains statistically lower throughout the first year Total 54 (100) 18 (100) 72 (100) (AUC0–12h, P = 0.005 and Cmax, P , 0.001). No statistical differences were found. The adjusted-by-dose PK shows a 25.6% lower Cmax (P = 0.039) and C12 (P = 0.021) on day 7 only, in the ome- prazole group. During 14, 30, 60, and 180 days, averagethe number of patients using omeprazole (CyA) and TAC and adjusted AUC0–12h was only 5.5%–10.6% lower in the ome-their respective doses at each time point. Two patients of 30- prazole group.day visits had been off CNIs 5 and 6 days, respectively, pre- On day 360, there was a lower MPA concentration atvious to PK sampling, and their PK studies were excluded C8 through C12 (P = 0.018), and a 26.5% lower AUC0–12hfrom this analysis at that specific period. (P = 0.04) in the PPI group. Table 3 shows the number of patients within the definedPharmacokinetic Studies therapeutic window for MPA (AUC $ 30 ng$h/mL). By The 348 PK sampling periods were grouped according univariate Cox analysis, the use of PPI was associated withto the following visits: day 7 (n = 72), 14 (n = 63), 30 (n = a 25% less chance of being adequately exposed to MPA66), 60 (n = 56), 180 (n = 61), and 360 (n = 30) after trans- (hazard ratio: 0.75; 0.58–0.99, P = 0.04) when all PK curvesplantation. They were also divided according to the CNI used were analyzed together.(either TAC or CyA). Figures 1A and B show the effect of Figure 3 shows the mean (±SD) of the unadjusted 12-PPI for all PK curves, adjusted for dose, performed in the hour AUC at all time points for the patients treated with andTABLE 2. Number of Patients Using Omeprazole, CyA, TAC, and MMF and Their Respective Doses at Each Time-Point Days Omeprazole CyA CyA TAC TAC MMFPosttransplant Group N (mg/d) N (mg$kg21$d21) N (mg$kg21$d21) MMF (mg/d) (mg$kg21$d21)7 With PPI 54 31.8 ± 12.0 22 11.3 ± 5.1 32 0.25 ± 0.08 1791.6 ± 282.1 28.8 ± 7.5 Without 18 4 9.8 ± 1.4 14 0.24 ± 0.07 1694.4 ± 250.8 30.7 ± 7.4 PPI14 With PPI 47 29.8 ± 10.1 17 9.4 ± 1.8 30 0.24 ± 0.08 1734.0 ± 373.7 28.0 ± 8.8 Without 16 5 9.6 ± 1.6 11 0.27 ± 0.10 1718.7 ± 256.1 30.7 ± 7.1 PPI30 With PPI 51 29.0 ± 12.2 20 7.5 ± 2.6 29 0.20 ± 0.06 1686.2 ± 360.0 27.0 ± 8.3 Without 15 5 8.7 ± 2.9 10 0.24 ± 0.08 1700.0 ± 316.2 30.6 ± 7.8 PPI60 With PPI 39 27.1 ± 12.5 14 6.1 ± 2.4 25 0.17 ± 0.08 1692.3 ± 336.7 27.6 ± 7.4 Without 17 6 5.9 ± 1.7 11 0.16 ± 0.10 1676.4 ± 303.1 29.5 ± 8.9 PPI180 With PPI 35 28.0 ± 13.0 11 4.7 ± 2.5 24 0.10 ± 0.04 1685.7 ± 322.8 26.7 ± 7.7 Without 26 10 4.3 ± 1.2 16 0.11 ± 0.04 1692.3 ± 285.5 28.5 ± 8.2 PPI360 With PPI 11 29.0 ± 10.4 4 3.6 ± 0.5 7 0.07 ± 0.02 1863.6 ± 393.1 29.5 ± 8.3 Without 19 4 3.5 ± 1.0 15 0.08 ± 0.04 1736.8 ± 256.5 30.0 ± 8.7 PPIÓ 2012 Lippincott Williams Wilkins 333
  4. 4. David-Neto et al Ther Drug Monit Volume 34, Number 3, June 2012 discussion because of the lack of assays to measure MPA in most centers and inconclusive data on whether or not MPA monitoring help prevent rejection and side effects.2,17 Until MPA monitoring is regularly performed in clinical practice, all possible influences on the MPA-PK should be analyzed both in adults14 and children.18 PPIs are often prescribed to renal transplant recipients to prevent peptic ulcers, as they can increase the gastric pH to .4.8 The solubility of MMF in buffer is approximately 4 mg/L at pH 4 but only 0.24 mg/L at pH 5.2.19 Therefore, the increase in gastric pH could lead to reduced MMF solu- bility, which could subsequently