Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
Pharmacotherapeutic group: immunosuppressive agents
ATC code: L04AA06
Mycophenolate mofetil is the 2-morpholinoethyl ester of MPA. MPA is a selective, uncompetitive and reversible inhibitor of IMPDH, and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines whereas other cell types can utilise salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells. In addition to its inhibition of IMPDH and the resulting deprivation of lymphocytes, MPA also influences cellular checkpoints responsible for metabolic programming of lymphocytes. It has been shown, using human CD4+ T-cells, that MPA shifts transcriptional activities in lymphocytes from a proliferative state to catabolic processes relevant to metabolism and survival leading to an anergic state of T-cells, whereby the cells become unresponsive to their specific antigen.
Following oral administration, mycophenolate mofetil undergoes rapid and extensive absorption and complete presystemic metabolism to the active metabolite, MPA. As evidenced by suppression of acute rejection following renal transplantation, the immunosuppressant activity of mycophenolate mofetil is correlated with MPA concentration. The mean bioavailability of oral mycophenolate mofetil, based on MPA AUC, is 94% relative to intravenous mycophenolate mofetil. Food had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g BID to renal transplant patients. However, MPA Cmax was decreased by 40% in the presence of food. Mycophenolate mofetil is not measurable systemically in plasma following oral administration.
As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually observed at approximately 6-12 hours post-dose. A reduction in the AUC of MPA of approximately 40% is associated with the co-administration of cholestyramine (4 g TID), indicating that there is a significant amount of enterohepatic recirculation. MPA at clinically relevant concentrations is 97% bound to plasma albumin.
In the early post-transplant period (<40 days post-transplant), renal, cardiac and hepatic transplant patients had mean MPA AUCs approximately 30% lower and Cmax approximately 40% lower compared to the late post-transplant period (3-6 months post-transplant).
MPA is metabolised principally by glucuronyl transferase (isoform UGT1A9) to form the inactive phenolic glucuronide of MPA (MPAG). In vivo, MPAG is converted back to free MPA via enterohepatic recirculation. A minor acylglucuronide (AcMPAG) is also formed. AcMPAG is pharmacologically active and is suspected to be responsible for some of mycophenolate mofetil’s side effects (diarrhoea, leukopenia).
A negligible amount of substance is excreted as MPA (<1% of the dose) in the urine. Oral administration of radiolabelled mycophenolate mofetil results in complete recovery of the administered dose with 93% of the administered dose recovered in the urine and 6% recovered in the faeces. Most (about 87%) of the administered dose is excreted in the urine as MPAG.
At clinically encountered concentrations, MPA and MPAG are not removed by haemodialysis. However, at high MPAG plasma concentrations (>100 μg/ml), small amounts of MPAG are removed. By interfering with enterohepatic recirculation of the drug, bile acid sequestrants such as cholestyramine reduce MPA AUC (see section 4.9).
MPA’s disposition depends on several transporters. Organic anion-transporting polypeptides (OATPs) and multidrug resistance-associated protein 2 (MRP2) are involved in MPA’s disposition; OATP isoforms, MRP2 and breast cancer resistance protein (BCRP) are transporters associated with the glucuronides' biliary excretion. Multidrug resistance protein 1 (MDR1) is also able to transport MPA, but its contribution seems to be confined to the absorption process. In the kidney, MPA and its metabolites potently interact with renal organic anion transporters.
Enterohepatic recirculation interferes with accurate determination of MPA’s disposition parameters; only apparent values can be indicated. In healthy volunteers and patients with autoimmune disease approximate clearance values of 10.6 L/h and 8.27 L/h respectively and half-life values of 17 h were observed. In transplant patients mean clearance values were higher (range 11.9-34.9 L/h) and mean half-life values shorter (5-11 h) with little difference between renal, hepatic or cardiac transplant patients. In the individual patients, these elimination parameters vary based on type of co-treatment with other immunosuppressants, time post-transplantation, plasma albumin concentration and renal function. These factors explain why reduced exposure to mycophenolate is seen when mycophenolate mofetil is co-administered with ciclosporin (see section 4.5) and why plasma concentrations tend to increase over time compared to what is observed immediately after transplantation.
