ORIGINAL ARTICLE

Diminished Mycophenolic Acid Exposure Caused byOmeprazole May Be Clinically Relevantin 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*

Background: Some studies have reported a decreased absorptionof mycophenolic acid (MPA) from mycophenolate mofetil (MMF)in renal transplanted (RTx) patients under proton-pump inhibitors(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) whetherthe effect has the same amplitude during the first year after RTx,and finally (3) whether this decrease in exposure is clinicallyrelevant.

Methods: We retrospectively analyzed the omeprazole effect in348 12-hour pharmacokinetic samplings [area under the curve(AUC)0–12h] performed on days 7, 14, 30, 60, 180, and 360 afterRTx in 77 patients who participated in previous trials.

Results: For all periods, the groups with and without PPI did notdiffer in all variables. By mixed-model analysis of variance, PPIreduced the MPA AUC0–12h (P , 0.0008) in the patients underboth CNIs mainly due to decreased absorption (P = 0.049). In thetacrolimus group, a lower exposure seemed also due to a decreasedMPA reabsorption at 10–12 hours. The PPI effect remains throug-hout the first year but was clinically more important on day 7. ByCox analysis, the use of PPI was associated with a 25% lesschance of being adequately exposed to MPA (95% confidenceinterval 0.58–0.99, P = 0.04). Similarly, the number of patientsunderexposed to MPA (AUC , 30 ng$h/mL) was higher at mostperiods in the PPI group but again not statistically significant.

Conclusions: These data indicate that PPI decreases the MPAexposure when associated with both CNIs but particularly in the firstweek after RTx. In this period, the MMF dose should be increased.This effect lasts throughout the first year but does not seem to beclinically relevant after the first week.

Key Words: renal transplantation, mycophenolic acid, pharmacoki-netic, proton-pump inhibitor, immunosuppression

(Ther Drug Monit 2012;34:331–336)

INTRODUCTIONMycophenolate mofetil (MMF) has replaced azathioprine

as the antiproliferative immunosuppressant in organ trans-plantation. Adequate exposure to mycophenolic acid (MPA)is associated with a decreased rate of acute rejection.1,2

After oral administration, MMF is absorbed in thestomach and metabolized to its active metabolite MPA byplasma and tissues esterases.3,4 The MPA peak concentrationoccurs within 1–2 hours after MMF administration.5 It hasbeen suggested that a higher pH level in the stomach canimpair MMF metabolism and therefore decrease its absorp-tion.3,6 Proton-pump inhibitors (PPIs) are often prescribed totransplant recipients to prevent gastrointestinal complications,which are common and cause significant morbidity and mor-tality post transplant.4,6,7 At our center, omeprazole was themost used PPI during the early 2000s. Based on the mean24-hour gastric pH, the relative potencies of the most usedPPIs as compared with omeprazole is 0.23 and, 0.90 for pan-toprazole, lansoprazole, and 1.60 and 1.82 for esomeprazole,and rabeprazole, respectively.8

Studies have demonstrated that comedication of PPIswith MMF decreases MMF absorption, thereby decreasingboth MPA and MPAG exposure.3,4,6,9,10 Nevertheless, thesestudies were performed either in the first week after trans-plantation or many years afterward with a single calcineurininhibitor (CNI) in heart transplant recipients or in healthyvolunteers in cross-sectional studies addressed to look at thiseffect.3,4,6,9,10

Exposure to MPA seems to be lower in patients treatedwith omeprazole during the first year, but this reduction inexposure seems to be clinically important in the first weekafter transplantation.

In the real world of renal transplantation, patients areadministered PPIs during variable periods of time, havea wide range of renal function that may affect the renalexcretion of the metabolite glucoronide MPA (MPAG), andmay use both kinds of CNIs, which may change the effect ofPPIs on MPA pharmacokinetics (PK). The use of tacrolimus

Received for publication November 24, 2011; accepted January 28, 2012.From the *Division of Urology, Renal Transplantation Service, University of

Sao Paulo; and †Division of Central Laboratory, Hospital das Clinicas,University of Sao Paulo, Sao Paulo, Brazil.

