Early Steroid Withdrawal and Optimization of Mycophenolic Acid Exposure in Kidney Transplant Recipients Receiving Mycophenolate Mofetil

Meur, Yann Le; Thierry, Antoine; Glowacki, François; Rérolle, Jean-Philippe; Garrigue, Valérie; Ouali, Nacéra; Heng, Anne-Élisabeth; Delahousse, Michel; Albano, L.; Lang, Philippe; Couzi, Lionel; Jaureguy, Maïté; Lebranchu, Yvon; Mousson, Christiane; Glotz, Denis; Kessler, Michèle; Vrtovsnik, François; Rouanet, Stéphanie; Tagieva, Nailya; Kamar, Nassim

doi:10.1097/tp.0b013e318234e134

Cited by 24 publications

(28 citation statements)

References 30 publications

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“…AUC 0–12h target attainment was lower than reported previously in adult studies despite dose adaptation based on TDM. In another study, 68% of patients reached an AUC >30 mg h/L, against 30% in the fixed dose arm .…”

Section: Discussioncontrasting

confidence: 76%

Pharmacokinetics and target attainment of mycophenolate in pediatric renal transplant patients

Martial

Jacobs

Cornelissen

et al. 2016

Pediatric Transplantation

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MPA is an immunosuppressive agent used to prevent graft rejection after renal transplantation. MPA shows considerable inter- and intraindividual variability in exposure in children and has a defined therapeutic window, and TDM is applied to individualize therapy. We aimed to study the exposure to MPA measured as the AUC in pediatric renal transplant patients, to identify factors influencing exposure and to assess target attainment. Children transplanted between 1998 and 2014 in a single center were included. Two groups were identified: Group 1 (AUC <3 wk post-transplantation) and Group 2 (AUC >18 months post-transplantation). Therapeutic targets were set at: AUC0-12h of 30-60 mg h/L. A total of 39 children were included in Group 1 (median age 13.3 yr) vs. 14 in Group 2 (median age 13.4 yr). AUC0-12h was 29.7 mg h/L in Group 1 and 56.6 mg h/L in Group 2, despite a lower dosage in Group 2 (584 and 426 mg/m(2) , respectively). About 46% of patients reached the target AUC0-12h in Group 1. Time since transplantation and serum creatinine were significantly associated with MPA exposure (p < 0.001), explaining 36% of the variability. Individualization of the mycophenolate dose by more intense and more early TDM could improve target attainment.

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Section: Discussioncontrasting

confidence: 76%

Pharmacokinetics and target attainment of mycophenolate in pediatric renal transplant patients

Martial

Jacobs

Cornelissen

et al. 2016

Pediatric Transplantation

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“…Interestingly, there was no AR episode associated with an AUC >45 mg.h/L in the first three months post-transplantation. The last randomized fixed-dose vs. concentration-controlled trial in patients with a low immunologic risk (OPERA) (16) failed to demonstrate the benefit of MPA TDM: at 12 months, the overall rejection rates were similar in both groups.…”

Section: Introductionmentioning

confidence: 99%

Impact of longitudinal exposure to mycophenolic acid on acute rejection in renal-transplant recipients using a joint modeling approach

Abdi

Essig

Rizopoulos

et al. 2013

Pharmacological Research

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This study aimed to investigate the association between longitudinal exposure to mycophenolic acid (MPA) and acute rejection (AR) risk in the first year after renal transplantation, and to propose MPA exposure targets conditionally to this association. A joint model, adjusted for monitoring strategy (fixed-dose versus concentration-controlled) and recipient age, was developed; it combined a mixed-effects model to describe the whole pattern of MPA exposure (i.e. area under the concentration-time curve (AUC)) and a survival model. MPA AUC thresholds were determined using time-dependent receiver-operating characteristics (ROC) curves. Data from 490 adult renal-transplant recipients, representative of the general population of adult renal-transplant patients (i.e. including patients considered at low immunological risk-enrolled in the OPERA trial as well as second renal transplant and patients co-treated by either cyclosporine or tacrolimus), were analyzed. A significant association was found between the longitudinal exposure to MPA (MPA AUCs=f(t)) and AR (p=0.0081), and validated by bootstrapping. A significant positive correlation was observed between time post-transplantation and ROC thresholds which increased in average from 35 mg h/L in the first days to 41 mg h/L beyond six months post-transplantation (p<0.001). Using a new modeling approach which recognizes the repeated measures in a same patient, this study supports the association between MPA exposure and AR.

