Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: immunosuppressant, ATC code: L04AA06

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.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Following oral administration, mycophenolate sodium is extensively absorbed. Consistent with its enteric coated design, the time to maximal concentration (Tmax) of MPA was approximately 1.5-2 hours. Approximately 10% of all morning pharmacokinetic profiles showed a delayed Tmax, 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%.
Myfortic 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 Myfortic 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 (Cmax). Moreover, Tlag and Tmax were on average 3-5 hours delayed, with several patients having a Tmax of >15 hours. The effect of food on Myfortic 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 Myfortic 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 Myfortic 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 Myfortic.
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 Myfortic. In the early post transplant period, mean MPA AUC and mean MPA Cmax were approximately one-half of the values measured six months post transplant.

Table 2     Mean (SD) pharmacokinetic parameters for MPA following oral administration of Myfortic to renal transplant patients on ciclosporin-based immunosuppression
Adult                           Dose          Tmax *      Cmax              AUC 0-12 chronic, multiple dosing                      (h)         (g/ml)           (g x h/ml) 720 mg BID
(Study ERLB 301) n=48
14 days post-transplant      720 mg        2           13.9 (8.6)        29.1 (10.4) 
3 months post-transplant      720 mg          2          24.6 (13.2)         50.7 (17.3) 
6 months post-transplant      720 mg          2          23.0 (10.1)         55.7 (14.6) 
Adult                           Dose            Tmax *     Cmax                AUC 0-12 chronic, multiple dosing                        (h)        (g/ml)             (g x h/ml) 720 mg BID                      720 mg          1.5        18.9 (7.9)          57.4 (15.0) 18 months post-transplant
(Study ERLB 302) n=18
Paediatric                      Dose            Tmax *     Cmax                AUC o- 450 mg/m2 single dose                           (h)        (g/ml)             (g x h/ml)
(Study ERL 0106)                450 mg/m  2
2.5        31.9 (18.2)         74.5 (28.3) n=16
* 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 Myfortic 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 Myfortic. The mean apparent clearance of MPA was approximately 6.7 l/h/m2.

Gender
There are no clinically significant gender differences in Myfortic 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.