Population pharmacokinetics of mycophenolic acid in adult kidney transplant patients under prednisone and tacrolimus regimen

Reséndiz-Galván, Juan Eduardo; Romano‐Aguilar, Melissa; Medellín‐Garibay, Susanna Edith; Milán‐Segovia, Rosa del Carmen; Niño-Moreno, Perla del Carmen; Jung‐Cook, Helgi; Chevaile-Ramos, José Alejandro; Romano‐Moreno, Silvia

doi:10.1016/j.ejps.2020.105370

Cited by 14 publications

(16 citation statements)

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“…Genetic polymorphisms in this isoform may contribute to PK variations. A previous study 25 conducted in Caucasians showed that carriers of a heterozygous genotype for UGT1A9 275T > A present a lower MPA concentration of 2.9 mg∙L −1 and MPA AUC 12 of 39 mg∙h∙L −1 compared to homozygous non‐carriers of the A allele (3.6 mg L −1 and MPA of 44 mg∙h∙L −1 , respectively). Consistent with previous reports in Chinese subjects, these polymorphisms were not found in our study; thus, they are not clinically important for MPA disposition in Asian patients 52,55 .…”

Section: Discussionmentioning

confidence: 91%

“…To identify any impact of genetic polymorphisms in metabolic enzymes and transporters, we investigated UGT1A8, 1A9, UGT2B7, ABCC2, ABCG2, SLCO1B1, SLCO1B3, and HNF1α, which have been previously reported 8‐10,15,17,19,20,23,45,49‐53 . Previous studies investigated the influence of genetic polymorphism on MPA in adult patients who underwent kidney transplant treated with tacrolimus 25,44 . We identified confounding factors and more appropriately assessed the effects of genetic polymorphisms in metabolic enzymes and transporters, including UGT, ABC, SLCO, and HNF1α, on MPA PKs.…”

Section: Discussionmentioning

confidence: 99%

“…Co‐therapy with commonly used calcineurin inhibitors tacrolimus or cyclosporine has a different impact on MPA PKs 19,21,23 . MPA exposure is 23–48% higher in co‐therapy with tacrolimus than with cyclosporine 24,25 . This is owing to the cyclosporine inhibited biliary excretion of MPAG, through inhibition of the multidrug resistance‐associated protein 2 transporter (MRP2), 26,27 so that less MPAG and MPA undergo enterohepatic circulation.…”

Section: What Is Known and Objectivementioning

confidence: 99%

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Genetic polymorphisms in metabolic enzymes and transporters have no impact on mycophenolic acid pharmacokinetics in adult kidney transplant patients co‐treated with tacrolimus: A population analysis

et al. 2021

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What is known and objective Mycophenolate mofetil, an ester prodrug of mycophenolic acid (MPA), is widely used to prevent graft rejection after kidney transplantation. The pharmacokinetic (PK) of MPA has been extensively studied, which revealed a high degree of variability. An integrated population PK (PopPK) model of MPA and its main metabolite mycophenolic acid glucuronide (MPAG) was developed using the adult patients who underwent kidney transplant and were administered oral mycophenolate mofetil combined with tacrolimus. Methods In total, 917 MPA and 740 MPAG concentrations in191 adult patients were analysed via nonlinear mixed‐effects modelling. The concentration‐time data were adequately described using a chain compartment model, including central and peripheral compartments for MPA and a central compartment for MPAG. Stepwise forward inclusion and backward elimination procedures were used to investigate the effects of genetic polymorphisms, including in UGT1A8, UGT1A9, UGT2B7, ABCB1, ABCC2, ABCG2, SLCO1B1, SLCO1B3, and HNF1α. Results and discussion These genetic polymorphisms in metabolic enzymes and transporters have no obvious impact on the PK of MPA in adult patients who underwent kidney transplant and were co‐treated with tacrolimus. The post‐transplant time, serum albumin, and creatinine clearance were identified as significant covariates affecting the PK of MPA and MPAG, which should be considered in the clinical use of mycophenolate mofetil. What is new and conclusion We established a PopPK model of MPA and MPAG in Chinese adult patients who underwent kidney transplant and were co‐treated with tacrolimus. Genetic polymorphisms in metabolic enzymes and transporters showed no obvious impact on MMF PK. A model‐informed dosing strategy was proposed by the established model, and MMF dose adjustment should be based on ALB levels and the post‐transplantation time.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: What Is Known and Objectivementioning

confidence: 99%

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Genetic polymorphisms in metabolic enzymes and transporters have no impact on mycophenolic acid pharmacokinetics in adult kidney transplant patients co‐treated with tacrolimus: A population analysis

et al. 2021

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“…UGT1A8 and UGT1A10 are responsible for MPA metabolism in the gastrointestinal tract. MPA and its metabolites are mainly excreted through urine probably mediated by Mrp2 (33,34).…”

