Circadian Pharmacokinetics of Mycophenolic Acid and Implication of Genetic Polymorphisms for Early Clinical Events in Renal Transplant Recipients

Satoh, Shigeru; Tada, Hitoshi; Murakami, Miho; Tsuchiya, Norihiko; Li, Zhenhua; Numakura, Kazuyuki; Saito, Mitsuru; Inoue, Takamitsu; Miura, Masatomo; Hayase, Yukitoshi; Suzuki, Toshio; Habuchi, Tomonori

doi:10.1097/01.tp.0000231874.53240.ba

Cited by 43 publications

(34 citation statements)

References 37 publications

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“…Accordingly, we have studied the circadian pharmacokinetics of immunosuppressive drugs (28Y30). Indeed, a lower AUC of mycophenolic acid (MPA) in both daytime and nighttime, especially at night, was associated with acute rejection in the early stages after transplantation, but not for Tac-BID (29). The pharmacokinetics of Tac-BID did not show circadian variation in this or our previous study (30).…”

Section: Discussionmentioning

confidence: 85%

Comparison of Pharmacokinetics and Pharmacogenetics of Once- and Twice-Daily Tacrolimus in the Early Stage After Renal Transplantation

et al. 2012

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C0-guided monitoring may lead to similar AUC0-24 values for both formulations. However, to maintain the same AUC0-24 value, a higher dose of Tac-QD than Tac-BID may be needed, especially for CYP3A5 expressers, in the early stage posttransplantation. The narrow interindividual variability of Tac-QD pharmacokinetics and its difference between CYP3A5 expressers and nonexpressers might contribute to a dosing strategy based on CYP3A5 genotype.

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Section: Discussionmentioning

confidence: 85%

Comparison of Pharmacokinetics and Pharmacogenetics of Once- and Twice-Daily Tacrolimus in the Early Stage After Renal Transplantation

et al. 2012

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“…Similarly, some patients show more adverse effects than do others, and hence require dose reductions more frequently. 9,15 Methods to predict individual MPA drug responsiveness or dose levels necessary for an adequate response are yet to be established. Drug monitoring was never correlated with a lower incidence of therapy failure with mycophenolate mofetil, which was confirmed in a recent study.…”

Section: Discussionmentioning

confidence: 99%

“…5,14 Furthermore, polymorphisms in the multidrug-resistance type I gene have been associated with gastrointestinal side effects of MPA therapy. 15 As IMPDH2 has an important role in purine metabolism and as MPA exerts its main effect on this enzyme, we searched for polymorphisms in the IMPDH2 gene, which might explain the varying efficacy of MPA therapy among patients. We identified three SNPs.…”

Section: Discussionmentioning

confidence: 99%

An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid

et al. 2009

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Mycophenolic acid (MPA) is a selective inhibitor of inosine 5 0 -monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme of de novo synthesis of guanine nucleotides. The isoenzyme IMPDH2 predominates in activated lymphocytes, and its inhibition by MPA is part of standard immunosuppressive regimens. Yet, there are significant unexplained differences in efficacy and tolerability among patients. The objective of this study was to analyze whether frequent variants in the IMPDH2 gene lead to changes in IMPDH activity and to differences in responsiveness to MPA therapy. All 14 exons and intron-exon boundary regions of IMPDH2 were sequenced from genomic DNA probes from 100 healthy individuals. Two novel exonic single-nucleotide polymorphisms were identified in 1% and one intronic polymorphism (rs11706052) in 19% of the study population. Lymphocyte IMPDH activity and proliferation under three MPA concentrations (2.5, 10 and 25 mmol l -1 ) were compared in rs11706052 carriers and wild-type individuals. The presence of rs11706052 polymorphism reduced the antiproliferative effect of MPA on lymphocytes by approximately 50% compared with the IMPDH2 wild-type form at therapeutic relevant concentrations of 10 mmol l -1 and 25 mmol l -1 . We conclude that a poorer response to MPA therapy can be explained in some individuals by the presence of the rs11706052 polymorphism.

