Longitudinal Pharmacokinetics of Mycophenolic Acid in Elderly Renal Transplant Recipients Compared to a Younger Control Group: Data from the nEverOld Trial

Romano, Paschoalina; Agena, Fabiana; Ebner, Pérsio de Almeida Rezende; Sumita, Nairo Massakazu; Triboni, Ana Heloísa Kamada; Ramos, Fernanda; Garcia, Márcio dos Santos; Duarte, Nilo José Coelho; Lemos, Francisco José Alves; Galante, Nelson Zocoler; David‐Neto, Elias

doi:10.1007/s13318-018-0506-6

Cited by 11 publications

(8 citation statements)

References 45 publications

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“…Plasma concentrations of mizoribine and MPA (the active product of MMF) were measured at the end of the treatment phase by LC-MS/MS and quantified using standard curves (Supplemental Figure 3, B and C). Plasma concentrations of both compounds were well within the therapeutically achievable ranges typically used for immunosuppression in humans ( Figure 3C) (32)(33)(34)(35). Tumor immunohistochemical (IHC) staining revealed a slight reduction in the proliferation marker Ki-67 in MMF-treated tumors compared with vehicle but no increase in tumor cell death as determined by H&E and cleaved caspase-3 staining ( Figure 3D S6K substrate ribosomal protein S6 (Figure 3, D and E).…”

Section: Resultsmentioning

confidence: 56%

IMPDH inhibitors for antitumor therapy in tuberous sclerosis complex

Valvezan¹,

McNamara²,

Miller³

et al. 2020

JCI Insight

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Section: Resultsmentioning

confidence: 56%

IMPDH inhibitors for antitumor therapy in tuberous sclerosis complex

Valvezan¹,

McNamara²,

Miller³

et al. 2020

JCI Insight

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“…20,22 These MPA pharmacokinetic differences during maintenance therapy conflict with previous pharmacokinetic studies conducted in young and old kidney allograft recipients within the first 6 months posttransplant where no differences were found, and EHR was not described. 17,18 These pharmacokinetic findings for these commonly prescribed immunosuppressives provides evidence in support of developing systematic ageadjusted dosing regimens.…”

Section: Discussionmentioning

confidence: 85%

“…Another important finding pertaining to the empiric MPA dosing in the combined groups of KTRs resulted in MPA AUC 0‐12h and troughs that exceeded the target ranges and may result in over‐immunosuppression or increased AEs especially in the elderly recipients 20,22 . These MPA pharmacokinetic differences during maintenance therapy conflict with previous pharmacokinetic studies conducted in young and old kidney allograft recipients within the first 6 months post‐transplant where no differences were found, and EHR was not described 17,18 . These pharmacokinetic findings for these commonly prescribed immunosuppressives provides evidence in support of developing systematic age‐adjusted dosing regimens.…”

Section: Discussionmentioning

confidence: 87%

Age associations with tacrolimus and mycophenolic acid pharmacokinetics in stable Black and White kidney transplant recipients: Implications for health inequities