Elias David-Neto has received research grants from Novartis, Pfizer andBristol-Meirs-Squibb. Otherwise, the authors declare no funding orconflicts of interest.

Correspondence: Elias David-Neto, MD, Renal Transplantation Service,Hospital das Clinicas, University of Sao Paulo, Sao Paulo 03127-030,Brazil (e-mail: elias.david.neto@attglobal.net).

Copyright © 2012 by Lippincott Williams & Wilkins

Ther Drug Monit � Volume 34, Number 3, June 2012 331

(TAC), associated with MMF, leads to an increased exposureto MPA particularly due to intestinal reabsorption of theMPAG between 6 and 12 hours after the oral dose.11,12 On theother hand, this intestinal reabsorption does not occur oroccurs in much smaller amounts when Cyclosporin A(CyA) is used with MMF.

Also, there is no substantial information regardingwhether the observed effect of PPIs on MPA absorption lastsover time. For example, the absorption of MPA presentsa time-dependent increase in exposure.13,14 It could be thatthis increase in bioavailability over time could make the PPIeffect on MPA absorption clinically irrelevant after a certainperiod of time.

Therefore, there are many aspects of the effect of PPIson MPA absorption that need to be addressed.

The aim of this study was to analyze the influence ofomeprazole on MPA-PK throughout the first year aftertransplantation in a large number of PK samplings performedin renal transplant recipients, using both CNIs along withMMF, in a cross-sectional retrospective analysis of MPA-PKsobtained at sequential periods of time after transplantation.

METHODS AND PATIENTS

Study Design and PatientsThe studies from which the data were derived were

approved by the Hospital das Clinicas of the University ofSao Paulo School of Medicine Committee on ethics inresearch (CAPPesq). Additionally, this retrospective analysisreceived approval by the same committee (0564/11).

This analysis included patients who had participated inthe previous studies13,15,16 from our group regarding MPA-PKand had at least 1 complete 12-hour PK. To summarize thepopulation of the 2 trials, male and female patients aged18–65 years, recipients of a non-HLA identical kidney allo-graft who presented panel reactive antibodies ,50% wereconsidered to be eligible for the trials. Women should useeffective contraception, and those of childbearing age shouldhave a negative pregnancy test before enrolment. The subjectswere excluded if they received a nonrenal organ, had a historyof alcohol or illicit drug abuse, and/or had liver enzymes.2 times the upper normal limit.

A search in the electronic database was performed tofind patients who were administered PPIs at each PK study.Only patients who used PPIs for at least 3 days before eachPK sampling were considered as “with PPI” to ascertain sta-ble PPI levels. Assumption was made that oral drugs take atleast 4 times the half life to reach steady-state concentration inplasma. The control patients were derived from the samestudies but did not received PPIs during the PK study. PPIdoses refer to those used on the day of the PK study.

At each period after RTx, the patients were divided into2 groups according to the administration of PPI: a controlgroup (without PPI) and a study group (with PPI).

PharmacokineticsThe patients received MMF twice a day. They were

submitted to a 12-hour MPA-PK on visits of 7, 14, 30, 60,

180, and 360 days (periods) posttransplant and were admittedon the evening before the PK study to ensure that medicationwas administered exactly at 8 PM on that the day. After a12-hour overnight fast, blood was drawn at 8 AM (C0), andthe patients were given the drugs. Blood samples were thencollected at 1, 2, 3, 4, 6, 8, 10, and 12 hours postdose, and thepatients were discharged after the last sample had beendrawn. Blood samples were stored in ethylenediaminetetra-acetic acid tubes. The total MPA concentration was deter-mined by MPA–enzyme multiplied immunoassay technique(EMIT) 2000 assay, with an EMIT 2000 (Dade-Behring,United States). Total blood TAC levels were measured bythe Abbott IMx and CyA by TDx. The MPA-EMIT 2000assay measures the total MPA and the acyl-metaboliteAcMPA and gives results 6%–8% higher than those obtainedusing high-performance liquid chromatography. All PKparameters were analyzed, including area under the curve(AUC)0–12h, maximum concentration (Cmax), trough level(C0), and MPA concentrations at 1, 2, 3, 4, 6, 8, 10, and 12hours postdose (C1, C2, C3, C4, C6, C8, C10, and C12, respec-tively). To take into account the confounding factor of MMFdrug dose changes, MPA-PK parameters were analyzed bothunadjusted and adjusted for the respective MMF dose (milli-grams per kilogram per dose) at each time point. The unad-justed AUC0–12h was analyzed to verify whether or notpatients were exposed to the MPA therapeutic window duringeach period after transplantation.

