Individualized Mycophenolate Mofetil Dosing Based on Drug Exposure Significantly Improves Patient Outcomes After Renal Transplantation

Meur, Yann Le; Büchler, Matthias; Thierry, Antoine; Caillard, Sophie; Villemain, Florence; Lavaud, Sylvie; Étienne, Isabelle; Westeel, Pierre-François; Ligny, Bruno Hurault de; Rostaing, Lionel; Thervet, Éric; Szelag, Jean-Christophe; Rérolle, Jean-Philippe; Rousseau, Annick; Touchard, Guy; Marquet, Pierre

doi:10.1111/j.1600-6143.2007.01983.x

Cited by 368 publications

(298 citation statements)

References 33 publications

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“…These results support the overall hypothesis that early adequate MPA exposure in renal transplant recipients can be achieved with a higher starting dosage and are consistent with findings from previous studies (4,7,12); however, data from larger studies are needed to confirm whether the pharmacokinetic and pharmacodynamic differences reported here can be translated into improvements in efficacy and safety.…”

Section: Discussionsupporting

confidence: 81%

“…Median MPA-AUC was only 33.7 mg/h per L on day 14 in the Apomygre study, and levels Ͼ40 mg/h per L were not achieved until month 1 using a concentration-controlled approach (12). Similarly, mean MPA-AUC of CsAtreated patients on day 10 was 34.4 mg/h per L in the FixedDose Concentration-Controlled (FDCC) Study (13).…”

Section: Discussionmentioning

confidence: 99%

“…Whereas the majority of tacrolimus-treated patients achieve adequate MPA exposure early after transplantation (13,14), studies have demonstrated that approximately 50% of patients who are treated with CsA and standard MPA dosages are underexposed (4,7,12,13). Larger initial MMF dosages (up to 4 g/d) have been suggested early after transplantation for achievement of sufficient MPA exposure in combination with CsA (13,15,16).…”

mentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Intensified versus Standard Dosing of Mycophenolate Sodium in Renal Transplant Patients

Glander¹,

Sommerer²,

Arns³

et al. 2010

Clinical Journal of the American Society of Nephrology

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Background and objectives: Adequate early mycophenolic acid (MPA) exposure is an important determinant for effective rejection prophylaxis. This pharmacokinetic study investigated whether an intensified dosing regimen of enteric-coated mycophenolate sodium (EC-MPS) could achieve higher mycophenolic acid (MPA) exposure early after transplantation versus a standard dosing regimen.Design, setting, participants, & measurements: De novo kidney transplant recipients (n ‫؍‬ 75) who were treated with basiliximab induction and cyclosporine were randomly assigned to receive EC-MPS as either standard dosing (1440 mg/d; n ‫؍‬ 37) or intensified dosing (days 0 through 14: 2880 mg/d; days 15 through 42: 2160 mg/d; followed by 1440 mg/d; n ‫؍‬ 38). Full 12-hour pharmacokinetic and pharmacodynamic profiles were taken at six time points during the first 3 months. Exploratory analysis of inosine monophosphate dehydrogenase (IMPDH) activity was also performed for better understanding of the pharmacokinetic-pharmacodynamic relationship between MPA exposure and IMPDH activity in the early posttransplantation period. Preliminary efficacy parameters, safety, and tolerability were assessed.Results: Exposure to MPA was significantly higher on days 3 and 10 after transplantation in the intensified versus standard EC-MPS group, with 52.9 versus 22.2% (P < 0.05) of patients reaching MPA exposure >40 mg/h per L in the first week. The intensified regimen resulted in significantly lower IMPDH activity on day 3 after transplantation, and the overall safety was comparable for both groups.Conclusions: These pharmacokinetic and safety data support further research on the hypothesis that early adequate MPA exposure could improve clinical outcome.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Intensified versus Standard Dosing of Mycophenolate Sodium in Renal Transplant Patients

Glander¹,

Sommerer²,

Arns³

et al. 2010

Clinical Journal of the American Society of Nephrology

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“…The clinical impact of UGT2B7 on the pharmacokinetics of MPA remains unclear. MPA area below the target therapeutic window increases the risk of adverse effects such as infection, anemia, and diarrhea (25). However, patients are at an increased risk of insufficient immunosuppression and acute rejection episodes.…”

Section: Ugt Polymorphisms and Mycophenolic Acidmentioning

confidence: 99%

“…However, patients are at an increased risk of insufficient immunosuppression and acute rejection episodes. These facts heighten the necessity of therapeutic drug monitoring because novel regimens increase the risk of inadequate or excessive immunosuppression (25).…”

Section: Ugt Polymorphisms and Mycophenolic Acidmentioning

confidence: 99%

Effect of uridine diphosphate-glucuronosyltransferase polymorphisms on the plasma concentrations of mycophenolic acid in Turkish renal transplant patients

Çiftçi¹,

Tefik²,

Karadeniz³

et al. 2017

İstanbul Tıp Fakültesi Dergisi

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Objective: The pharmacokinetics of mycophenolic acid (MPA) differ among individuals. MPA is primarily metabolized by uridine diphosphate-glucuronosyltransferase (UGT), and UGT2B7 is an important UGT for the glucuronidation of MPA. This study aimed to examine the pharmacokinetics of MPA in Turkish renal transplant patients with UGT2B7 His268Tyr (802C>T) polymorphisms. Materials and Methods: Sixty-five renal transplants patients were included in this study. UGT2B7 (802C>T) genotyping was performed using PCR-RFLP. Concentrations of MPA were determined using a cloned enzyme donor immunoassay (CEDIA). All patients were monitored for acute rejection and graft function during the study period. Results: The UGT2B7 (802C>T) CC, CT, and TT genotype frequencies among patients were 24 (36.9%), 36 (55.4%), and 5 (7.7%) respectively. At three and six months post-transplant respectively, levels of MPA were significantly higher in UGT2B7 (802C>T) TT carriers than in CT and CC carriers (p=0.038; p=0.021). The ratio of plasma concentration to MPA dosage for patients with 802C>T TT genotype was higher than that of CC and CT genotypes at six months post-transplant (p=0.042). Individuals carrying the TT genotype demonstrated lower dose requirements at three and six months compared with those of the CC and CT genotypes respectively (p=0.109, p=0.238). Additionally, there was no association found between UGT2B7 (802C>T) polymorphism and acute rejection (p>0.05). Conclusion: Our results demonstrated a correlation between the UGT2B7 (802C>T) polymorphism and MPA pharmacokinetics among renal transplant patients. Determination of UGT2B7 polymorphism may be helpful for determining the optimum dose of MPA to achieve the target plasma concentration.

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Preventing Relapses in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Arnaud¹

2011

JAMA

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Individualized Mycophenolate Mofetil Dosing Based on Drug Exposure Significantly Improves Patient Outcomes After Renal Transplantation

Cited by 368 publications

References 33 publications

Pharmacokinetics and Pharmacodynamics of Intensified versus Standard Dosing of Mycophenolate Sodium in Renal Transplant Patients

Pharmacokinetics and Pharmacodynamics of Intensified versus Standard Dosing of Mycophenolate Sodium in Renal Transplant Patients

Effect of uridine diphosphate-glucuronosyltransferase polymorphisms on the plasma concentrations of mycophenolic acid in Turkish renal transplant patients

Preventing Relapses in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

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