Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: immunosuppressive agents ATC code L04AA06

Mechanism of action
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.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties
Absorption
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 CellCept is correlated with MPA concentration. The mean bioavailability of oral mycophenolate mofetil, based on MPA AUC, is 94% relative to IV 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.

Distribution
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).


Biotransformation
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 MMF´s side effects (diarrhoea, leukopenia).

Elimination
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 is seen when CellCept is co-administered with cyclosporine (see section 4.5) and why plasma concentrations tend to increase over time compared to what is observed immediately after transplantation.
Special populations

Renal impairment
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.

Delayed renal graft function
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 CellCept does not appear to be necessary.

Hepatic impairment
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.

Paediatric population
Pharmacokinetic parameters were evaluated in 49 paediatric renal transplant patients (aged 2 to 18 years) given 600 mg/m2 mycophenolate mofetil orally twice daily. This dose achieved MPA AUC values similar to those seen in adult renal transplant patients receiving CellCept at a dose of 1 g BID in the early and late post-transplant period. MPA AUC values across age groups were similar in the early and late post-transplant period.

Elderly
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.

Patients taking oral contraceptives
A study of the co-administration of CellCept (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 CellCept 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 CellCept (see also section 4.5).