CLINICAL PHARMACOLOGY
Mechanism of Action
MPA is an uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation to 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 potent cytostatic effects on lymphocytes.
Mycophenolate sodium has been shown to prevent the occurrence of acute rejection in rat models of kidney and heart allotransplantation. Mycophenolate sodium also decreases antibody production in mice.
Pharmacokinetics
Absorption
In vitro studies demonstrated that the enteric-coated Myfortic® (mycophenolic acid) tablet does not release MPA under acidic conditions (pH <5) as in the stomach but is highly soluble in neutral pH conditions as in the intestine. Following Myfortic oral administration without food in several pharmacokinetic studies conducted in renal transplant patients, consistent with its enteric-coated formulation, the median delay (Tlag) in the rise of MPA concentration ranged between 0.25 and 1.25 hours and the median time to maximum concentration (Tmax) of MPA ranged between 1.5 and 2.75 hours. In comparison, following the administration of mycophenolate mofetil, the median Tmax ranged between 0.5 and 1.0 hours. In stable renal transplant patients on cyclosporine, USP (MODIFIED) based immunosuppression, gastrointestinal absorption and absolute bioavailability of MPA following the administration of Myfortic delayed-release tablet was 93% and 72%, respectively. Myfortic pharmacokinetics is dose proportional over the dose range of 360 to 2160 mg.
Distribution
The mean (± SD) volume of distribution at steady state and elimination phase for MPA is 54 (± 25) L and 112 (± 48) L, respectively. MPA is highly protein bound to albumin, >98%. The protein binding of mycophenolic acid glucuronide (MPAG) is 82%. The free MPA concentration may increase under conditions of decreased protein binding (uremia, hepatic failure, and hypoalbuminemia).
Metabolism
MPA is metabolized principally by glucuronyl transferase to glucuronidated metabolites. The phenolic glucuronide of MPA, mycophenolic acid glucuronide (MPAG), is the predominant metabolite of MPA and does not manifest pharmacological activity. The acyl glucuronide is a minor metabolite and has comparable pharmacological activity to MPA. In stable renal transplant patients on cyclosporine, USP (MODIFIED) based immunosuppression, approximately 28% of the oral Myfortic dose was converted to MPAG by pre-systemic metabolism. The AUC ratio of MPA:MPAG:acyl glucuronide is approximately 1:24:0.28 at steady state. The mean clearance of MPA was 140 (± 30) mL/min.
Elimination
The majority of MPA dose administered is eliminated in the urine primarily as MPAG (>60%) and approximately 3% as unchanged MPA following Myfortic administration to stable renal transplant patients. The mean renal clearance of MPAG was 15.5 (± 5.9) mL/min. MPAG is also secreted in the bile and available for deconjugation by gut flora. MPA resulting from the deconjugation may then be reabsorbed and produce a second peak of MPA approximately 6 – 8 hours after Myfortic dosing. The mean elimination half-life of MPA and MPAG ranged between 8 and 16 hours, and 13 and 17 hours, respectively.
Food Effect
Compared to the fasting state, administration of Myfortic 720 mg with a high-fat meal (55 g fat, 1000 calories) had no effect on the systemic exposure (AUC) of MPA. However, there was a 33% decrease in the maximal concentration (C max), a 3.5-hour delay in the Tlag (range, -6 to 18 hours), and 5.0-hour delay in the Tmax (range, -9 to 20 hours) of MPA. To avoid the variability in MPA absorption between doses, Myfortic should be taken on an empty stomach (see DOSAGE AND ADMINISTRATION and PRECAUTIONS, Information for Patients).
Pharmacokinetics in Renal Transplant Patients
The mean pharmacokinetic parameters for MPA following the administration of Myfortic in renal transplant patients on cyclosporine, USP (MODIFIED) based immunosuppression are shown in Table 1. Single-dose Myfortic pharmacokinetics predicts multiple-dose pharmacokinetics. However, in the early post-transplant period, mean MPA AUC and Cmax were approximately one-half of those measured 6 months post-transplant.
After near equimolar dosing of Myfortic 720 mg BID and mycophenolate mofetil 1000 mg BID (739 mg as MPA) in both the single- and multiple-dose cross-over trials, mean systemic MPA exposure (AUC) was similar.
