Developmental changes of MPA exposure in children

Yoo, Elisa; Álvarez-Elías, Ana Catalina; Todorova, Ekaterina Kirilova; Filler, Guido

doi:10.1007/s00467-015-3303-3

Cited by 13 publications

(8 citation statements)

References 35 publications

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“…Concerning the influence of age and gender on the pharmacokinetics of MPA, Tang et al [54] reported that age did not significantly affect the pharmacokinetics or pharmacodynamics of MPA. However, Yoo et al [55] reported that MPA exposure was associated with developmental changes in children, and demonstrated that small children are at a significantly greater risk of low MPA trough levels than adolescents, highlighting the need for pharmacokinetic monitoring of MPA. The influence of patient gender on the pharmacokinetics of MPA has been evaluated in three previous population pharmacokinetic studies in renal transplant patients.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in Chinese adult renal transplant recipients

Zhou

Wang

et al. 2017

Acta Pharmacol Sin

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Mycophenolate mofetil (MMF) is an important immunosuppressant used in renal transplantation, and mycophenolic acid (MPA) is the active component released from the ester prodrug MMF. The objective of this study was to investigate the population pharmacokinetics of mycophenolic acid (MPA) following oral administration of MMF in Chinese adult renal transplant recipients and to identify factors that explain MPA pharmacokinetic variability. Pharmacokinetic data for MPA and covariate information were retrospectively collected from 118 patients (79 patients were assigned to the group for building the population pharmacokinetic model, while 39 patients were assigned to the validation group). Population pharmacokinetic data analysis was performed using the NONMEM software. The pharmacokinetics of MPA was best described by a two-compartment model with a first-order absorption rate with no lag time. Body weight and serum creatinine level were positively correlated with apparent clearance (CL/F). The polymorphism in uridine diphosphate glucuronosyltransferase gene, UGT2B7, significantly explained the interindividual variability in the initial volume of distribution (V/F). The estimated population parameters (and interindividual variability) were CL/F 18.3 L/h (34.2%) and V/F 27.9 L (21.3%). The interoccasion variability was 13.7%. These population pharmacokinetic data have significant clinical value for the individualization of MMF therapy in Chinese adult renal transplant patients.

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Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in Chinese adult renal transplant recipients

Zhou

Wang

et al. 2017

Acta Pharmacol Sin

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“…Compared to adults, it may be that children and adolescents are more susceptible to MMF‐related leukopenia and/or the effects of SNPs due to maturation of these enzymes. Indeed, it has been reported that the levels of some key drug‐metabolizing enzymes commonly reach adult levels after 3 years of age, while the isoforms of the UGT enzymes (especially UGT1A9, UGT2B7, and UGT1A6) develop more slowly and typically do not reach adult levels until 10 years of age . As such, it is important to recognize that the ability to metabolize various drugs is dynamic throughout childhood and that age‐related studies, specifically looking at pharmacokinetics and how SNPs contribute to metabolism, are required.…”

Section: Discussionmentioning

confidence: 99%

Mycophenolate mofetil‐related leukopenia in children and young adults following kidney transplantation: Influence of genes and drugs

Varnell

Fukuda

Kirby

et al. 2017

Pediatric Transplantation

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MMF is commonly prescribed following kidney transplantation, yet its use is complicated by leukopenia. Understanding the genetics mediating this risk will help clinicians administer MMF safely. We evaluated 284 patients under 21 years of age for incidence and time course of MMF-related leukopenia and performed a candidate gene association study comparing the frequency of 26 SNPs between cases with MMF-related leukopenia and controls. We matched cases by induction, steroid duration, race, center, and age. We also evaluated the impact of induction and SNPs on time to leukopenia in all cases. Sixty-eight (24%) patients had MMF-related leukopenia, of which 59 consented for genotyping and 38 were matched with controls. Among matched pairs, no SNPs were associated with leukopenia. With non-depleting induction, UGT2B7-900A>G (rs7438135) was associated with increased risk of MMF-related leukopenia (P = .038). Time to leukopenia did not differ between patients by induction agent, but 2 SNPs (rs2228075, rs2278294) in IMPDH1 were associated with increased time to leukopenia. MMF-related leukopenia is common after transplantation. UGT2B7 may influence leukopenia risk especially in patients without lymphocyte-depleting induction. IMPDH1 may influence time course of leukopenia after transplant.

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“…A post-hoc analysis of a single-center cohort study that was approved by the Western University Research Ethics Board (HSREB File Number 105148) was conducted retrospectively [ 14 – 16 ]. We analyzed all existing data on 37 pediatric renal transplant recipients who were followed between January 1, 2006, and March 31, 2014.…”

Section: Methodsmentioning

confidence: 99%

Does Vitamin D Affect Chronic Renal Allograft Function in Pediatric Transplant Patients?

et al. 2018

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BackgroundCorrection of hypovitaminosis D is simple, but it is unclear whether it is associated with an accelerated decline of renal allograft function in pediatric renal transplantation patients. This retrospective single center cohort study aimed at analyzing the effect of vitamin D and covariates on the slope of 1/creatinine after the first year.Material/MethodsAfter ethics committee approval, 37 (14 male) pediatric renal transplant recipients on mycophenolate mofetil, who were followed between 2006 and 2014, were included in this study. We analyzed the slope of 1/creatinine, length of follow-up, average vitamin D levels, calcium, phosphate, alkaline phosphatase levels, intact parathyroid hormone (PTH) levels, and therapeutic drug monitoring parameters.ResultsMedian slope of 1/creatinine was −2.587e-006 L/μmol. We divided the 37 patients into two groups based on slope: 18 patients with a poorer slope and 19 patients with a good slope, with the median slope of 1/creatinine being significantly different between the two groups. Creatinine and cystatin C at one-year post-transplantation did not differ between the two groups. Average vitamin D levels were 71.4±31.01 pmol/L and identical in each group (averages 71.67 and 69.23 pmol/L, respectively). Only the mycophenolic acid coefficient of variation (MPA CV), which may promote formation of donor-specific antibodies, and PTH levels were significantly associated with 1/creatinine slope.ConclusionsOur data suggest that the impact of mild and moderate decreased levels of vitamin D can have a mild impact on the progression of allograft dysfunction in transplant recipients. However, given the medication burden and adherence challenges in adolescents, correction of mildly decreased vitamin D levels may not be necessary.

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Developmental changes of MPA exposure in children

Abstract: Small children are at a significantly greater risk for low MPA trough levels than adolescents, highlighting the need for pharmacokinetic monitoring of MPA.

Cited by 13 publications

References 35 publications

Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in Chinese adult renal transplant recipients

Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in Chinese adult renal transplant recipients

Mycophenolate mofetil‐related leukopenia in children and young adults following kidney transplantation: Influence of genes and drugs

Does Vitamin D Affect Chronic Renal Allograft Function in Pediatric Transplant Patients?

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