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Myfortic

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Myfortic

Myfortic

CLINICAL PHARMACOLOGY

Mechanism of Action

Mycophenolic acid (MPA), an immunosuppressant, 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. 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 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

Myfortic exhibits linear and dose-proportional pharmacokinetics over the dose-range (360 to 2160 mg) evaluated. The absolute bioavailability of Myfortic in stable renal transplant patients on cyclosporine was 72%. MPA is highly protein bound ( > 98% bound to albumin). The predominant metabolite of MPA is the phenolic glucuronide (MPAG) which is pharmacologically inactive. A minor metabolite AcMPAG which is an acyl glucuronide of MPAG is also formed and has pharmacological activity comparable to MPA. MPAG undergoes renal elimination. A fraction of MPAG also undergoes biliary excretion, followed by deconjugation by gut flora and subsequent reabsorption as MPA. The mean elimination half-lives of MPA and MPAG ranged between 8 and 16 hours, and 13 and 17 hours, respectively.

Absorption

In vitro studies demonstrated that the enteric-coated Myfortic 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 MMF, 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 presystemic 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 to 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 (Cmax), 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].

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 6. 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 twice daily and MMF 1000 mg twice daily (739 mg as MPA) in both the single- and multiple-dose cross-over trials, mean systemic MPA exposure (AUC) was similar.

Table 6: Mean ± SD Pharmacokinetic Parameters for MPA Following the Oral Administration of Myfortic to Renal Transplant Patients on Cyclosporine, USP MODIFIED Based Immunosuppression

Patient Myfortic Dosing N Dose (mg) Tmax*(h) Cmax (mcg/mL) AUC (0-12h) (mcg*h/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, twice daily 10 720 2 (1.5–3.0) 37.0 ± 13.3 67.9 ± 20.3
Adult Multiple x 28 days, twice daily 36 720 2.5 (1.5–8) 31.2 ± 18.1 71.2 ± 26.3
Adult Chronic, multiple dose, twice daily          
  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, twice daily 18 720 1.5 (0–6) 18.9 ± 7.9 57.4 ± 15.0
*median (range),
**AUCinf,
***age range of 5–16 years

Specific Populations

Renal Insufficiency: No specific pharmacokinetic studies in individuals with renal impairment were conducted with Myfortic. However, based on studies of renal impairment with MMF, 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 (MMF 1000 mg) trial 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 trial were compared. However, it should be noted that for unexplained reasons, the healthy volunteers in this trial had about a 50% lower AUC compared to healthy volunteers in other studies, thus making comparison between volunteers with alcoholic cirrhosis and healthy 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 to 16 years, on cyclosporine, USP MODIFIED are shown in Table 6. 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 [see DOSAGE AND ADMINISTRATION].

Gender: There are no significant gender differences in Myfortic pharmacokinetics.

Elderly: Pharmacokinetics in the elderly have not been formally studied.

Ethnicity: Following a single dose administration of 720 mg of Myfortic to 18 Japanese and 18 Caucasian healthy subjects, the exposure (AUCinf) for MPA and MPAG were 15% and 22% lower in Japanese subjects compared to Caucasians. The peak concentrations (Cmax) for MPAG were similar between the two populations, however, Japanese subjects had 9.6% higher Cmax for MPA. These results do not suggest any clinically relevant differences.

Drug Interactions

Antacids with Magnesium and Aluminum Hydroxides

Absorption of a single dose of Myfortic was decreased when administered to 12 stable kidney transplant patients also taking magnesium-aluminum-containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions [see DRUG INTERACTIONS].

Pantoprazole

In a trial conducted in 12 healthy volunteers, the pharmacokinetics of MPA were observed to be similar when a single dose of 720 mg of Myfortic was administered alone and following concomitant administration of Myfortic and pantoprazole, which was administered at a dose of 40 mg twice daily for 4 days [see DRUG INTERACTIONS].

The following drug interaction studies were conducted following the administration of MMF:

Cholestyramine

Following single-dose oral administration of 1.5 grams MMF to 12 healthy volunteers pretreated with 4 grams three times daily of cholestyramine for 4 days, MPA AUC decreased approximately 40%. This decrease is consistent with interruption of enterohepatic recirculation which may be due to binding of recirculating MPAG with cholestyramine in the intestine [see DRUG INTERACTIONS].

