Pharmacokinetics of mycophenolic acid associated with calcineurin inhibitors: long-term monitoring in stable lung recipients with and without cystic fibrosis

doi:10.1016/S1053-2498(02)01159-2

The Journal of Heart and Lung Transplantation

Volume 22, Issue 5, May 2003, Pages 587-590

https://doi.org/10.1016/S1053-2498(02)01159-2 Get rights and content

Abstract

Pharmacologic interactions and absorption disturbances after transplantation may induce serologic fluctuation of immunosuppression and adversely affect outcome. We present data showing that trough levels of mycophenolic acid decreased by 50% during combined mycophenolate mofetil (MMF) and cyclosporine therapy compared with levels during combined MMF and tacrolimus therapy. In addition, cystic fibrosis patients required 30% higher doses of MMF to achieve the therapeutic levels of recipients without cystic fibrosis.

Section snippets

Methods

We observed 30 patients (mean age, 46.4 ± 10.7 years) for at least 2 years after transplantation. During follow-up, 14 patients were switched from cyclosporine to tacrolimus, mainly for recurring acute rejection, development of bronchiolitis obliterans/bronchiolitis obliterans syndrome, or persisting adverse effects. The MPA values during combined MMF and tacrolimus therapy in the 14 patients were compared with the MPA values during combined MMF and cyclosporine therapy in the remaining 16

Results

The average number of blood samples collected to evaluate MPA dosage during the follow-up period (52.5 ± 20.1 months) was 1.4 per patient-month. The duration of immunosuppression with cyclosporine or with tacrolimus was 17.7 ± 3.1 months and 20.8 ± 2.4 months, respectively. Mean doses of cyclosporine and tacrolimus were 2.8 ± 1.2 mg/kg/day and 0.07 ± 0.01 mg/kg/day, respectively. Mean trough levels were 125.9 ± 37.4 μg/liter for cyclosporine and 7.7 ± 2.8 μg/liter for tacrolimus. Mean doses of

Discussion

It has been suggested that the combination of MMF and cyclosporine may decrease serum MPA levels. Gregoor et al,4 compared MPA results of patients receiving a triple-immunosuppression regimen and showed that MPA levels increased by nearly 70% after discontinuing cyclosporine. Our study is consistent with this observation; pre-dose MPA results nearly doubled in patients who switched to combined tacrolimus therapy, compared with combined cyclosporine therapy. Recent results of Vidal et al5

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Cited by (35)

