Beoordelingsrapport mycofenolaat mofetil

Transcriptie

1 Beoordelingsrapport mycofenolaat mofetil Veiligheid en doseeradvies Conclusie: Child-Pugh A+B: geen nadelige effecten bekend Child-Pugh C: onbekend Dosering: Child-Pugh A+B: Aanpassing van de dosering is niet nodig Child-Pugh C: Doseeradvies niet mogelijk Toelichting: De farmacokinetiek van mycofenolaat mofetil lijkt weinig beïnvloed te worden door cirrose, waardoor de dosering niet aangepast hoeft te worden. Het is alleen onderzocht bij patiënten met Child-Pugh A- en B-cirrose en daarbij werden geen extra nadelige effecten waargenomen. Er zijn geen onderzoeken gedaan in patiënten met een ernstige cirrose (Child-Pugh C) en daarom kan er ook geen doseeradvies worden gegeven voor deze patiënten. Samenvatting literatuur Overwegingen: Er zijn drie studies (bewijsniveau 3,4) gedaan naar de veiligheid van mycofenolaat mofetil (MMF) bij 45 patiënten met levercirrose. De kinetiek van MMF lijkt bijna niet beïnvloed te worden door Child- Pugh (CTP) A- en B-cirrose. De bijwerkingen uit de veiligheidsstudies zijn vergelijkbaar met bijwerkingen bij mensen zonder cirrose en zijn met name immuungerelateerd (aften en infecties) of hebben betrekking op het bloedbeeld (leukopenie). Vanwege de ongewijzigde kinetiek en een vergelijkbaar bijwerkingenprofiel als bij mensen zonder cirrose, krijgt MMF de status geen nadelige effecten bekend bij CTP A- en B-patiënten. Omdat er geen onderzoek gedaan is bij patiënten met CTP C krijgt MMF de categorie onbekend bij deze patiënten. Omdat er geen veranderingen in de kinetiek zijn waargenomen, wordt er geen dosisaanpassing aanbevolen. Deskundigen gaven aan in de praktijk therapeutic drug monitoring toe te passen bij het gebruik van MMF bij cirrose. Farmacokinetische gegevens Absorptie: Mycofenolaat mofetil wordt presystemisch omgezet in mycofenolzuur (MPA). De systemische beschikbaarheid is goed (94%). In de farmacokinetische studie van Parker bij met name patiënten met CTP A bleek dat de C max en de t max van MPA niet verschillend waren bij deze patiënten in vergelijking met gezonde vrijwilligers. Deze studie staat ook genoemd in het FDA-label. Distributie: MPA is sterk gebonden aan albumine (97%) in het plasma. Parker en collega s suggereren dat levercirrose geen invloed heeft op de vrije fractie MPA, ze baseren dit echter op gegevens van cirrotische patiënten met een normale albumine concentratie. Uit andere studies (niet bij patiënten met cirrose) bleek dat hypoalbuminemie wel degelijk invloed heeft op de vrije fractie MPA. Deze vrije fractie bleek verhoogd bij een verminderde hoeveelheid albumine, waardoor de klaring toenam en de blootstelling (AUC) afnam. Metabolisme: Mycofenolzuur wordt voornamelijk geglucuronideerd tot het inactieve mycofenolzuur glucuronidine (MPAG), waarna het via enterohepatische circulatie weer wordt omgezet in MPA. De vorming van het MPAG lijkt vertraagd te zijn bij cirrose. Uit één studie bleek dat ook de hoeveelheid bilirubine van invloed was op de kinetiek van MPA. Een verhoogd bilirubine kan de vorming van MPAG verminderen en de transport en biliaire excretie verminderen tijdens cholestase. Dit werd echter tegengesproken in een andere studie, waarbij geen relatie tussen het bilirubine en de AUC van MPA werd gevonden. Eliminatie: Minder dan 1% wordt uitgescheiden als MPA in de urine. Het grootste deel (87%) wordt uitgescheiden als MPAG in de urine, 6% wordt nog teruggevonden in de feces. Uit de literatuur bleek dat de renale excretie van MPAG verhoogd was, wat correleerde met de ernst van de cirrose. De enterohepatische circulatie neemt waarschijnlijk af met de ernst van de cirrose, waardoor meer renaal wordt geklaard. Veiligheid De veiligheid van MMF bij patiënten met cirrose is onderzocht in drie studies. In deze studies werden met name bijwerkingen gemeld die vergelijkbaar zijn met mensen zonder cirrose; namelijk immuungerelateerde bijwerkingen (aften, sepsis, luchtweginfecties en herpes zoster). In een studie werd de behandeling bij twee cirrotische patiënten (8%) gestaakt vanwege de bijwerkingen (sepsis). Bij drie cirrotische patiënten (12%) in dezelfde studie trad er leukopenie op, wat ook een bekende bijwerking is en die verdween na het verlagen van de dosering. In het algemeen adviseert de fabrikant het bloedbeeld met enige regelmaat te controleren (met name in het eerste jaar). 1