In a single dose study (6 subjects/group), mean plasma MPA AUC observed in subjects with severe chronic renal impairment (glomerular filtration rate <25 ml/min/1.73 m²) were 28–75% higher relative to the means observed in normal healthy subjects or subjects with lesser degrees of renal impairment. The mean single dose MPAG AUC was 3–6-fold higher in subjects with severe renal impairment than in subjects with mild renal impairment or normal healthy subjects, consistent with the known renal elimination of MPAG. Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied. No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.
In patients with delayed renal graft function post-transplant, mean MPA AUC0-12h was comparable to that seen in post-transplant patients without delayed graft function. Mean plasma MPAG AUC0-12h was 2–3-fold higher than in post-transplant patients without delayed graft function. There may be a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. Dose adjustment of mycophenolate mofetil does not appear to be necessary.
In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on these processes probably depend on the particular disease. Hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect.
In 33 paediatric renal allograft recipients it was established that the dose predicted to provide an MPA AUC0-12h closest to the target exposure of 27.2 h⋅mg/l was 600 mg/m², and that doses calculated based on estimated BSA reduced interindividual variability (coefficient of variation, (CV)) by about 10%. Therefore, dosing based on BSA is preferred rather than dosing based on body weight.
Pharmacokinetic parameters were evaluated in up to 55 paediatric renal transplant patients (aged 1 to 18 years) given 600 mg/m², up to 1 g/m² of mycophenolate mofetil orally twice daily. This dose achieved MPA AUC values similar to those seen in adult renal transplant patients receiving mycophenolate mofetil at a dose of 1 g BID in the early and late post-transplant period as per Table 3 below. MPA AUC values across paediatric age groups were similar in the early and late post-transplant period.
For paediatric hepatic transplant recipients an open-label study of the safety, tolerability and pharmacokinetics of oral mycophenolate mofetil included 7 evaluable patients on concomitant ciclosporin and corticosteroid treatment. The dose predicted to achieve an exposure of 58 h⋅mg/l in the stable post-transplant period was estimated. The mean ± SD AUC0-12h (adjusted to a dose of 600 mg/m²) was 47.0±21.8 h⋅mg/l, adjusted Cmax was 14.5±4.21 mg/l, with a median time to maximum concentration of 0.75 h. To achieve the target AUC0-12h of 58 h⋅mg/l in the late post-transplant period, a dose in the range of 740-806 mg/m² BID would therefore have been required in the study population.
A comparison of dose-normalised (to 600 mg/m²) MPA AUC values in 12 paediatric renal transplant patients less than 6 years of age at 9 months post-transplant with those values in 7 paediatric hepatic transplant patients [median age 17 months (range: 10-60 months at enrolment)] at 6 months and beyond post-transplant revealed that, at the same dose, the AUC values were on average 23% lower in the paediatric hepatic patients compared to paediatric renal patients. This is consistent with the need for higher dosing in adult hepatic transplant patients compared to adult renal transplant patients to achieve the same exposure.
In adult transplant patients administered the same dosage of mycophenolate mofetil, there is similar MPA exposure among renal transplant and cardiac transplant patients. In line with the established similarity in MPA exposure between paediatric renal transplant and adult renal transplant patients at their respective approved doses, existing data allows to conclude that MPA exposure at the recommended dosage will be similar in paediatric cardiac transplant, and adult cardiac transplant patients.