Table 1 Mean ± SD Pharmacokinetic Parameters for MPA Following the Oral Administration of Myfortic® to Renal Transplant Patients on Cyclosporine, USP (MODIFIED) Based Immunosuppression
| Study Patient | Myfortic®
Dosing | n | Dose (mg) | Tmax* (hr) | Cmax (µg/mL) | AUC0-12hr (µg*hr/mL) |
| Adult | Single | 24 | 720 | 2 (0.8 – 8) | 26.1 ± 12.0 | 66.5 ± 22.6** |
| Pediatric*** | Single | 10 | 450 /m2 | 2.5 (1.5 – 24) | 36.3 ± 20.9 | 74.3 ± 22.5** |
| Adult | Multiple x 6 days, BID | 10 | 720 | 2 (1.5 – 3.0) | 37.0 ± 13.3 | 67.9 ± 20.3 |
| Adult | Multiple x 28 days, BID | 36 | 720 | 2.5 (1.5 – 8) | 31.2 ± 18.1 | 71.2 ± 26.3 |
| Adult | Chronic, multiple dose, BID | | | | | |
| 2 weeks post-transplant | 12 | 720 | 1.8 (1.0 – 5.3) | 15.0 ± 10.7 | 28.6 ± 11.5 |
| 3 months post-transplant | 12 | 720 | 2 (0.5 – 2.5) | 26.2 ± 12.7 | 52.3 ± 17.4 |
| 6 months post-transplant | 12 | 720 | 2 (0 – 3) | 24.1 ± 9.6 | 57.2 ± 15.3 |
| Adult | Chronic, multiple dose, BID | 18 | 720 | 1.5 (0 – 6) | 18.9 ± 7.9 | 57.4 ± 15.0 |
| *median (range), ** AUC0-∞, *** age range of 5 – 16 years |
Special Populations
Renal Insufficiency : No specific pharmacokinetic studies in individuals with renal impairment were conducted with Myfortic. However, based on studies of renal impairment with mycophenolate mofetil, MPA exposure is not expected to be appreciably increased over the range of normal to severely-impaired renal function following Myfortic administration. In contrast, MPAG exposure would be increased markedly with decreased renal function; MPAG exposure being approximately 8-fold higher in the setting of anuria. Although dialysis may be used to remove the inactive metabolite MPAG, it would not be expected to remove clinically significant amounts of the active moiety MPA. This is in large part due to the high plasma protein binding of MPA.
Hepatic Insufficiency: No specific pharmacokinetic studies in individuals with hepatic impairment were conducted with Myfortic. In a single dose (mycophenolate mofetil 1000 mg) study of 18 volunteers with alcoholic cirrhosis and 6 healthy volunteers, hepatic MPA glucuronidation processes appeared to be relatively unaffected by hepatic parenchymal disease when the pharmacokinetic parameters of healthy volunteers and alcoholic cirrhosis patients within this study were compared. However, it should be noted that for unexplained reasons, the healthy volunteers in this study had about a 50% lower AUC compared to healthy volunteers in other studies, thus making comparison between volunteers with alcoholic cirrhosis and health volunteers difficult. Effects of hepatic disease on this process probably depend on the particular disease. Hepatic disease, such as primary biliary cirrhosis, with other etiologies may show a different effect.
Pediatrics: Limited data are available on the use of Myfortic at a dose of 450 mg/m2 body surface area in children. The mean MPA pharmacokinetic parameters for stable pediatric renal transplant patients, 5–16 years, on cyclosporine, USP (MODIFIED) are shown in Table 1. At the same dose administered based on body surface area, the respective mean Cmax and AUC of MPA determined in children were higher by 33% and 18% than those determined for adults. The clinical impact of the increase in MPA exposure is not known.
Gender: There are no significant gender differences in Myfortic pharmacokinetics.
Elderly: Pharmacokinetics in the elderly have not been formally studied.
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CLINICAL STUDIES
The safety and efficacy of Myfortic® (mycophenolic acid) in combination with cyclosporine, USP (MODIFIED) and corticosteroids for the prevention of organ rejection was assessed in two multicenter, randomized, double-blind trials in de novo and maintenance renal transplant patients compared to mycophenolate mofetil.
The de novo study was conducted in 423 renal transplant patients (ages 18-75 years) in Austria, Canada, Germany, Hungary, Italy, Norway, Spain, UK and USA. Cadaveric donor specimens accounted for 84% of randomized patients. Patients were administered either Myfortic 1.44 g/day or mycophenolate mofetil 2 g/day within 48 hours post-transplant for 12 months in combination with cyclosporine, USP (MODIFIED) and corticosteroids. Forty-one percent of patients received antibody therapy as induction treatment. Treatment failure was defined as the first occurrence of biopsy-proven acute rejection, graft loss, death or lost to follow-up at 6 months. The incidence of treatment failure was similar in Myfortic- and mycophenolate mofetil-treated patients at 6 and 12 months (Table 2). The cumulative incidence of graft loss, death and lost to follow-up at 12 months is also given in Table 2.