2 Beoordelingsrapport mycofenolaat mofetil 1. Farmacokinetische gegevens (SPC) Section CellCept, 250 mg capsules EPAR 5.2 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. 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. Metabolism 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, leucopenia). Elimination A negligible amount of substance is excreted as MPA (< 1% of 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. 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. 4.2 Posology No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease. No data are available for cardiac transplant patients with severe hepatic parenchymal disease. 2

3 Section CellCept, 250 mg capsules FDA Label Absorption Oral absorption of the drug is rapid and essentially complete. In 12 healthy volunteers, the mean absolute bioavailability of oral mycophenolate mofetil relative to intravenous mycophenolate mofetil (based on MPA AUC) was 94%. The AUC for MPA appears to increase in a dose-proportional fashion in renal transplant patients receiving multiple doses of mycophenolate mofetil up to a daily dose of 3 g. Distribution The mean (±SD) apparent volume of distribution of MPA in 12 healthy volunteers is approximately 3.6 (±1.5) and 4.0 (±1.2) L/kg following intravenous and oral administration, respectively. MPA, at clinically relevant concentrations, is 97% bound to plasma albumin. MPAG is 82% bound to plasma albumin at MPAG concentration ranges that are normally seen in stable renal transplant patients; however, at higher MPAG concentrations, the binding of MPA may be reduced as a result of competition between MPAG and MPA for protein binding. Mean blood to plasma ratio of radioactivity concentrations was approximately 0.6 indicating that MPA and MPAG do not extensively distribute into the cellular fractions of blood. Metabolism MMF undergoes complete metabolism to MPA, the active metabolite. Metabolism to MPA occurs presystemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. In vivo, MPAG is converted to MPA via enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil to healthy subjects: N-(2- carboxymethyl)-morpholine, N-(2- hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)- morpholine. Secondary peaks in the plasma MPA concentration-time profile are usually observed 6 to 12 h postdose. Elimination Negligible amount of drug is excreted as MPA (100 µg/ml), small amounts of MPAG are removed. Bile acid sequestrants, such as cholestyramine, reduce MPA AUC by interfering with enterohepatic circulation of the drug. Mean (±SD) apparent half-life and plasma clearance of MPA are 17.9 (±6.5) hours and 193 (±48) ml/min following oral administration and 16.6 (±5.8) hours and 177 (±31) ml/min following intravenous administration, respectively. Hepatic insufficiency In a single-dose (1 g oral) 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 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 as compared to healthy volunteers in other studies, thus making comparisons between volunteers with alcoholic cirrhosis and healthy volunteers difficult. Effects of hepatic disease on this process probably depend on the particular disease. Hepatic disease with other etiologies, such as primary biliary cirrhosis, may show a different effect. In a single-dose (1 g intravenous) study of 6 volunteers with severe hepatic impairment (aminopyrine breath test less than 0.2% of dose) due to alcoholic cirrhosis, MMF was rapidly converted to MPA. MPA AUC was 44.1 µg h/ml (±15.5). Posology No dose adjustments are recommended for renal patients with severe hepatic parenchymal disease. However, it is not known whether dose adjustments are needed for hepatic disease with other etiologies. 3

4 2. Literatuuronderzoek Zoektermen Pubmed ("Liver cirrhosis"[mesh] OR cirrho*[ti] OR "hepatic impairment"[ti] OR liver impairment [ti] OR hepatic dysfunction [ti] OR liver dysfunction [ti] OR hepatic insufficiency [ti] OR liver insufficiency [ti]) AND ("mycophenolate mofetil" [Supplementary Concept] OR "mycophenolate mofetil"[tiab]) AND "humans"[mesh Terms] Embase 'liver cirrhosis'/exp/mj OR cirrho*:ti OR 'hepatic impairment':ti OR 'liver impairment':ti OR 'hepatic dysfunction':ti OR 'liver dysfunction':ti OR 'hepatic insufficiency':ti OR 'liver insufficiency':ti NOT 'primary biliary cirrhosis'/exp/mj AND ('mycophenolate mofetil'/exp OR 'mycophenolate mofetil' OR 'mycophenolate mofetil':ab,ti) AND [humans]/lim Zoekstrategie Publicaties gevonden in databases Pubmed: n= 76 Embase: n=135 Titel en abstract gescreend (n= 211) Aantal exclusies (n=200) - Geen cirrose (n= 179) o AIH (n=11) o Hepatitis (n=5) o Transplantatie (n=142) o Cholest. leverziekte (n=16) o Anders (n=5) - Niet specifiek MMF (n=21) Dubbele publicaties verwijderd (n=3) Volledige artikelen geraadpleegd (n= 8) Aantal exclusies (n=6) - Niet specifiek cirrose (n=3) - Niet specifiek MMF (n=1) - Andere uitkomst (n=1) - Niet beschikbaar (n=1) Aanvullende publicaties gevonden in andere bronnen: Referentielijsten: n=0 Citation tracking via Web of Science: n=3 Anders: n=1 Artikelen opgenomen in kwalitatieve synthese n=6 4