Sevelamer

Concomitant administration of sevelamer and MMF in stable adult and pediatric kidney transplant patients decreased the mean MPA Cmax and AUC(0-12h) by 36% and 26% respectively [see DRUG INTERACTIONS].

Cyclosporine

Cyclosporine (Sandimmune®) pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.5 grams twice daily of MMF in 10 stable kidney transplant patients. The mean (±SD) AUC (0-12h) and Cmax of cyclosporine after 14 days of multiple doses of MMF were 3290 (±822) ng•h/mL and 753 (±161) ng/mL, respectively, compared to 3245 (±1088) ng•h/mL and 700 (±246) ng/mL, respectively, 1 week before administration of MMF.

A total of 73 de novo kidney allograft recipients on MMF therapy received either low dose cyclosporine withdrawal by 6 months post-transplant (50 to 100 ng/mL for up to 3 months post-transplant followed by complete withdrawal at month 6 post-transplant) or standard dose cyclosporine (150 to 300 ng/mL from baseline through to month 4 post-transplant and 100 to 200 ng/mL thereafter). At month 12 post-transplant, the mean MPA (AUC(0-12h)) in the cyclosporine withdrawal group was approximately 40% higher, than that of the standard dose cyclosporine group.

Cyclosporine inhibits multidrug-resistance-associated protein 2 (MRP-2) transporter in the biliary tract, thereby preventing the excretion of MPAG into the bile that would lead to enterohepatic recirculation of MPA [see DRUG INTERACTIONS].

Norfloxacin and Metronidazole

Following single-dose administration of MMF (1 g) to 11 healthy volunteers on day 4 of a 5-day course of a combination of norfloxacin and metronidazole, the mean MPA AUC(0-48h) was reduced by 33% compared to the administration of MMF alone (p < 0.05). There was no significant effect on mean MPA AUC(0-48h) when MMF was concomitantly administered with norfloxacin or metronidazole separately. The mean (±SD) MPA AUC(0-48h) after coadministration of MMF with norfloxacin or metronidazole separately was 48.3 (±24) mcg•h/mL and 42.7 (±23) mcg•h/mL, respectively, compared with 56.2 (±24) mcg•h/mL after administration of MMF alone [see DRUG INTERACTIONS].

Rifampin

In a single heart-lung transplant patient on MMF therapy (1 gram twice daily), a 67% decrease in MPA exposure (AUC(012h)) was observed with concomitant administration of MMF and 600 mg rifampin daily.

In 8 kidney transplant patients on stable MMF therapy (1 gram twice daily), administration of 300 mg rifampin twice daily resulted in a 17.5% decrease in MPA AUC(0-12h) due to inhibition of enterohepatic recirculation of MPAG by rifampin. Rifampin coadministration also resulted in a 22.4% increase in MPAG AUC(0-12h) [see DRUG INTERACTIONS].

Oral Contraceptives

In a drug-drug interaction trial, mean AUCs were similar for ethinyl estradiol and norethindrone, when coadministered with MMF as compared to administration of the oral contraceptives alone [see DRUG INTERACTIONS].

Acyclovir

Coadministration of MMF (1 gram) and acyclovir (800 mg) to 12 healthy volunteers resulted in no significant change in MPA AUC and Cmax. However, MPAG and acyclovir plasma mean AUC(0-24h) were increased 10% and 18%, respectively. Because MPAG plasma concentrations are increased in the presence of kidney impairment, as are acyclovir concentrations, the potential exists for mycophenolate and acyclovir or its prodrug (e.g., valacyclovir) to compete for tubular secretion, further increasing the concentrations of both drugs [see DRUG INTERACTIONS].

Ganciclovir

Following single-dose administration to 12 stable kidney transplant patients, no pharmacokinetic interaction was observed between MMF (1.5 grams) and intravenous ganciclovir (5 mg per kg). Mean (±SD) ganciclovir AUC and Cmax (n=10) were 54.3 (±19.0) mcg•h/mL and 11.5 (±1.8) mcg/mL, respectively, after coadministration of the two drugs, compared to 51.0 (±17.0) mcg•h/mL and 10.6 (±2.0) mcg/mL, respectively, after administration of intravenous ganciclovir alone. The mean (±SD) AUC and Cmax of MPA (n=12) after coadministration were 80.9 (±21.6) mcg•h/mL and 27.8 (±13.9) mcg/mL, respectively, compared to values of 80.3 (±16.4) mcg•h/mL and 30.9 (±11.2) mcg/mL, respectively, after administration of MMF alone.