Statistical AnalysesFor statistical data analysis, the SPSS software package

was used (SPSS 16.0 for Windows; SPSS Inc, Chicago, IL).Values of continuous variables are expressed as the mean ±SD. The chi-square test was used to test differences in ratesand proportions. One-way analysis of variance (ANOVA)was used to compare differences among continuous variablesbetween groups. Differences were considered statistically sig-nificant at P , 0.05. Because not all the patients performedall the PKs and due to differences in the frequency of usingthe 2 calcineurin inhibitors, mixed-model ANOVA usingSAS version 9 (SAS Institute Inc Cary, NC) was used toanalyze the PKs considering 3 concurrent variables: PPI,period after transplantation, and TAC or CyA.

RESULTSSeventy-seven patients underwent 348 MPA-PK

assessments during the analyzed period. The demographicsof those who performed the MPA-PK on day 7 (n = 72) underPPI or not are given in Table 1. These patients representeda sample of our transplanted population, with the exceptionthat our current practice was to use TAC with all the patientswith a few exceptions. The mean age of this study populationwas 41.7 ± 12.5 years, and most patients were white by origin(69.4%). Most patients’ immunosuppression consisted ofTAC and MMF (63.9%), and there were more organs trans-planted from deceased donors (61.1%) than live donors.

Omeprazole was the only PPI prescribed to thispopulation. Single doses were taken in the morning andtwice-a-day doses in the morning and at night. Table 2 shows

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the number of patients using omeprazole (CyA) and TAC andtheir respective doses at each time point. Two patients of 30-day visits had been off CNIs 5 and 6 days, respectively, pre-vious to PK sampling, and their PK studies were excludedfrom this analysis at that specific period.

Pharmacokinetic StudiesThe 348 PK sampling periods were grouped according

to the following visits: day 7 (n = 72), 14 (n = 63), 30 (n =66), 60 (n = 56), 180 (n = 61), and 360 (n = 30) after trans-plantation. They were also divided according to the CNI used(either TAC or CyA). Figures 1A and B show the effect ofPPI for all PK curves, adjusted for dose, performed in the

TAC (n = 224) and CyA (n = 124) patients, analyzed togetherin all the periods.

By the mixed-model ANOVA, the PPI group hada lower AUC0–12h (P = 0.0008) and lower Cmax (P =0.049), and these differences were not changed by the CNIsused either TAC or CyA and remain during the first year.

In the TAC group, the AUC0–12h and Cmax (adjusted bydose) were 17.3% and 14.1% lower in the omeprazole group,respectively. There was also a lower MPA level at C10 (20%)to C12 (22%) in the PPI group, the period of time when reab-sorption of MPA from MPAG occurs. In the CyA group, theAUC0–12h and Cmax (adjusted by dose) were 17.9% and 22%lower in the omeprazole group, respectively. Figures 2A–Fshow the 12-hour unadjusted PKs at all visits. The AUC0–12h

was lower in the PPI group compared with that in the non-PPIgroup at all visits. Similarly, the Cmax was lower at all the visitswith the exception of days 14 and 360. By mixed-modelANOVA, the effect of diminished exposure to MPA in thePPI group remains statistically lower throughout the first year(AUC0–12h, P = 0.005 and Cmax, P , 0.001).

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, averageadjusted AUC0–12h was only 5.5%–10.6% lower in the ome-prazole group.