lead to less MPA absorption. This effect was first described by Miura et al.3 Other studies confirmed these findings by reporting a lower MPA maximal concentration and exposure in patients using PPIs. Kofler et al4 studied MPA-PK using a 2-hour AUC in 33 heart transplant patients, including 21 patients prescribed 40 mg of pantoprazole daily and 12 control sub- jects, 2 years posttransplant. They also performed a complete 12-hour AUC in a subgroup of patients (6 in the control group and 15 in the PPI group) and found a lower MPA AUC0–12h, AUC0–12h, AUC0–12h adjusted for dose and Cmax. The same authors repeated this observation in 22 heart transplant patients (transplanted for a mean of 2.5 years) who were given pantoprazole and then again underwent 4-point PK studies 1 month later without the PPI. They found a lower Cmax (1.9-fold lower) and AUC (34% lower) with concomi- tant use of PPI.9 Transplanted patients are usually placed under either CyA or TAC treatment along with MMF, and exposure to MPA in patients using TAC is higher than in patients using CyA due to the enteric reabsorption of MPA from the MPAG excreted in the biliary tract.11,12 In our study, we have con- firmed that the PPI effect occurs when MMF is used with both CNIs (Figs. 1A, B). However, in our study, the patients with TAC showed that the PPI effect also occurred at the time of MPA reabsorption (6–12 hours), leading to a lower troughFIGURE 1. A, MPA-PK for all the curves, adjusted for dose, concentration and consequently a lower AUC0–12h.performed in the patients using TAC. B, MPA-PK for all curves, MPA reabsorption is derived from the gut-transformedadjusted for dose, performed in the patients using CyA. By MPAG. In the patients using PPI, there is a lower biliarymixed-model ANOVA, AUC0–12h and Cmax were statistically MPAG excretion due to a lower MPA plasma concentration.5lower in the PPI group (P = 0.008 and P = 0.049, respectively),for both TAC and cyclosporine curves and does not change As with many other immunosuppressants, MPAaccording to CNI used (P = NS). presents a time-dependent increase in bioavailability.13,14 This increase could make the PPI effect less important after a cer- tain time after transplantation, which is exactly what we havewithout PPI. The therapeutic window (30–60 ng$h/mL) is found. Although the exposure to MPA was lower in thedesignated by dotted lines. As indicated, the mean AUC patients using PPI throughout the entire time period, the dif-was lower in the PPI group. However, there was a steady ference was not clinically significant. The mean AUC0–12hincrease in MPA exposure over time in both groups indepen- was in the lower limit of the therapeutic window on day 7dently of PPI, reflecting that the time-dependent increase in in patients using PPI but quickly increased on day 14 andMPA exposure was maintained even in the presence of PPI. thereafter, such that most patients were within the therapeuticOn day 7, the mean exposure to MPA in patients with PPI window after day 7. This information is essential becausewas at the lower limit of the therapeutic window. there is a decreased incidence of acute rejection when the patients are adequately exposed to MPA during the first week.2,14 DISCUSSION Our study has some limitations. We only measured the MMF is the most used antiproliferative immunosup- MPA concentration at 1-hour intervals, which may havepressant in renal transplantation and regularly administered at caused us to lose the true Cmax in the PK curves. This mayfixed doses. The need for MPA monitoring is still a matter of be the reason why we did not find a highly statistically334 Ó 2012 Lippincott Williams Wilkins