5 3. Samenvatting belangrijkste onderzoeken Uitkomsten farmacokinetische studies Level of evidence 3 Parker; 1996 Design Intervention Openlabel parrallel group study Reference Single dose of 1 gram MMF Results Healthy controls Degree of hepatic APBT impairment a Mild Moderate Severe MPA n=6 n=6 n=6 n=6 Cmax (µg/ml) 24.3± ± ± ±9.0 Ratio AUC(0-96h) (µg.h/ml) 29.0± ± ± ±14.4 Ratio tmax (h) 0.6± ± ± ±0.3 MMF excreted (%) 0.6± ± ± ±1.5 ClR 0-24 (ml/min) 1.5± ± ± ±5.2 MPAG Cmax (µg/l) 31.4± ± ± ±5.5 Ratio AUCtotal (µg.h/l) 261± ± ± ±44.4 Ratio tmax (h) 1.3± ± ± ±0.5 t1/2 (h) 12.5± ± ± ±2.0 MMF excreted (%) 46.7± ± ± ±11.1 ClR0-24 (ml/min) 25.0± ± ± ±25.2 Remarks All patients had cirrhosis, mostly CTP-A (n=15) except for 3 CTP-B subjects in the severe group Protein binding of MPA appears to be only marginally affected by cirrhosis (nb. but albumin levels were normal in these subjects) Plasma concentrations of MPA in patients with cirrhosis (all groups) were higher at 2, 3 and 4 hours compared to healthy controls. This suggests an effect on metabolism of MPA 8 patients reported 10 adverse events, only apothous stomatitis was felt to be drug-related The enterohepatic circulation of MPAG seems to be reduced in cirrhosis, as seen by the increase in renal clearance of MPAg The creatinine clearance was somewhat lower in the group with moderatie impairment, compared with other groups Results are expressed as mean±sd. APBT= aminopyrine breath test, MPA=mycophenolic acid, MMF excreted= percentage of mycophenolate mofetil excreted in urine as MPA or MPAG, MPAG= mycophenolic acid glucuronide conjugate, ratio= ratio [cirrhotic patients/healthy controls]. a. Aminopyrine breath test was used to classify patients by degree of hepatic oxidative impairment. This test measured the percentage of a radiolabeled dose of aminopyrine exhaled in the breath during a 30-minute period. Mild, moderate, and severe impairment were defined as 0.4 to 0.6%, 0.2 to 0.39%, and <0.2% of dose exhaled, respectively. 5

6 Uitkomsten studies naar veiligheid Level of evidence 3 Reference Zachou; Design Patients Intervention Prospective cohort study Autoimmune hepatitis (n=158; cirrhosis n=50) 73-year-old woman with Ierardi; HCV related 4 Case-report 2003 liver cirrhosis and mild protal hypertension HCV= hepatitis C virus, MMF=mycophenolate mofetil Prednisolone + MMF g daily (n=109; cirrhosis n=26) Started with 1 g MMF per day for an autoimmune hemolytic anemia Control Results Remarks Prednisolone + azathioprine mg/kg/day - In general, MMF was well tolerated In only 2 cirrhotic patients, MMF was discontinued because of septicaemia. 4 patients reported mild gastrointestinal symptoms, which were temporary and did not need dose reduction. 5 patients developed leukopenia during treatment, 3 of whom had also mild thrombocytopenia. 3 of these 5 patients were already cirrhotic at diagnosis, whereas the remaining had severe fibrosis. MMF was reduced in all of them (5) without on-going problems 6 patients developed respiratory tract infections and 2 herpes zoster. Although none of these 8 patients needed hospitalisation, MMF was stopped temporary and started gradually to the standard dose, 15 days after recovery without new side effects. Overall, discontinuation or permanent reduction in MMF was observed in 2/109 (1.8%) and 5/109 (4.6%), respectively. MMF was well tolerated and no relevant side effects were observed Study from 2008 is small cohort of total study from 2016 Appr. 1/3 of patients suffered from cirrhosis (severity not specified) 6