Section: Mpo Play An Integral Role In Aanmentioning

confidence: 99%

Cystatin C and myeloperoxidase based mycophenolic acid dosage optimization in pediatric anti-neutrophilic cytoplasmic antibody-associated nephritis

Huang

2021

Preprint

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Aims Mycophenolic acid (MPA) is typically used for anti-neutrophilic cytoplasmic antibody associated nephritis (AAN) but with large individual variability of pharmacokinetics. This study aims to investigate clinical factors impacting MPA disposal so as to simulate dosage regimen in pediatric AAN. Methods We conducted a retrospective study in 25 children with AAN treated with MPA. A population pharmacokinetic model was developed to explore the effects of demographics and biochemical covariates on MPA. Monte Carlo simulations were performed to optimize dosage regimens. Results A total of 391 MPA concentrations from 25 patients were analyzed. MPA pharmacokinetics best fitted a two-compartment model with first-order absorption and linear elimination. The pharmacokinetic parameters for Ka, CL, Vc, Vp, and Q were 0.45 h-1, 9.86 L/h, 19.69 L, 408.32 L and 23.01 L/h, respectively. Dosage form significantly affected drug absorption. CL significantly decreased with increasing cystatin C, while with decreasing myeloperoxidase. Cystatin C was superior to serum creatinine in predicting CL of MPA. A dose of 650 mg/m2 was required to achieve the target exposure in children with normal renal function and no inflammation. Dose of MPA in patients with renal failure was almost 1/3 that of normal kidney function. The combined effects of myeloperoxidase and renal function resulted in a 6-fold range in MPA dose. Conclusions Myeloperoxidase was not only a biomarker of AAN, but also an inflammatory factor to impact drug CL. The influence of renal function and underlying diseases on drug metabolism should be fully considered in personalized medication for AAN children.

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“…Mycophenolate mofetil is usually used in combination with prednisone and tacrolimus to avoid graft rejection in kidney transplant recipients. 22 Patients using MMF frequently experience nausea, vomiting, heartburn, indigestion, anorexia, and especially diarrhea. 23 Flannigan et al 24 reported that mice treated with MMF exhibit significant weight loss related to body fat and muscle loss and marked colon inflammation.…”

Section: T 2 > T 0 T 3 > T 0 T 2 > T 1 T 3 > T 1 T 3 > Tmentioning

confidence: 99%

Weight Gain, Energy Intake, Energy Expenditure, and Immunosuppressive Therapy in Kidney Transplant Recipients

Taşdemir

Aksoy

2020

Prog Transpl

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Background: Weight gain after kidney transplantation is a common health problem. The factors in weight gain after kidney transplant include many factors such as age, ethnicity, gender, change in lifestyle (eg, kilocalorie intake and physical activity level), and immunosuppressive therapy. Research Questions: This study aimed to evaluate the relationship between weight gain and energy intake in dietary, energy expenditure in physical activity, and immunosuppressive therapy in kidney transplant recipients. Design: This prospective, observational study included 51 participants who underwent kidney transplant, during 6 months from the start of the study. Anthropometric measurements were performed at first week, third- and sixth-month follow-ups of transplant recipients. Participants also completed 3-day “Dietary Record Form” and the “Physical Activity Record Form” at each follow-up. Simple frequency, analysis of variance analysis, and correlation analysis were used for data analysis. Results: Weight gain in sixth month follow-up compared to baseline value was positively related to energy intake in first week (r = 0.59), third month (r = 0.75), and sixth month (r = 0.67) follow-ups, and energy expenditure in first week (r = 0.35) and sixth month (r = 0.34) follow-ups. However, weight gain was negatively related to mycophenolate mofetil dose (mg/d) in sixth month (r = −0.31) follow-up ( P < .05). Discussion: The results of this study provide an opportunity to reflect and discuss on modifiable risk factors such as energy intake and energy expenditure that affect weight gain posttransplantation in participants. It also examines the relationship between immunosuppressive therapy. Additionally, these results can be effective in designing interventions and managing risk factors to achieve weight management goals.

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Population pharmacokinetics of mycophenolic acid in adult kidney transplant patients under prednisone and tacrolimus regimen

Cited by 14 publications

References 54 publications

Genetic polymorphisms in metabolic enzymes and transporters have no impact on mycophenolic acid pharmacokinetics in adult kidney transplant patients co‐treated with tacrolimus: A population analysis

Genetic polymorphisms in metabolic enzymes and transporters have no impact on mycophenolic acid pharmacokinetics in adult kidney transplant patients co‐treated with tacrolimus: A population analysis

Cystatin C and myeloperoxidase based mycophenolic acid dosage optimization in pediatric anti-neutrophilic cytoplasmic antibody-associated nephritis

Weight Gain, Energy Intake, Energy Expenditure, and Immunosuppressive Therapy in Kidney Transplant Recipients

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