  5. 5. Ther Drug Monit Volume 34, Number 3, June 2012 MPA Pharmacokinetics and PPIsFIGURE 2. A–F, MPA-PK in the patients with and without PPI on days 7, 14, 30, 60, 180, and 360 after transplantation.significant Cmax values at different periods in our analysis, as seems that it is the AUC that matters for a clinical point ofreported by others. However, by mixed-model ANOVA with view and not Cmax.all curves, Cmax was statistically lower in the PPI group. Additionally, we have only performed PK during dayNevertheless, MPA activity is related to exposure,20 and it time after the morning dose of MMF. Half of our patients wereÓ 2012 Lippincott Williams Wilkins 335
  6. 6. David-Neto et al Ther Drug Monit Volume 34, Number 3, June 2012 MMF dose should be increased in patients with PPI; however,TABLE 3. Number of Patients Above or Below the Minimum after this period, the time-dependent increase in the MPATherapeutic 12-hour Area Under the Curve (AUC0–12h)$30 ng$mL/h absorption causes the PPI effect to be clinically irrelevant. With PPI Without PPI REFERENCESPK AUC ‡ 30 AUC , 30 AUC ‡ 30 AUC , 30 1. Kiberd BA, Lawen J, Fraser AD, et al. Early adequate mycophenolic acidNum (%) (%) (%) (%) P exposure is associated with less rejection in kidney transplantation. Am J1 25 (46.3) 29 (53.7) 11 (61.1) 7 (38.9) NS Transplant. 2004;4:1079–1083. 2. Le Meur Y, Buchler M, Thierry A, et al. Individualized mycophenolate2 30 (63.8) 17 (36.2) 11 (68.8) 5 (31.2) NS mofetil dosing based on drug exposure significantly improves patient out-3 35 (68.6) 16 (31.4) 14 (93.3) 1 (6.7) 0.091 comes after renal transplantation. Am J Transplant. 2007;7:2496–2503.4 25 (64.1) 14 (35.9) 14 (82.4) 3 (17.6) NS 3. Miura M, Satoh S, Inoue K, et al. Influence of lansoprazole and rabe-5 29 (82.9) 6 (17.1) 23 (88.4) 3 (11.5) NS prazole on mycophenolic acid pharmacokinetics one year after renal transplantation. Ther Drug Monit. 2008;30:46–51.6 9 (81.8) 2 (18.2) 18 (94.7) 1 (5.3) NS 4. Kofler S, Deutsch MA, Bigdeli AK, et al. Proton pump inhibitorTotal 153 (64.6) 84 (35.4) 91 (82.0) 20 (18.0) co-medication reduces mycophenolate acid drug exposure in heart trans- plant recipients. J Heart Lung Transplant. 2009;28:605–611. 5. Rupprecht K, Schmidt C, Raspe A, et al. Bioavailability of mycophenolategiven omeprazole at breakfast only, which means that the mofetil and enteric-coated mycophenolate sodium is differentially affected byresults presented in our study refer to the omeprazole effect at pantoprazole in healthy volunteers. J Clin Pharmacol. 2009;49:1196–1201. 6. Kiberd BA, Wrobel M, Dandavino R, et al. The role of proton pumpthe day-time PK and cannot be extended to the nighttime PK. inhibitors on early mycophenolic acid exposure in kidney transplantation:PPIs inhibits the parietal cell proton-pump H,K-ATPase, and evidence from the CLEAR study. Ther Drug Monit. 2011;33:120–123.this inhibition requires an acidic gastric pH. The gastric H, 7. Logan AJ, Morris-Stiff GJ, Bowrey DJ, et al. Upper gastrointestinalK-ATPase has a half life of 50 hours, and approximately 25% complications after renal transplantation: a 3-yr sequential study. Clinof the pumps are synthesized each day at a rate of about 1% Transplant. 2002;16:163–167. 