UGT Genotype May Contribute to Adverse Events Following Medication With Mycophenolate Mofetil in Pediatric Kidney Transplant Recipients

Prausa, SE; Fukuda, Tsuyoshi; Maseck, Denise; Curtsinger, KL; Liu, C; Zhang, K; Nick, TG; Sherbotie, JR; En, Ellis; Goebel, Jens; Vinks, Alexander A.

doi:10.1038/clpt.2009.3

Cited by 39 publications

(25 citation statements)

References 26 publications

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“…All three patients who were homozygous for UGT1A9 2331T.C developed leucopenia, and heterozygous individuals presented significantly higher toxicity. 132 How to Monitor Mycophenolate Mofetil in Children: Is It Different From Monitoring in Adults?…”

Section: Mycophenolate Mofetil In Children: Impact Of Age and Pharmacmentioning

confidence: 99%

Developmental Pharmacogenetics of Immunosuppressants in Pediatric Organ Transplantation

Zhao

Fakhoury

Jacqz-Aigrain

2010

Therapeutic Drug Monitoring

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Cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil are the primary immunosuppressants used on pediatric organ transplantation. Therapeutic drug monitoring is used in daily practice, because their clinical use is hampered by a narrow therapeutic index and large variability. Tailoring immunosuppressive therapy to the individual patient to optimize efficacy and minimize toxicity is therefore essential. Because research in pharmacogenetics already identified polymorphisms impacting their pharmacokinetic parameters in adults, developmental pharmacogenetics of immunosuppressants holds promises for optimizing dosage regimens and improving clinical outcome in children. In this review, we focus on the impact of age and pharmacogenetics on these immunosuppressants in children undergoing organ transplantation.

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Section: Mycophenolate Mofetil In Children: Impact Of Age and Pharmacmentioning

confidence: 99%

Developmental Pharmacogenetics of Immunosuppressants in Pediatric Organ Transplantation

Zhao

Fakhoury

Jacqz-Aigrain

2010

Therapeutic Drug Monitoring

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“…[26] The investigators reported that they could not detect the effect of UGT1A9 polymorphisms on the pharmacokinetics of MPA and MPAG. However, this was probably related to the exclusion of subjects with functional SNPs such as UGT1A9− 275 and −331/−440 [96] from the study analysis. WinNonLin® was used by Yau et al [69] to produce a five-compartment parent drug and metabolite EHC model (tables I and II, figure 2e).…”

Section: Outline Of Population Pharmacokinetic Modelling Of Mpa Pumentioning

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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“…16 Genetic variants in the genes encoding MMF's primary drug metabolizing enzymes, uridine diphosphate-glucuronosyl transferases (UGTs) 1A9 and 2B7, result in variability in drug exposure and risk for sub- or supratherapeutic effects. 17 This study aims to identify genetic variants that increase risk for MMF-related leukopenia in order to inform personalized drug monitoring and dosing regimens.…”

Section: Resultsmentioning

confidence: 99%

Characteristics of Successful Recruitment in Prospective Pediatric Pharmacogenetic Studies

Saldaña¹,

Hooper²,

Froehlich³

et al. 2011

Clinical Therapeutics

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Objective The aim was to identify factors affecting recruitment of eligible subjects in pharmacogenetic studies at a large Midwestern pediatric academic medical center. Objectives were to evaluate recruitment success of ongoing trials and ascertain contributors to differential recruitment rates. We hypothesized studies with good recruitment of eligible subjects would share characteristics not present in studies with lower than anticipated recruitment. The goal was to better understand barriers to good recruitment in pharmacogenetic studies to help inform future trial and infrastructure design. Study Design Investigators designed a survey with proposed elements of success, which was then completed by lead/site investigators of all pharmacogenetics studies at the institution. Results were evaluated using an investigator-developed likelihood of success scoring system. Results Two studies recruited over 95% of eligible patients approached, four studies were consistent with investigator-anticipated recruitment (>50%), and one study did not meet expected recruitment. A study's total score on the investigator-devised scoring tool correlated well with the proportion of approached patients recruited (Pearson correlation, r = 0.82; P<0.001). Multiple factors impact successful recruitment into these pharmacogenetic studies. Features of studies with successful recruitment included standardized clinical care, an ongoing team/patient relationship, severe/life-threatening outcome measure, study coordinator with experience in clinical research, a study medication with few or no alternative treatment options, and active involvement of the research team in clinical care. Conclusions A scoring system for study characteristics may be useful to calculate the risk of failure for successful recruitment, allow discrimination among characteristics contributing to the risk, and permit study design alterations to improve likelihood of successful recruitment in pediatric pharmacogenetic studies.

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UGT Genotype May Contribute to Adverse Events Following Medication With Mycophenolate Mofetil in Pediatric Kidney Transplant Recipients

Cited by 39 publications

References 26 publications

Developmental Pharmacogenetics of Immunosuppressants in Pediatric Organ Transplantation

Developmental Pharmacogenetics of Immunosuppressants in Pediatric Organ Transplantation

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

Characteristics of Successful Recruitment in Prospective Pediatric Pharmacogenetic Studies

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