On day 360, there was a lower MPA concentration atC8 through C12 (P = 0.018), and a 26.5% lower AUC0–12h

(P = 0.04) in the PPI group.Table 3 shows the number of patients within the defined

therapeutic window for MPA (AUC $ 30 ng$h/mL). Byunivariate Cox analysis, the use of PPI was associated witha 25% less chance of being adequately exposed to MPA(hazard ratio: 0.75; 0.58–0.99, P = 0.04) when all PK curveswere analyzed together.

Figure 3 shows the mean (±SD) of the unadjusted 12-hour AUC at all time points for the patients treated with and

TABLE 1. Demographic Data of 72 Kidney TransplantRecipients With and Without PPIs Medication on Day 7 AfterTransplantation

Demographics PPI (%) No PPI (%) Total (%)

Gender

Female 23 (42.6) 10 (55.6) 33 (45.8)

Male 31 (57.4) 8 (44.4) 39 (54.2)

Age (yrs) 41.7 ± 12.5 41.8 ± 12.5 41.7 ± 12.5

Race

Oriental 1 (1.8) 1 (1.4)

White 36 (66.7) 14 (77.8) 50 (69.4)

African Brazilian 17 (31.5) 4 (22.2) 21 (29.2)

Baseline immunosuppression

Cyclosporine/MMF 22 (40.7) 4 (22.2) 26 (36.1)

TAC/MMF 32 (59.3) 14 (77.8) 46 (63.9)

Donor

Deceased 34 (63.0) 10 (55.6) 44 (61.1)

Live 20 (37.0) 8 (44.4) 28 (38.9)

Total 54 (100) 18 (100) 72 (100)

No statistical differences were found.

TABLE 2. Number of Patients Using Omeprazole, CyA, TAC, and MMF and Their Respective Doses at Each Time-Point

DaysPosttransplant Group N

Omeprazole(mg/d)

CyAN

CyA(mg$kg21$d21)

TACN

TAC(mg$kg21$d21) MMF (mg/d)

MMF(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

WithoutPPI

18 4 9.8 ± 1.4 14 0.24 ± 0.07 1694.4 ± 250.8 30.7 ± 7.4

14 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

WithoutPPI

16 5 9.6 ± 1.6 11 0.27 ± 0.10 1718.7 ± 256.1 30.7 ± 7.1

30 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

WithoutPPI

15 5 8.7 ± 2.9 10 0.24 ± 0.08 1700.0 ± 316.2 30.6 ± 7.8

60 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

WithoutPPI

17 6 5.9 ± 1.7 11 0.16 ± 0.10 1676.4 ± 303.1 29.5 ± 8.9

180 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

WithoutPPI

26 10 4.3 ± 1.2 16 0.11 ± 0.04 1692.3 ± 285.5 28.5 ± 8.2

360 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

WithoutPPI

19 4 3.5 ± 1.0 15 0.08 ± 0.04 1736.8 ± 256.5 30.0 ± 8.7

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without PPI. The therapeutic window (30–60 ng$h/mL) isdesignated by dotted lines. As indicated, the mean AUCwas lower in the PPI group. However, there was a steadyincrease in MPA exposure over time in both groups indepen-dently of PPI, reflecting that the time-dependent increase inMPA exposure was maintained even in the presence of PPI.On day 7, the mean exposure to MPA in patients with PPIwas at the lower limit of the therapeutic window.

DISCUSSIONMMF is the most used antiproliferative immunosup-

pressant in renal transplantation and regularly administered atfixed doses. The need for MPA monitoring is still a matter of

discussion because of the lack of assays to measure MPA inmost centers and inconclusive data on whether or not MPAmonitoring help prevent rejection and side effects.2,17 UntilMPA monitoring is regularly performed in clinical practice,all possible influences on the MPA-PK should be analyzedboth in adults14 and children.18

PPIs are often prescribed to renal transplant recipientsto prevent peptic ulcers, as they can increase the gastric pHto .4.8 The solubility of MMF in buffer is approximately4 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 reportinga lower MPA maximal concentration and exposure in patientsusing PPIs. Kofler et al4 studied MPA-PK using a 2-hourAUC in 33 heart transplant patients, including 21 patientsprescribed 40 mg of pantoprazole daily and 12 control sub-jects, 2 years posttransplant. They also performed a complete12-hour AUC in a subgroup of patients (6 in the control groupand 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 hearttransplant patients (transplanted for a mean of 2.5 years) whowere given pantoprazole and then again underwent 4-pointPK studies 1 month later without the PPI. They found a lowerCmax (1.9-fold lower) and AUC (34% lower) with concomi-tant use of PPI.9