8. Kirchheiner J, Glatt S, Fuhr U, et al. Relative potency of proton-pumpper hour.21 The persistence of nighttime acid secretion when inhibitors-comparison of effects on intragastric pH. Eur J Clin Pharma-PPIs are given in the morning may occur because of the pres- col. 2009;65:19–31.ence of “de novo” synthesized pumps that have never been 9. Kofler S, Shvets N, Bigdeli AK, et al. Proton pump inhibitors reduceexposed to PPI.22 Therefore, the effect observed in the day- mycophenolate exposure in heart transplant recipients—a prospective case-controlled study. Am J Transplant. 2009;9:1650–1656.time PK cannot be extended to the nighttime PK, which makes 10. Schaier M, Scholl C, Scharpf D, et al. Proton pump inhibitors interferethe PPI effect even less clinically important. with the immunosuppressive potency of mycophenolate mofetil. Rheu- matology (Oxford). 2010;49:2061–2067. 11. Hesselink DA, van Hest RM, Mathot RA, et al. Cyclosporine interacts CONCLUSIONS with mycophenolic acid by inhibiting the multidrug resistance-associated This study shows the results of a longitudinal analysis protein 2. Am J Transplant. 2005;5:987–994. 12. Haufroid V, Mourad M, Van Kerckhove V, et al. The effect of CYP3A5of the exposure to MPA of patients using PPI during the first and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimusyear after renal transplantation. We confirm the effect of PPIs dose requirements and trough blood levels in stable renal transplantin reducing MPA absorption from MMF in patients using patients. Pharmacogenetics. 2004;14:147–154.either CyA or TAC. This reduction in exposure is clinically 13. Pereira L, Castro M, Ventura C, et al. The modify study in renal trans- plantation (modification of doses to improve function through the years).important in the first week after transplantation, when the Am J Transplant. 2005;11(suppl 5):466. 14. Kuypers DR, Le Meur Y, Cantarovich M, et al. Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ trans- plantation. Clin J Am Soc Nephrol. 2011;5:341–358. 15. David-Neto E. Mycophenolic acid (MPA) pharmacokinetics (PK) in sta- ble renal transplanted (RTX) children. Am J Transpl. 2002;2(suppl 3): 192. Abstract 214. 16. David-Neto E, Pereira LM, Kakehashi E, et al. The need of mycophe- nolic acid monitoring in long-term renal transplants. Clin Transplant. 2005;19:19–25. 17. 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. 18. Tonshoff B, David-Neto E, Ettenger R, et al. Pediatric aspects of thera- peutic drug monitoring of mycophenolic acid in renal transplantation. Transplant Rev. 2011;25:78–89. 19. Lidgate D, Brandl M, Holper M, et al. Influence of ferrous sulfate on the solubility, partition coefficient, and stability of mycophenolic acid and the ester mycophenolate mofetil. Drug Dev Ind Pharm. 2002;28:1275–1283. 20. Gaston RS, Kaplan B, Shah T, et al. Fixed- or controlled-dose mycophe- nolate mofetil with standard- or reduced-dose calcineurin inhibitors: the Opticept trial. Am J Transplant. 2009;9:1607–1619. 21. Gedda K, Scott D, Besancon M, et al. Turnover of the gastric H+, K(+)-adenosine triphosphatase alpha subunit and its effect on inhibition of rat gastric acid secretion. Gastroenterology. 1995;109:1134–1141.FIGURE 3. The mean (±SD) AUC0–12h for all periods for the 22. Sachs G, Shin JM, Hunt R. Novel approaches to inhibition of gastric acidpatients with and without PPI. secretion. Curr Gastroenterol Rep. 2010;12:437–447.336 Ó 2012 Lippincott Williams Wilkins

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