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“…Both rapid (days to weeks) steroid withdrawal and late (months) steroid withdrawal have been subject of a number of studies and meta‐analyses with conflicting results . Notably, only a few of these studies used a uniform Tac‐MPA‐based immunosuppression and current risk stratification based on detection of pretransplant DSA.…”

Section: Introductionmentioning

confidence: 99%

“…Both rapid (days to weeks) steroid withdrawal and late (months) steroid withdrawal have been subject of a number of studies and meta-analyses with conflicting results. [9][10][11][12][13][14][15][16] Notably, only a few of these studies used a uniform Tac-MPA-based immunosuppression and current risk stratification based on detection of pretransplant DSA. One of those, the "Harmony" trial, recently demonstrated feasibility of steroid withdrawal in about 80% at 1 year in a population without pretransplant DSA and treated with basiliximab induction and Tac-MPA maintenance immunosuppressive therapy.…”

Section: Introductionmentioning

confidence: 99%

Successful steroid withdrawal guided by surveillance biopsies—A single‐center experience

Wehmeier

Hirt‐Minkowski

Amico

et al. 2018

Clinical Transplantation

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Steroid withdrawal following renal transplantation is challenging and widely debated. This retrospective study aimed at investigating the frequency and determinants of successful steroid withdrawal guided by surveillance biopsies. We analyzed 156 pretransplant DSA-negative renal transplants receiving basiliximab induction and maintenance immunosuppression with tacrolimus-mycophenolate-steroids. The absence of rejection in surveillance biopsies at 3 or 6 months post-transplant initiated steroid withdrawal, which was monitored by subsequent indication and/or surveillance biopsies. The primary outcome was the frequency of successful (i.e., rejection-free) steroid withdrawal at 1 year post-transplant. In the whole study population, successful steroid withdrawal was achieved in 73 of 156 patients (47%). Steroid withdrawal was initiated in 98 of 156 patients (63%) and successful in 73 of 98 patients (74%). Subsequent clinical rejection occurred in only one of 98 patients (1%), whereas 24 of 98 patients (24%) experienced subclinical rejection. Steroid withdrawal was not initiated in 58 of 156 patients (37%) mainly due to current or prior severe (Banff TCMR ≥IA) subclinical rejection. Prediction of successful steroid withdrawal by pretransplant or early post-transplant parameters was poor. In conclusion, (sub)clinical rejection-free steroid withdrawal can be expected in about half of pretransplant DSA-negative patients. As successful steroid withdrawal cannot be well predicted by pre- and early post-transplant parameters, guidance by surveillance biopsies is an attractive strategy.

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Early Steroid Withdrawal and Optimization of Mycophenolic Acid Exposure in Kidney Transplant Recipients Receiving Mycophenolate Mofetil

Abstract: In low-immunological risk kidney recipients, MMF combined with CsA allows early corticosteroid discontinuation with good tolerability. In this group of patients, TDM of MMF does not improve clinical outcome.

Cited by 24 publications

References 30 publications

Pharmacokinetics and target attainment of mycophenolate in pediatric renal transplant patients

Pharmacokinetics and target attainment of mycophenolate in pediatric renal transplant patients

Impact of longitudinal exposure to mycophenolic acid on acute rejection in renal-transplant recipients using a joint modeling approach

Successful steroid withdrawal guided by surveillance biopsies—A single‐center experience

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