Because MPAG plasma concentrations are increased in the presence of renal impairment, as are ganciclovir concentrations, the two drugs will compete for tubular secretion and thus further increases in concentrations of both drugs may occur. In patients with renal impairment in which MMF and ganciclovir or its prodrug (e.g., valganciclovir) are coadministered, patients should be monitored carefully [see DRUG INTERACTIONS].

Ciprofloxacin and Amoxicillin plus Clavulanic Acid

A total of 64 MMF treated kidney transplant recipients received either oral ciprofloxacin 500 mg twice daily or amoxicillin plus clavulanic acid 375 mg three times daily for 7 or at least 14 days. Approximately 50% reductions in median trough MPA concentrations (predose) from baseline (MMF alone) were observed in 3 days following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. These reductions in trough MPA concentrations tended to diminish within 14 days of antibiotic therapy and ceased within 3 days after discontinuation of antibiotics. The postulated mechanism for this interaction is an antibiotic-induced reduction in glucuronidase-possessing enteric organisms leading to a decrease in enterohepatic recirculation of MPA. The change in trough level may not accurately represent changes in overall MPA exposure; therefore, clinical relevance of these observations is unclear [see DRUG INTERACTIONS].

Clinical Studies

Prophylaxis of Organ Rejection in Patients Receiving Allogeneic Renal Transplants

The safety and efficacy of Myfortic in combination with cyclosporine, USP MODIFIED and corticosteroids for the prevention of organ rejection was assessed in two multicenter, randomized, double-blind, active-controlled trials in de novo and conversion renal transplant patients compared to MMF.

The de novo trial was conducted in 423 renal transplant patients (ages 18–75 years) in Austria, Canada, Germany, Hungary, Italy, Norway, Spain, UK, and USA. Eighty-four percent of randomized patients received kidneys from deceased donors. Patients were excluded if they had second or multiorgan (e.g., kidney and pancreas) transplants, or previous transplant with any other organs; kidneys from non-heart beating donors; panel reactive antibodies (PRA) of > 50% at last assessment prior to transplantation, and presence of severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus. Patients were administered either Myfortic 1.44 grams per day or MMF 2 grams per 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 MMF-treated patients at 6 and 12 months (Table 7). The cumulative incidence of graft loss, death and lost to follow-up at 12 months is also shown in Table 7.

Table 7: 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 grams per day
(n=213)
mycophenolate mofetil (MMF) 2 grams per 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 MMF patients)
#95% confidence interval of the difference in treatment failure at 6 months (Myfortic–MMF) is (-8.7%, 8.0%).
##95% confidence interval of the difference in treatment failure at 12 months (Myfortic–MMF) is (-8.0%, 9.1%).

The conversion trial was conducted in 322 renal transplant patients (ages 18–75 years), who were at least 6 months post-transplant and had undergone primary or secondary, deceased donor, living related, or unrelated donor kidney transplant, stable graft function (serum creatinine < 2.3 mg/mL), no change in immunosuppressive regimen due to graft malfunction, and no known clinically significant physical and/or laboratory changes for at least 2 months prior to enrollment. Patients were excluded if they had 3 or more kidney transplants, multiorgan transplants (e.g., kidney and pancreas), previous organ transplants, evidence of graft rejection or who had been treated for acute rejection within 2 months prior to screening, clinically significant infections requiring continued therapy, presence of severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus.

Patients received 2 grams per day MMF in combination with cyclosporine USP MODIFIED, with or without corticosteroids for at least two weeks prior to entry in the trial. Patients were randomized to Myfortic 1.44 grams per day or MMF 2 grams per day for 12 months. The trial 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 MMF-treated patients (Table 8). The cumulative incidence of graft loss, death and lost to follow-up at 12 months is also shown in Table 8.

Table 8: Treatment Failure in Conversion 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 grams per day
(n=159)
mycophenolate mofetil (MMF) 2 grams per 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 MMF patients)
#95% confidence interval of the difference in treatment failure at 6 months (Myfortic–MMF) is (-7.3%, 2.7%).
##95% confidence interval of the difference in treatment failure at 12 months (Myfortic–MMF) is (-11.2%, 1.8%).

Last reviewed on RxList: 10/14/2013
This monograph has been modified to include the generic and brand name in many instances.

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