Mycophenolic acid pharmacokinetics in stable pediatric renal transplantation

David‐Neto, Elias; Araújo, Lilian M. P.; Sumita, Nairo Massakazu; Mendes, Maria E.; Castro, Maria Cristina Ribeiro de; Alves, Caroline L.; Kakehashi, Erica; Romano, Paschoalina; Yagyu, Elisa Midori; Queiroga, Margaret; Nahas, William Carlos; Ianhez, Luiz Estevam

doi:10.1007/s00467-002-1057-1

Cited by 41 publications

(32 citation statements)

References 38 publications

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“…Accordingly, possible benefits of therapeutic drug monitoring of MMF therapy have been outlined by several groups. [9][10][11] In addition, data from adult populations indicate that concentration-controlled dosing strategies with an exposure target of 30 to 60 mg⋅h/L are associated with improved clinical outcomes and reduced drug-related toxicity. [12][13][14][15] However, MPA PK are quite complex both in adult and pediatric transplant recipients because of variable absorption profiles, enterohepatic recycling, and changing drug clearance over time.…”

mentioning

confidence: 99%

Inosine Monophosphate Dehydrogenase (IMPDH) Activity as a Pharmacodynamic Biomarker of Mycophenolic Acid Effects in Pediatric Kidney Transplant Recipients

Fukuda

Goebel

Thøgersen

et al. 2011

The Journal of Clinical Pharmacology

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Monitoring inosine monophosphate dehydrogenase (IMPDH) activity as a biomarker of mycophenolic acid (MPA)–induced immunosuppression may serve as a novel approach in pharmacokinetics (PK)/pharmacodynamics (PD)–guided therapy. The authors prospectively studied MPA pharmacokinetics and IMPDH inhibition in 28 pediatric de novo kidney transplant recipients. Pretransplant IMPDH activity and full PK/PD profiles were obtained at 3 different occasions: 1 to 3 days, 4 to 9 days, and approximately 6 months after transplant. Large intra- and interpatient variability was noted in MPA pharmacokinetics and exposure and IMPDH inhibition. MPA exposure (AUC0-12 h) was low early posttransplant and increased over time and stabilized at months 3 to 6. Mean pretransplant IMPDH activity (6.4 ± 4.6 nmol/h/mg protein) was lower than previously reported in adults. In most of the patients, IMPDH enzyme activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory Emax model (EC50 = 0.97 mg/L). This study suggests the importance of early PK/PD monitoring to improve drug exposure. Because IMPDH inhibition is well correlated to MPA concentration, pre-transplant IMPDH activity may serve as an early marker to guide the initial level of MPA exposure required in a pediatric population.

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confidence: 99%

Inosine Monophosphate Dehydrogenase (IMPDH) Activity as a Pharmacodynamic Biomarker of Mycophenolic Acid Effects in Pediatric Kidney Transplant Recipients

Fukuda

Goebel

Thøgersen

et al. 2011

The Journal of Clinical Pharmacology

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“…The typical maintenance therapy consists of a calcineurin inhibitor (tacrolimus or ciclosporin), an anti-proliferative agent (mycophenolate or azathioprine) and steroids (11,12). …”

Section: Immunosuppressionmentioning

confidence: 99%

Current management issues of immediate postoperative care in pediatric kidney transplantation

Torricelli¹,

Watanabe²,

David‐Neto³

et al. 2014

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The number of pediatric kidney transplants has been increasing in many centers worldwide, as the procedure provides long-lasting and favorable outcomes; however, few papers have addressed the immediate postoperative care of this unique population. Herein, we describe the management of these patients in the early postoperative phase. After the surgical procedure, children should ideally be managed in a pediatric intensive care unit, and special attention should be given to fluid balance, electrolyte disturbances and blood pressure control. Antibiotic and antiviral prophylaxes are usually performed and are based on the recipient and donor characteristics. Thrombotic prophylaxis is recommended for children at high risk for thrombosis, although consensus on the optimum therapy is lacking. Image exams are essential for good graft control, and Doppler ultrasound must be routinely performed on the first operative day and promptly repeated if there is any suspicion of kidney dysfunction. Abdominal drains can be helpful for surveillance in patients with increased risk of surgical complications, such as urinary fistula or bleeding, but are not routinely required. The immunosuppressive regimen starts before or at the time of kidney transplantation and is usually based on induction with monoclonal or polyclonal antibodies, depending on the immunological risk, and maintenance with a calcineurin inhibitor (tacrolimus or ciclosporin), an anti-proliferative agent (mycophenolate or azathioprine) and steroids.

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“…There is currently insufficient evidence to suggest that any specific LSS for mycophenolate is superior adjust MMF dosages to target an MPA AUC 30-60 mg*h/L. 14,15 The primary objective of this study was to describe the relationship between the AUC of MPA and adverse effects of MMF in pediatric renal transplant patients. The secondary objectives were to compare clinical outcomes between different MPA therapeutic drug monitoring practices (ie, AUC compared to trough plasma concentration) and to describe the relationship between the AUC and rates of rejection.…”

mentioning

confidence: 99%

RELATE: Relationship of limited sampling strategy and adverse effects of mycophenolate mofetil in pediatric renal transplant patients

Berger

Haubrich

Ensom

et al. 2019

Pediatric Transplantation

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MMF, a prodrug converted to the active form MPA, is an immunosuppressant used to prevent rejection in solid organ transplant recipients. MPA exposure, defined by AUC, can be estimated using limited sampling strategies (LSS). The relationship between MPA AUC and clinical outcomes has not been studied in pediatrics. The objectives were to describe the relationship of MPA AUC (estimated via LSS) with adverse effects and rates of rejection, and to compare clinical outcomes between different MPA monitoring practices. Descriptive statistics were used to summarize demographics, adverse effects, and rejection. Thirty‐three patients (91 trough concentrations and 12 LSS sets) aged 2‐20 years old were included. The estimated median MPA AUCs (David‐Neto and Filler) were higher for those who did not have any adverse effects reported (65.85 and 85.05 mg*h/L, respectively) compared to those who had an adverse effect (60.75 and 54.2 mg*h/L, respectively). The median trough concentration when no adverse effects occurred was comparable to when adverse effects occurred. The median MPA AUC at which rejection occurred was lower than in those without rejection. The median trough concentration at which rejection occurred was higher than those without rejection (3.1 mg/L compared to 1.9 mg/L). The occurrence of adverse effects or rejection was not shown to be related to measured MPA trough or AUC outside of the target therapeutic range. The value of MPA concentration monitoring remains unclear; therefore, the practice of monitoring MPA AUC by LSS or trough concentrations should be reconsidered.

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Mycophenolic acid pharmacokinetics in stable pediatric renal transplantation

Cited by 41 publications

References 38 publications

Inosine Monophosphate Dehydrogenase (IMPDH) Activity as a Pharmacodynamic Biomarker of Mycophenolic Acid Effects in Pediatric Kidney Transplant Recipients

Inosine Monophosphate Dehydrogenase (IMPDH) Activity as a Pharmacodynamic Biomarker of Mycophenolic Acid Effects in Pediatric Kidney Transplant Recipients

Current management issues of immediate postoperative care in pediatric kidney transplantation

RELATE: Relationship of limited sampling strategy and adverse effects of mycophenolate mofetil in pediatric renal transplant patients

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