Table 2 Treatment Failure in de novo Renal Transplant Patients (Percent of Patients) at 6- and 12-Months of Treatment when Administered in Combination with Cyclosporine* and Corticosteroids
| Myfortic®
1.44 g/day
(n=213) | mycophenolate mofetil
2 g/day
(n=210) |
| 6 Months | n (%) | n (%) |
| Treatment failure# | 55 (25.8) | 55 (26.2) |
| Biopsy-proven acute rejection | 46 (21.6) | 48 (22.9) |
| Graft loss | 7 (3.3) | 9 (4.3) |
| Death | 1 (0.5) | 2 (1.0) |
| Lost to follow-up** | 3 (1.4) | 0 |
| 12 Months | n (%) | n (%) |
| Graft loss or death or lost to follow up*** | 20 (9.4) | 18 (8.6) |
| Treatment failure | 61 (28.6) | 59 (28.1) |
| Biopsy-proven acute rejection | 48 (22.5) | 51 (24.3) |
| Graft loss | 9 (4.2) | 9 (4.3) |
| Death | 2 (0.9) | 5 (2.4) |
| Lost to follow-up** | 5 (2.3) | 0 |
*USP (MODIFIED)
**Lost to follow-up indicates patients who were lost to follow-up without prior biopsy-proven acute rejection, graft loss or death
***Lost to follow-up indicates patients who were lost to follow-up without prior graft loss or death (9 Myfortic patients and 4 mycophenolate mofetil patients)
#95% confidence interval of the difference in treatment failure at 6 months (Myfortic – mycophenolate mofetil) is (-8.7%, 8.0%). |
The maintenance study was conducted in 322 renal transplant patients (ages 18–75 years), who were at least 6 months post-transplant receiving 2 g/day mycophenolate mofetil in combination with cyclosporine USP (MODIFIED), with or without corticosteroids for at least two weeks prior to entry in the study. Patients were randomized to Myfortic 1.44 g/day or mycophenolate mofetil 2 g/day for 12 months. The study was conducted in Austria, Belgium, Canada, Germany, Italy, Spain, and USA. Treatment failure was defined as the first occurrence of biopsy-proven acute rejection, graft loss, death, or lost to follow-up at 6 and 12 months. The incidences of treatment failure at 6 and 12 months were similar between Myfortic- and mycophenolate mofetil-treated patients (Table 3). The cumulative incidence of graft loss, death and lost to follow-up at 12 months is also given in Table 3.
Table 3 Treatment Failure in Maintenance Transplant Patients (Percent of Patients) at 6- and 12-Months of Treatment when Administered in Combination with Cyclosporine* and with or without Corticosteroids
| Myfortic®
1.44 g/day
(n = 159) | mycophenolate mofetil
2 g/day
(n = 163) |
| 6 Months | n (%) | n (%) |
| Treatment failure# | 7 (4.4) | 11 (6.7) |
| Biopsy-proven acute rejection | 2 (1.3) | 2 (1.2) |
| Graft loss | 0 | 1 (0.6) |
| Death | 0 | 1 (0.6) |
| Lost to follow-up** | 5 (3.1) | 7 (4.3) |
| 12 Months | n (%) | n (%) |
| Graft loss or death or lost to follow-up*** | 10 (6.3) | 17 (10.4) |
| Treatment failure | 12 (7.5) | 20 (12.3) |
| Biopsy-proven acute rejection | 2 (1.3) | 5 (3.1) |
| Graft loss | 0 | 1 (0.6) |
| Death | 2 (1.3) | 4 (2.5) |
| Lost to follow-up** | 8 (5.0) | 10 (6.1) |
*USP (MODIFIED)
**Lost to follow-up indicates patients who were lost to follow-up without prior biopsy-proven acute rejection, graft loss, or death
***Lost to follow-up indicates patients who were lost to follow-up without prior graft loss or death (8 Myfortic patients and 12 mycophenolate mofetil patients)
#95% confidence interval of the difference in treatment failure at 6 months (Myfortic – mycophenolate mofetil) is (7.4%, 2.7%). |
The safety and efficacy of Myfortic has not been studied in hepatic or cardiac transplant trials.
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