Transplanted patients are usually placed under eitherCyA or TAC treatment along with MMF, and exposure toMPA in patients using TAC is higher than in patients usingCyA due to the enteric reabsorption of MPA from the MPAGexcreted in the biliary tract.11,12 In our study, we have con-firmed that the PPI effect occurs when MMF is used with bothCNIs (Figs. 1A, B). However, in our study, the patients withTAC showed that the PPI effect also occurred at the time ofMPA reabsorption (6–12 hours), leading to a lower troughconcentration and consequently a lower AUC0–12h.

MPA reabsorption is derived from the gut-transformedMPAG. In the patients using PPI, there is a lower biliaryMPAG excretion due to a lower MPA plasma concentration.5

As with many other immunosuppressants, MPApresents a time-dependent increase in bioavailability.13,14 Thisincrease could make the PPI effect less important after a cer-tain time after transplantation, which is exactly what we havefound. Although the exposure to MPA was lower in thepatients using PPI throughout the entire time period, the dif-ference was not clinically significant. The mean AUC0–12h

was in the lower limit of the therapeutic window on day 7in patients using PPI but quickly increased on day 14 andthereafter, such that most patients were within the therapeuticwindow after day 7. This information is essential becausethere is a decreased incidence of acute rejection when thepatients are adequately exposed to MPA during the firstweek.2,14

Our study has some limitations. We only measured theMPA concentration at 1-hour intervals, which may havecaused us to lose the true Cmax in the PK curves. This maybe the reason why we did not find a highly statistically

FIGURE 1. A, MPA-PK for all the curves, adjusted for dose,performed in the patients using TAC. B, MPA-PK for all curves,adjusted for dose, performed in the patients using CyA. Bymixed-model ANOVA, AUC0–12h and Cmax were statisticallylower in the PPI group (P = 0.008 and P = 0.049, respectively),for both TAC and cyclosporine curves and does not changeaccording to CNI used (P = NS).

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334 � 2012 Lippincott Williams & Wilkins

significant Cmax values at different periods in our analysis, asreported by others. However, by mixed-model ANOVA withall curves, Cmax was statistically lower in the PPI group.Nevertheless, MPA activity is related to exposure,20 and it

seems that it is the AUC that matters for a clinical point ofview and not Cmax.

Additionally, we have only performed PK during daytime after the morning dose of MMF. Half of our patients were

FIGURE 2. A–F, MPA-PK in the patients with and without PPI on days 7, 14, 30, 60, 180, and 360 after transplantation.

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given omeprazole at breakfast only, which means that theresults presented in our study refer to the omeprazole effect atthe day-time PK and cannot be extended to the nighttime PK.PPIs inhibits the parietal cell proton-pump H,K-ATPase, andthis inhibition requires an acidic gastric pH. The gastric H,K-ATPase has a half life of 50 hours, and approximately 25%of the pumps are synthesized each day at a rate of about 1%per hour.21 The persistence of nighttime acid secretion whenPPIs are given in the morning may occur because of the pres-ence of “de novo” synthesized pumps that have never beenexposed to PPI.22 Therefore, the effect observed in the day-time PK cannot be extended to the nighttime PK, which makesthe PPI effect even less clinically important.

CONCLUSIONSThis study shows the results of a longitudinal analysis

of the exposure to MPA of patients using PPI during the firstyear after renal transplantation. We confirm the effect of PPIsin reducing MPA absorption from MMF in patients usingeither CyA or TAC. This reduction in exposure is clinicallyimportant in the first week after transplantation, when the

MMF dose should be increased in patients with PPI; however,after this period, the time-dependent increase in the MPAabsorption causes the PPI effect to be clinically irrelevant.