Tornatore

Attwood

Venuto

et al. 2023

Clinical Translational Sci

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Tacrolimus (TAC) and mycophenolic acid (MPA) provide maintenance immunosuppression and is dosed empirically in elderly kidney transplant recipients (KTRs) resulting in health inequities. Limited immunosuppressive pharmacokinetics are available comparing adult ages. This secondary analysis compared TAC and MPA pharmacokinetics and adverse effects (AEs) among young, middleaged, and elderly Black and White KTRs. The 12-h TAC and MPA pharmacokinetics with AE evaluation were conducted in 67 stable KTRs greater than or equal to 6 months post-transplant. TAC regimens were adjusted to target troughs. MPA regimens were adjusted using clinical response. Participants were: young: less than or equal to 40 years; middle age: greater than 40 to 60 years, and elderly greater than 60 years. Noncompartmental pharmacokinetic analysis determined area under the concentration-time curve 0-12 h (AUC 0-12h ), clearance (CL), and CL/body mass index (BMI) with 0-h troughs. MPA enterohepatic recirculation (EHR), MPA-AUC 6-12h /MPA-AUC 0-12h , and MPA glucuronide (MPAG)-AUC 0-12h / MPA-AUC 0-12h were determined. Univariate analysis of variance (ANOVA) was conducted using SAS version 9.4. No group differences were noted for estimated glomerular filtration rate, MPA, and TAC doses. EHR was reduced in elderly with decreased MPA-AUC 6-12h /MPA-AUC 0-12h (p = 0.049) and increased MPAG-AUC 0-12h /MPA-AUC 0-12h (p = 0.036). MPA troughs (p = 0.045) were reduced in the elderly. TAC CL/BMI (p = 0.043) was reduced in the elderly. For therapeutic MPA AUC 0-12h : 30-60 mg•h/L, 34.3% KTRs achieved this target with 55.2% greater than the therapeutic range. 77.6% KTR were in the TAC AUC 0-12h target: 100-190 ng•h/mL and 19.4% were below this range with no age relationship. In 44% young, 26% middle-age and 7.8% elderly subjects achieved target AUC 0-12h for both medications (p = 0.036). Neurologic AEs were manifested in the elderly (p = 0.014). Immunosuppressive pharmacokinetics demonstrated age-related

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“…We have described other changes induced by senescence in some aspects of transplantation. For example, a reduced clearance of TAC 43 and EVL 44 but not in MPA 45 was found in elderly KTR.…”

Section: Discussionmentioning

confidence: 95%

The impact of mTOR inhibitors in the regression of left ventricular hypertrophy in elderly kidney transplant recipients

David‐Neto

Filho

Sá

et al. 2022

Clinical Transplantation

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End-stage kidney disease is frequently associated with left ventricular hypertrophy (LVH), a condition more prevalent in the elderly, that may increase mortality after renal transplantation (RTx). Previous studies suggested that mTOR inhibitors (mTORi) can improve LVH, but this has never been tested in elderly kidney transplant recipients.In this prospective randomized clinical trial, we analyzed the impact of Everolimus (EVL) on the reversal of LVH after RTx in elderly recipients (≥60 years) submitted to different immunosuppressive regimens: EVL/lowTacrolimus (EVL group, n = 53) or mycophenolate sodium/regularTacrolimus (MPS group, n = 47). Patients performed echocardiograms (Echo) up to 3 months after RTx and then annually. At baseline, mean age was 65±3 years in both groups and LVH was observed in 63.6% of patients in EVL group and in 61.8% of MPS group. Last Echo was performed at mean time of 47 and 49 months after RTx in EVL and MPS groups, respectively (P = .34). LVH regression was observed in 23.8% (EVL group) and 19% (MPS group) of patients (P = 1.00). Mean eGFR, blood pressure, and use of RAS blockers were similar between groups throughout follow-up. EVL did not improve LVH in this cohort, and this lack of benefit may be attributed to concomitant use of TAC, senescence, or both.

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Longitudinal Pharmacokinetics of Mycophenolic Acid in Elderly Renal Transplant Recipients Compared to a Younger Control Group: Data from the nEverOld Trial

Abstract: These data show that the pharmacokinetics of MPA in elderly renal transplant recipients were no different to those of younger-adult recipients in this study population. CLINICALTRIALS.GOV: NCT 01631058.

Cited by 11 publications

References 45 publications

IMPDH inhibitors for antitumor therapy in tuberous sclerosis complex

IMPDH inhibitors for antitumor therapy in tuberous sclerosis complex

Age associations with tacrolimus and mycophenolic acid pharmacokinetics in stable Black and White kidney transplant recipients: Implications for health inequities

The impact of mTOR inhibitors in the regression of left ventricular hypertrophy in elderly kidney transplant recipients

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