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“…This result is in keeping with previous observations of MPA absorption being more delayed at night in renal transplant patients receiving MMF. [94,95] …”

Section: Outline Of Population Pharmacokinetic Modelling Of Mpa Pumentioning

confidence: 99%

“…There is large variability observed even in estimating gastric emptying based on time of day as outlined by de Winter et al, [89] and supported by results from other pharmacokinetic studies. [94,95] In addition, secondary peaks are not observed in all subjects and the number of sampling points around the secondary peak is usually limited. Given the complex physiology involved it makes sense to take a more physiologically and mechanism-based approach.…”

Section: Future Approachesmentioning

confidence: 99%

The Evolution of Population Pharmacokinetic Models to Describe the Enterohepatic Recycling of Mycophenolic Acid in Solid Organ Transplantation and Autoimmune Disease

Sherwin

Fukuda

Brunner

et al. 2011

Clinical Pharmacokinetics

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With the increasing use of mycophenolic acid (MPA) as an immunosuppressant in solid organ transplantation and in treating autoimmune diseases such as systemic lupus erythematosus, the need for strategies to optimize therapy with this agent has become increasingly apparent. This need is largely based on MPA’s significant between-subject and between-occasion (within-subject) pharmacokinetic variability. While there is a strong relationship between MPA exposure and effect, the relationship between drug dose, plasma concentration and exposure (area under the concentration-time curve [AUC]) is very complex and remains to be completely defined. Population pharmacokinetic models using various approaches have been proposed over the past 10 years to further evaluate the pharmacokinetic and pharmacodynamic behaviour of MPA. These models have evolved from simple one-compartment linear iterations to complex multi-compartment versions that try to include various factors, which may influence MPA’s pharmacokinetic variability, such as enterohepatic recycling and pharmacogenetic polymorphisms. There have been major advances in the understanding of the roles transport mechanisms, metabolizing and other enzymes, drug-drug interactions and pharmacogenetic polymorphisms play in MPA’s pharmacokinetic variability. Given these advances, the usefulness of empirical-based models and the limitations of nonlinear mixed-effects modelling in developing mechanism-based models need to be considered and discussed. If the goal is to individualize MPA dosing, it needs to be determined whether factors which may contribute significantly to variability can be utilized in the population pharmacokinetic models. Some pharmacokinetic models developed to date show promise in being able to describe the impact of physiological processes such as enterohepatic recycling. Most studies have historically been based on retrospective data or poorly designed studies which do not take these factors into consideration. Modelling typically has been undertaken using non-controlled therapeutic drug monitoring data, which do not have the information content to support the development of complex mechanistic models. Only a few recent modelling approaches have moved away from empiricism and have included mechanisms considered important, such as enterohepatic recycling. It is recognized that well thought-out sampling schedules allow for better evaluation of the pharmacokinetic data. It is not possible to undertake complex absorption modelling with very few samples being obtained during the absorption phase (which has often been the case). It is important to utilize robust AUC monitoring which is now being propagated in the latest consensus guideline on MPA therapeutic drug monitoring. This review aims to explore the biological factors that contribute to the clinical pharmacokinetics of MPA and how these have been introduced in the development of population pharmacokinetic models. An overview of the processes involved in the enterohepatic recycling of MPA will be provided. ...

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Circadian Pharmacokinetics of Mycophenolic Acid and Implication of Genetic Polymorphisms for Early Clinical Events in Renal Transplant Recipients

Abstract: MPA pharmacokinetics showed circadian variations, and a lower MPA AUC in both daytime and nighttime was associated with the occurrence of AR in the early stage after renal transplantation. The MDR1 C3435T polymorphism might be associated with diarrhea due to MPA.

Cited by 43 publications

References 37 publications

Comparison of Pharmacokinetics and Pharmacogenetics of Once- and Twice-Daily Tacrolimus in the Early Stage After Renal Transplantation

Comparison of Pharmacokinetics and Pharmacogenetics of Once- and Twice-Daily Tacrolimus in the Early Stage After Renal Transplantation

An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid

The Evolution of Population Pharmacokinetic Models to Describe the Enterohepatic Recycling of Mycophenolic Acid in Solid Organ Transplantation and Autoimmune Disease

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