Cystic fibrosis foundation consensus statements for the care of cystic fibrosis lung transplant recipients
2021, Journal of Heart and Lung Transplantation
Cystic fibrosis (CF) is the indication for transplantation in approximately 15% of recipients worldwide, and Cystic Fibrosis Lung Transplant Recipients (CFLTRs) have excellent long-term outcomes. Yet, CFLTRs have unique comorbidities that require specialized care. The objective of this document is to provide recommendations to CF and lung transplant clinicians for the management of perioperative and underlying comorbidities of CFLTRs and the impact of transplantation on these comorbidities. The Cystic Fibrosis Foundation (CFF) organized a multidisciplinary committee to develop CF Lung Transplant Clinical Care Recommendations. Three workgroups were formed to develop focused questions. Following a literature search, consensus recommendations were developed by the committee members based on literature review, committee experience and iterative revisions, and in response to public comment. The committee formulated 32 recommendation statements in the topics related to infectious disease, endocrine, gastroenterology, pharmacology, mental health and family planning. Broadly, the committee recommends close coordination of care between the lung transplant team, the cystic fibrosis care center, and specialists in other disciplines with experience in the care of CF and lung transplant recipients. These consensus statements will help lung transplant providers care for CFLTRs in order to improve post-transplant outcomes in this population.
Monitoring of nonsteroidal immunosuppressive drugs in patients with lung disease and lung transplant recipients: American College of Chest Physicians evidence-based clinical practice guidelines
2012, Chest
Citation Excerpt :
Table 35 summarizes 11 trials in which mycophenolate was administered to patients for various conditions and provides important information regarding toxicity.310,312,482–486,495–498 This table includes seven studies in which the drug was given for pulmonary diseases.312,482–486,495 The elimination half-life of immediate-release MPA is 16 to 18 h,481,499 and that of delayed-release MPA is 8 to 16 h.500 Mycophenolate is extensively converted to MPA glucuronide, which is extensively cleared through renal excretion.481
Immunosuppressive pharmacologic agents prescribed to patients with diffuse interstitial and inflammatory lung disease and lung transplant recipients are associated with potential risks for adverse reactions. Strategies for minimizing such risks include administering these drugs according to established, safe protocols; monitoring to detect manifestations of toxicity; and patient education. Hence, an evidence-based guideline for physicians can improve safety and optimize the likelihood of a successful outcome. To maximize the likelihood that these agents will be used safely, the American College of Chest Physicians established a committee to examine the clinical evidence for the administration and monitoring of immunosuppressive drugs (with the exception of corticosteroids) to identify associated toxicities associated with each drug and appropriate protocols for monitoring these agents.
Committee members developed and refined a series of questions about toxicities of immunosuppressives and current approaches to administration and monitoring. A systematic review was carried out by the American College of Chest Physicians. Committee members were supplied with this information and created this evidence-based guideline.
It is hoped that these guidelines will improve patient safety when immunosuppressive drugs are given to lung transplant recipients and to patients with diffuse interstitial lung disease.
Advances in Lung Transplantation for Patients Who Have Cystic Fibrosis
2007, Clinics in Chest Medicine
Citation Excerpt :
Similar, but less marked, abnormalities in drug absorption have been described with tacrolimus administration in patients who have CF, with monitoring of tacrolimus levels 3 hours after administration suggested as optimal [82,83]. Finally, cell cycle inhibitors, such as mycophenolic acid, which are used as a second arm in immune suppression postlung transplantation, are absorbed to lesser degrees in patients who have CF, and higher doses may be required to achieve optimal effect [84]. Other considerations in lung transplant recipients who have CF include vitamin deficiencies and osteoporosis prevention.
Transplantation in patients who have cystic fibrosis (CF) presents important challenges regarding candidate selection and preoperative management, technical obstacles in the perioperative period, the postoperative management of medical comorbidities related to CF, and the psychosocial impact of transplantation. This article outlines some of these challenges and describes recent advances in approaching this endeavor in patients who have CF.
Simple high performance liquid chromatographic assay for mycophenolic acid in renal transplant patients
2007, Journal of Pharmaceutical and Biomedical Analysis