Table 3. Mean computed MPA PK parameters by age and time post-transplant (renal):
Age group (n) | Adjusted Cmax mg/lA mean ± SD | Adjusted AUC0-12 h⋅mg/l mean ± SD (CI)A |
---|---|---|
Day 7 | ||
<6 y (17) | 13.2±7.16 | 27.4±9.54 (22.8-31.9) |
6 - <12 y (16) | 13.1±6.30 | 33.2±12.1 (27.3-39.2) |
12-18 y (21) | 11.7±10.7 | 26.3±9.14 (22.3-30.3)D |
p-valueB | - | - |
<2 yC (6) | 10.3±5.80 | 22.5±6.68 (17.2-27.8) |
>18 y (141) | 27.2±11.6 | |
Month 3 | ||
<6 y (15) | 22.7±10.1 | 49.7±18.2 |
6 - <12 y (14)E | 27.8±14.3 | 61.9±19.6 |
12-18 y (17) | 17.9±9.57 | 53.6±20.2F |
p-valueB | - | - |
<2 yC (4) | 23.8±13.4 | 47.4±14.7 |
>18 y (104) | 50.3±23.1 | |
Month 9 | ||
<6 y (12) | 30.4±9.16 | 60.9±10.7 |
6 - <12 y (11) | 29.2±12.6 | 66.8±21.2 |
12-18 y (14) | 18.1±7.29 | 56.7±14.0 |
p-valueB | 0.004 | - |
<2 yC (4) | 25.6±4.25 | 55.8±11.6 |
>18 y (70) | 53.5±18.3 |
AUC0-12h = area under the plasma concentration-time curve from time 0 h to time 12 h; CI = confidence interval; Cmax = maximum concentration; MPA = mycophenolic acid; SD = standard deviation; n=number of patients; y = year.
A In the paediatric age groups Cmax and AUC0-12h are adjusted to a dose of 600 mg/m² (95% confidence intervals (Cls) for AUC0-12h Day 7 only); in the adult group AUC0-12h is adjusted to a dose of 1 g.
B p-value represents the combined p-values for the three major paediatric age groups, and is noted only if significant (p<0.05).
C The <2-year group is a subset of the <6-year group: no statistical comparisons were made.
D n=20.
E Data for one patient was unavailable due to sampling error.
F n=16.
The pharmacokinetics of mycophenolate mofetil and its metabolites have not been found to be altered in the elderly patients (≥65 years) when compared to younger transplant patients.
A study of the co-administration of mycophenolate mofetil (1 g BID) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.20 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) conducted in 18 non-transplant women (not taking other immunosuppressants) over 3 consecutive menstrual cycles showed no clinically relevant influence of mycophenolate mofetil on the ovulation-suppressing action of the oral contraceptives. Serum levels of LH, FSH and progesterone were not significantly affected. The pharmacokinetics of oral contraceptives were not affected to a clinically relevant degree by co-administration of mycophenolate mofetil (see also section 4.5).
In experimental models, mycophenolate mofetil was not tumourigenic. The highest dose tested in the animal carcinogenicity studies resulted in approximately 2–3 times the systemic exposure (AUC or Cmax) observed in renal transplant patients at the recommended clinical dose of 2 g/day and 1.3–2 times the systemic exposure (AUC or Cmax) observed in cardiac transplant patients at the recommended clinical dose of 3 g/day.
Two genotoxicity assays (in vitro mouse lymphoma assay and in vivo mouse bone marrow micronucleus test) showed a potential of mycophenolate mofetil to cause chromosomal aberrations. These effects can be related to the pharmacodynamic mode of action, i.e. inhibition of nucleotide synthesis in sensitive cells. Other in vitro tests for detection of gene mutation did not demonstrate genotoxic activity.
In teratology studies in rats and rabbits, foetal resorptions and malformations occurred in rats at 6 mg/kg/day (including anophthalmia, agnathia, and hydrocephaly) and in rabbits at 90 mg/kg/day (including cardiovascular and renal anomalies, such as ectopia cordis and ectopic kidneys, and diaphragmatic and umbilical hernia), in the absence of maternal toxicity. The systemic exposure at these levels is approximately equivalent to or less than 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients (see section 4.6).
The haematopoietic and lymphoid systems were the primary organs affected in toxicology studies conducted with mycophenolate mofetil in the rat, mouse, dog and monkey. These effects occurred at systemic exposure levels that are equivalent to or less than the clinical exposure at the recommended dose of 2 g/day for renal transplant recipients. Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent to or less than the clinical exposure at the recommended dose. Gastrointestinal and renal effects consistent with dehydration were also observed in the monkey at the highest dose (systemic exposure levels equivalent to or greater than clinical exposure). The non-clinical toxicity profile of mycophenolate mofetil appears to be consistent with adverse events observed in human clinical trials, which now provide safety data of more relevance to the patient population (see section 4.8).
Environmental risk assessment studies have shown that the active substance, MPA may pose a risk for groundwater via bank filtration.
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