Mycophenolic acid

Mycophenolic acid (MPA) is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, 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 utilize salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.

Absorption

Following oral administration, mycophenolate sodium is extensively absorbed. Consistent with its enteric coated design, the time to maximal concentration (T_max) of MPA was approximately 1.5-2 hours. Approximately 10% of all morning pharmacokinetic profiles showed a delayed T_max, sometimes up to several hours, without any expected impact on 24 hour/daily MPA exposure.

In stable renal transplant patients on ciclosporin based immunosuppression, the gastrointestinal absorption of MPA was 93% and the absolute bioavailability was 72%. Mycophenolic acid pharmacokinetics are dose proportional and linear over the studied dose range of 180 to 2,160 mg.

Compared to the fasting state, administration of a single dose of mycophenolic acid 720 mg with a high fat meal (55 g fat, 1,000 calories) had no effect on the systemic exposure of MPA (AUC), which is the most relevant pharmacokinetic parameter linked to efficacy. However there was a 33% decrease in the maximal concentration of MPA (C_max). Moreover, T_lag and T_max were on average 3-5 hours delayed, with several patients having a T_max of >15 hours. The effect of food on mycophenolic acid may lead to an absorption overlap from one dose interval to another. However, this effect was not shown to be clinically significant.

Distribution

The volume of distribution at steady state for MPA is 50 litres. Both mycophenolic acid and mycophenolic acid glucuronide are highly protein bound (97% and 82%, respectively). The free MPA concentration may increase under conditions of decreased protein binding sites (uraemia, hepatic failure, hypoalbuminaemia, concomitant use of drugs with high protein binding). This may put patients at increased risk of MPA-related adverse effects.

Biotransformation

MPA is metabolised principally by glucuronyl transferase to form the phenolic glucuronide of MPA, mycophenolic acid glucuronide (MPAG). MPAG is the predominant metabolite of MPA and does not manifest biological activity. In stable renal transplant patients on ciclosporin-based immunosuppression, approximately 28% of the oral mycophenolic acid dose is converted to MPAG by presystemic metabolism. The half life of MPAG is longer than that of MPA, approximately 16 hours, and its clearance is 0.45 l/h.

Elimination

The half life of MPA is approximately 12 hours and the clearance is 8.6 l/h. Although negligible amounts of MPA are present in the urine (<1.0%), the majority of MPA is eliminated in the urine as MPAG. MPAG secreted in the bile is available for deconjugation by gut flora. The MPA resulting from this deconjugation may then be reabsorbed. Approximately 6-8 hours after mycophenolic acid dosing a second peak of MPA concentration can be measured, consistent with reabsorption of the deconjugated MPA. There is large variability in the MPA trough levels inherent to MPA preparations, and high morning trough levels (C₀>10 µg/ml) have been observed in approximately 2% of patients treated with mycophenolic acid. However, across studies, the AUC at steady state (0-12h) which is indicative of the overall exposure showed a lower variability than the one corresponding to Ctrough.

Pharmacokinetics in renal transplant patients on ciclosporin-based immunosuppression

Shown in Table 2 are mean pharmacokinetic parameters for MPA following the administration of mycophenolic acid. In the early post transplant period, mean MPA AUC and mean MPA C_max were approximately one-half of the values measured six months post transplant.

Table 2. Mean (SD) pharmacokinetic parameters for MPA following oral administration of mycophenolic acid to renal transplant patients on ciclosporin-based immunosuppression:

* median values

Renal impairment

MPA pharmacokinetics appeared to be unchanged over the range of normal to absent renal function. In contrast, MPAG exposure increased with decreased renal function; MPAG exposure being approximately 8 fold higher in the setting of anuria. Clearance of either MPA or MPAG was unaffected by haemodialysis. Free MPA may also significantly increase in the setting of renal failure. This may be due to decreased plasma protein binding of MPA in the presence of high blood urea concentration.

Hepatic impairment

In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on this process probably depend on the particular disease. However, hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect.

Paediatric population and adolescents

Limited data are available on the use of mycophenolic acid in children and adolescents. In Table 2 above the mean (SD) MPA pharmacokinetics are shown for stable paediatric renal transplant patients (aged 5-16 years) on ciclosporin-based immunosuppression. Mean MPA AUC at a dose of 450 mg/m² was similar to that measured in adults receiving 720 mg mycophenolic acid. The mean apparent clearance of MPA was approximately 6.7 l/h/m².

Gender

There are no clinically significant gender differences in mycophenolic acid pharmacokinetics.

Older people

Pharmacokinetics in the elderly have not formally been studied. MPA exposure does not appear to vary to a clinically significant degree by age.

The haematopoetic and lymphoid system were the primary organs affected in repeated-dose toxicity studies conducted with mycophenolate sodium in rats and mice. Aplastic, regenerative anemia was identified as being the dose-limiting toxicity in rodents exposed to MPA. Evaluation of myelograms showed a marked decrease in erythroid cells (polychromatic erythroblasts and normoblasts) and a dose-dependent enlargement of the spleen and increase in extramedullary hematopoiesis. These effects occurred at systemic exposure levels which are equivalent to or less than the clinical exposure at the recommended dose of 1.44 g/day of mycophenolic acid in renal transplant patients.

Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent to or less than the clinical exposure at the recommended doses.

The non-clinical toxicity profile of mycophenolic acid (as sodium salt) appears to be consistent with adverse events observed in human clinical trials which now provide safety data of more relevance to the patient population.

Three genotoxicity assays (in vitro mouse lymphoma assay, micronucleus test in V79 Chinese hamster cells and in vivo mouse bone marrow micronucleus test) showed a potential of mycophenolic acid 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.

Mycophenolic acid (as sodium salt) was not tumourigenic in rats and mice. The highest dose tested in the animal carcinogenicity studies resulted in approximately 0.6-5 times the systemic exposure (AUC or C_max) observed in renal transplant patients at the recommended clinical dose of 1.44 g/day.

Mycophenolic acid (as sodium salt) had no effect on fertility of male or female rats up to dose levels at which general toxicity and embryotoxicity were observed.

In a teratology study performed with mycophenolic acid (as sodium salt) in rats, at a dose as low as 1 mg/kg, malformations in the offspring were observed, including anophthalmia, exencephaly and umbilical hernia. The systemic exposure at this dose represents 0.05 times the clinical exposure at the dose of 1.44 g/day of mycophenolic acid.

In a pre- and postnatal development study in rat, mycophenolic acid (as sodium salt) caused developmental delays (abnormal pupillary reflex in females and preputial separation in males) at the highest dose of 3 mg/kg that also induced malformations.

Mycophenolic acid (as sodium salt) showed a phototoxic potential in an in vitro 3T3 NRU phototoxicity assay.