7 Uitkomsten reviews Level of evidence Reference Outcome Expert opinion Chen; 2014 De Jonge; 2009 Staatz; 2007 Pharmacokinetic parameters Pharmacokinetic parameters Pharmacokinetic parameters Impairment of liver function has complex effects on mycophenolic acid (MPA) kinetics, although cirrhosis affects neither MPA absorption nor MPA plasma protein binding or pharmacokinetics [study Parker 1996]. It is believed that free MPA levels are affected by hypoalbuminemia, uremia and hyperbilirubinemia. Chen et al showed that MPA AUC0-12h in patients with abnormal albumin levels were significantly lower than that in patients with normal albumin levels (P=0.009). MPA AUC0-12h was related significantly with serum albumin levels (r 2 =0.412, P=0.001). However, other parameters of hepatic function including total serum bilirubin concentration did not influence the change of MPA AUC0-12h. In 8 liver graft recipients, Jain et al reported that MPA AUC correlated with serum bilirubin and MPA C0h with albumin concentration [Jain, Clin Pharmacol 2001; 41: ]. Higher serum bilirubin levels may impair hepatic mycophenolic acid glucuronide (MPAG) production, transport and biliary excretion during cholestasis. The decreased hepatic glucuronidation and enterohepatic recirculation with moderate hepatic impairment may result in increased urinary MPAG concentrations [Jain, Clin Pharmacol 2001; 41: ]. Tredger et al showed that recipients with low serum albumin levels (<35 g/l) frequently failed to achieve the therapeutic levels of MPA [Tredger, Liver Transpl 2004; 10: ]. In adults and children with lower serum albumin concentrations, median levels of MPA C0h were 42% and 19%, respectively, of those in patients with normal serum albumin levels given corresponding doses (P<0.001). However, another study [Brunet et al] showed no relationship between liver function tests and MPA exposure. Hepatic impairment: mycophenolic acid (MPA) AUC MPA clearance Decreased serum albumin leading to increased MPA free fraction and MPA clearance and/or decreased enterohepatic MPA(G) recirculation In a single-dose pharmacokinetic study of oral mycophenolate mofetil in 18 patients with compensated alcoholic cirrhosis, cirrhosis did not significantly affect the pharmacokinetic profile of MPA or MPAG compared with controls [study Parker 1996]. It was suggested that reduced hepatic glucuronidation of MPA may be compensated by enhanced renal glucuronidation. It should be noted, however, that healthy control subjects in this investigation had approximately 50% lower MPA AUC compared with healthy volunteers in other studies. According to manufacturer recommendations, no mycophenolate adjustment is required for patients with hepatic parenchymal disease. To date, it is not known whether mycophenolate dosage should be altered in patients with disease of a different aetiology, such as primary biliary cirrhosis. Given the central role of the liver in the pharmacokinetics of mycophenolate, more research is required in this area. T-tube clamping did not affect the pharmacokinetics of MPA or MPAG over one dosing interval in eight liver transplant recipients on concomitant tacrolimus and corticosteroid therapy. 7

8 4. Alle publicaties uit literatuursearch 1. Parker G, et al. Pharmacokinetics of oral mycophenolate mofetil in volunteer subjects with varying degrees of hepatic oxidative impairment. J Clinic Pharmacol (4) 2. Zachou K, et al. A real world study focused on the long term efficacy of mycophenolate mofetil as first line treatment of autoimmune hepatitis. Alim Pharmacol & Therap Ierardi E, et al. Mycophenolate mofetil in the treatment of autoimmune HCV-associated haematological disorders showing steroid resistance or dependence. J Vir Hepatitis (5): Chen, et al. Clinical mycophenolic acid monitoring in liver transplant recipients. World Journal of Gastroenterology (31): de Jonge, H et al. New insights into the pharmacokinetics and pharmacodynamics of the calcineurin inhibitors and mycophenolic acid: possible consequences for therapeutic drug monitoring in solid organ transplantation. Therap drug monit 31.4 (2009): Staatz, C et al. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokin (1): Tredger JM, et al. Monitoring mycophenolate in liver transplant recipients: toward a therapeutic range. Liver transplantation 10.4 (2004): Jain A, et al. Pharmacokinetics of mycophenolic acid after mycophenolate mofetil administration in liver transplant patients treated with tacrolimus. The Journal of Clinical Pharmacology 41.3 (2001):