A selective and highly accurate HPLC-UV method is described to determine plasma concentrations of mycophenolic acid (MPA), the active metabolite of the prodrugs Cellcept^® and Myfortic^®. The method is simple and utilizes acidification of plasma and protein precipitation step using a mixture of acetonitrile and phosphate buffer (pH 3). Following vortex mixing and centrifugation, the supernatant (50 μL) was injected onto a Zorbax Eclipse XDB C₁₈ column (150 mm × 4.6 mm I.D., 5 μm particle size). A mobile phase composed of acetonitrile and 0.1 M phosphate buffer, pH 3 (43:57) delivered at 1.0 mL/min produced peaks for MPA and the internal standard (Naproxen) in <7 min. Calibration curves were linear (r² > 0.994) from 1.0–40 μg/mL with intra- and inter-day precision <15% and accuracy >95%. The method's improved sensitivity (LOQ = 1.0 μg/mL) and minimal sample processing allowed rapid monitoring of MPA in human plasma.
Preventing Cardiac Allograft Vasculopathy: Long-term Beneficial Effects of Mycophenolate Mofetil
2006, Journal of Heart and Lung Transplantation
The impact of long-term mycophenolate mofetil (MMF) treatment on the development of cardiac allograft vasculopathy (CAV) after heart transplantation is an area of much recent interest. This study analyzed the effects of various immunosuppressive combinations, including cyclosporine (CsA), azathioprine (Aza), tacrolimus (Tac) and MMF, on the time of onset, extent and progression of CAV.
Two hundred seventy-three consecutive heart transplant recipients (mean age: 51.2 ± 12.2 years; mean follow-up: 6.8 ± 1.9 years) were examined by coronary angiography on a yearly basis between 1995 and 2003. The extent of CAV was evaluated using a scoring system based on the severity of vessel stenosis. The onset of CAV was analyzed using Kaplan–Meier estimates and the log rank test for four treatment combinations, CsA/Aza (n = 47, 17.2%), CsA/MMF (n = 26, 9.5%), Tac/Aza (n = 62, 22.7%) and Tac/MMF (n = 138, 50.5%), and for the primary and the secondary immunosuppressants alone.
The rate of freedom from CAV at 5 years was 47% with CsA/Aza, 66% with CsA/MMF, 60% with Tac/Aza and 70% with Tac/MMF. After 5 years, the Tac/MMF group showed a significantly lower incidence of CAV than the CsA/Aza group (log rank 7.58, p = 0.0059). CsA (n = 73) was compared with Tac (n = 200) and MMF (n = 164) with Aza (n = 109): the rate of freedom from CAV was 51.2% in CsA patients vs 66.1% in Tac patients (log rank 5.7, p = 0.017), and 54.6% in Aza patients vs 67% in MMF patients (log rank 4.36, p = 0.037). Multivariate Cox regression analysis revealed that MMF decreased the incidence of CAV significantly (p = 0.041). In this patient cohort, Tac or CsA medication was not an independent risk factor for incidence of CAV nor for decreased survival.
The choice of immunosuppression has an impact on the incidence of CAV. In terms of prevention of CAV, MMF is superior to Aza in either combination. A trend toward improved survival in MMF patients was noted. The lower number of rejection episodes in the MMF groups may have contributed to these results.
Therapeutic Drug Monitoring of Prednisolone After Lung Transplantation
2006, Journal of Heart and Lung Transplantation
Despite well-known and serious potential side-effects of corticosteroid therapy, therapeutic drug monitoring (TDM) of prednisolone is rarely performed after lung transplantation (LTx).
We measured prednisolone exposure using a 6-hour area-under-the-curve (AUC) analysis in 52 LTx recipients (41 bilateral, 9 single and 2 heart–lung), who were 99 ± 13 (mean ± SEM) weeks (range 4 to 380) post-LTx. Fourteen of 52 had cystic fibrosis (CF), and 36 of 52 were on cyclosporine and 16 of 52 on tacrolimus. Prednisolone dose was 9.8 ± 0.7 mg/day (range 1 to 20).
Only 9 of 52 LTx patients had a prednisolone AUC within the previously reported reference range for healthy adult control subjects (170 to 260 nmol.hr/liter/milligram prednisolone). Six patients had values below and 37 above this range. Prednisolone AUC was higher in patients with CF compared with non-CF patients (511 ± 82 vs 349 ± 27 nmol.hr/liter/milligram, p < 0.02) and 70% of LTx recipients had measurable prednisolone levels at baseline (26.5 ± 4.5 nmol/liter), unlike normal controls.
LTx recipients show a wide inter-individual variation in prednisolone pharmacokinetics; therefore, many are overdosed on conventional protocols. Side-effects of corticosteroid therapy remain a major clinical problem after transplantation, justifying the use of prednisolone TDM to optimize dosing and minimize morbidity.

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^☆: This study was partially supported by a research grant form Roche Pharma (Switzerland) AG, Reinach.

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Brief communicationPharmacokinetics of mycophenolic acid associated with calcineurin inhibitors: long-term monitoring in stable lung recipients with and without cystic fibrosis☆

Abstract

Section snippets

Methods

Results

Discussion

Transplant Proc

Transplant Proc

Transplant Proc

Drug interaction between mycophenolate mofetil and tacrolimus detectable within therapeutic mycophenolic acid monitoring in renal transplant patients

Ther Drug Monit

Brief communication
Pharmacokinetics of mycophenolic acid associated with calcineurin inhibitors: long-term monitoring in stable lung recipients with and without cystic fibrosis☆