REFERENCES1. Kiberd BA, Lawen J, Fraser AD, et al. Early adequate mycophenolic acid

exposure is associated with less rejection in kidney transplantation. Am JTransplant. 2004;4:1079–1083.

2. Le Meur Y, Buchler M, Thierry A, et al. Individualized mycophenolatemofetil dosing based on drug exposure significantly improves patient out-comes after renal transplantation. Am J Transplant. 2007;7:2496–2503.

3. Miura M, Satoh S, Inoue K, et al. Influence of lansoprazole and rabe-prazole on mycophenolic acid pharmacokinetics one year after renaltransplantation. Ther Drug Monit. 2008;30:46–51.

4. Kofler S, Deutsch MA, Bigdeli AK, et al. Proton pump inhibitorco-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 mycophenolatemofetil and enteric-coated mycophenolate sodium is differentially affected bypantoprazole in healthy volunteers. J Clin Pharmacol. 2009;49:1196–1201.

6. Kiberd BA, Wrobel M, Dandavino R, et al. The role of proton pumpinhibitors on early mycophenolic acid exposure in kidney transplantation:evidence from the CLEAR study. Ther Drug Monit. 2011;33:120–123.

7. Logan AJ, Morris-Stiff GJ, Bowrey DJ, et al. Upper gastrointestinalcomplications after renal transplantation: a 3-yr sequential study. ClinTransplant. 2002;16:163–167.

8. Kirchheiner J, Glatt S, Fuhr U, et al. Relative potency of proton-pumpinhibitors-comparison of effects on intragastric pH. Eur J Clin Pharma-col. 2009;65:19–31.

9. Kofler S, Shvets N, Bigdeli AK, et al. Proton pump inhibitors reducemycophenolate exposure in heart transplant recipients—a prospectivecase-controlled study. Am J Transplant. 2009;9:1650–1656.

10. Schaier M, Scholl C, Scharpf D, et al. Proton pump inhibitors interferewith the immunosuppressive potency of mycophenolate mofetil. Rheu-matology (Oxford). 2010;49:2061–2067.

11. Hesselink DA, van Hest RM, Mathot RA, et al. Cyclosporine interactswith mycophenolic acid by inhibiting the multidrug resistance-associatedprotein 2. Am J Transplant. 2005;5:987–994.

12. Haufroid V, Mourad M, Van Kerckhove V, et al. The effect of CYP3A5and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimusdose requirements and trough blood levels in stable renal transplantpatients. Pharmacogenetics. 2004;14:147–154.

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).Am J Transplant. 2005;11(suppl 5):466.

14. Kuypers DR, Le Meur Y, Cantarovich M, et al. Consensus report ontherapeutic 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 mycophenolatemofetil regimens for de novo renal transplant recipients: the fixed-doseconcentration-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 thesolubility, partition coefficient, and stability of mycophenolic acid and theester 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: theOpticept 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 inhibitionof rat gastric acid secretion. Gastroenterology. 1995;109:1134–1141.

22. Sachs G, Shin JM, Hunt R. Novel approaches to inhibition of gastric acidsecretion. Curr Gastroenterol Rep. 2010;12:437–447.

TABLE 3. Number of Patients Above or Below the MinimumTherapeutic 12-hour Area Under the Curve (AUC0–12h)$30 ng$mL/h

PKNum

With PPI Without PPI

AUC ‡ 30(%)

AUC , 30(%)

AUC ‡ 30(%)

AUC , 30(%) P

1 25 (46.3) 29 (53.7) 11 (61.1) 7 (38.9) NS

2 30 (63.8) 17 (36.2) 11 (68.8) 5 (31.2) NS

3 35 (68.6) 16 (31.4) 14 (93.3) 1 (6.7) 0.091

4 25 (64.1) 14 (35.9) 14 (82.4) 3 (17.6) NS

5 29 (82.9) 6 (17.1) 23 (88.4) 3 (11.5) NS

6 9 (81.8) 2 (18.2) 18 (94.7) 1 (5.3) NS

Total 153 (64.6) 84 (35.4) 91 (82.0) 20 (18.0)

FIGURE 3. The mean (±SD) AUC0–12h for all periods for thepatients with and without PPI.

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