How cyclosporine reduces mycophenolic acid exposure by 40% while other calcineurin inhibitors do not

Abstract

The most frequently used immunosuppressive treatment in kidney transplant recipients is the combination therapy of a calcineurin inhibitor (CNI) and mycophenolate mofetil, with or without corticosteroids. Cyclosporine and tacrolimus are the 2 CNIs registered for this indication. Also, in the treatment of glomerular diseases, CNIs and mycophenolate are being used on a worldwide scale, either alone or as combined treatment. In January 2021, the US Food and Drug Administration approved voclosporin, a novel CNI, for the treatment of adult patients with active lupus nephritis. There is a clinically relevant drug–drug interaction between cyclosporine and mycophenolate. As a result of cyclosporine-induced inhibition of the enterohepatic recirculation of mycophenolate, the mycophenolic acid area under the curve is significantly lower (40%) in case of cyclosporine coadministration compared with cotreatment with either tacrolimus or voclosporin (or no CNI cotreatment). The aim of this mini review is to summarize this potential drug–drug interaction and explain how cyclosporine affects the pharmacokinetics of mycophenolate. The optimal dose of mycophenolate mofetil is likely to depend on the CNI with which it is coadministered. Furthermore, clinical implications are discussed, including the potential emergence of mycophenolic acid–related adverse effects after discontinuation of cyclosporine cotreatment. The most frequently used immunosuppressive treatment in kidney transplant recipients is the combination therapy of a calcineurin inhibitor (CNI) and mycophenolate mofetil, with or without corticosteroids. Cyclosporine and tacrolimus are the 2 CNIs registered for this indication. Also, in the treatment of glomerular diseases, CNIs and mycophenolate are being used on a worldwide scale, either alone or as combined treatment. In January 2021, the US Food and Drug Administration approved voclosporin, a novel CNI, for the treatment of adult patients with active lupus nephritis. There is a clinically relevant drug–drug interaction between cyclosporine and mycophenolate. As a result of cyclosporine-induced inhibition of the enterohepatic recirculation of mycophenolate, the mycophenolic acid area under the curve is significantly lower (40%) in case of cyclosporine coadministration compared with cotreatment with either tacrolimus or voclosporin (or no CNI cotreatment). The aim of this mini review is to summarize this potential drug–drug interaction and explain how cyclosporine affects the pharmacokinetics of mycophenolate. The optimal dose of mycophenolate mofetil is likely to depend on the CNI with which it is coadministered. Furthermore, clinical implications are discussed, including the potential emergence of mycophenolic acid–related adverse effects after discontinuation of cyclosporine cotreatment. Mycophenolic acid (MPA) was developed as an immunosuppressive drug by Anthony Allison and Elsie Eugui.1Allison A.C. Eugui E.M. Mycophenolate mofetil and its mechanisms of action.Immunopharmacology. 2000; 47: 85-118Crossref PubMed Scopus (1066) Google Scholar MPA inhibits inosine monophosphate dehydrogenase, the rate-limiting enzyme in the de novo synthesis of guanosine nucleotides. MPA has a relatively strong effect on lymphocytes because it is a more potent inhibitor of the type II isoform of inosine monophosphate dehydrogenase. The type II isoform is more expressed in activated lymphocytes than the type I isoform of inosine monophosphate dehydrogenase, which is expressed in most other cell types. MPA has poor bioavailability, but this was solved by addition of the morpholinoethyl ester. The resulting mycophenolate mofetil (MMF) proved suitable for pharmaceutical formulation. Clinical development started after demonstration of treatment of heart transplant rejection in an experimental model.2Morris R.E. Hoyt E.G. Murphy M.P. et al.Mycophenolic acid morpholinoethylester (RS-61443) is a new immunosuppressant that prevents and halts heart allograft rejection by selective inhibition of T- and B-cell purine synthesis.Transplant Proc. 1990; 22: 1659-1662PubMed Google Scholar MMF is a prodrug, and the active metabolite is MPA. Three phase 3 randomized clinical trials led to the registration of MMF for the prevention of kidney allograft rejection in the mid-1990s.3Halloran P. Mathew T. Tomlanovich S. et al.The International Mycophenolate Mofetil Renal Transplant Study Groups. Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection.Transplantation. 1997; 63: 39-47Crossref PubMed Scopus (534) Google Scholar In all 3 studies, a standard dose of 1000 mg twice a day (bid) MMF was combined with cyclosporine. Within a couple of years, MMF had almost completely replaced azathioprine as an antiproliferative immunosuppressive drug for this indication. Also in the mid-1990s, tacrolimus was introduced as a new calcineurin inhibitor (CNI). A meta-analysis of 30 randomized trials reported that at 1 year post-transplant, tacrolimus-treated patients had 31% less acute rejection (relative risk, 0.69; 95% confidence interval, 0.60–0.79), less steroid-resistant rejection (relative risk, 0.49; 95% confidence interval, 0.37–0.64), and better graft survival with tacrolimus compared with cyclosporine.4Webster A.C. Woodroffe R.C. Taylor R.S. et al.Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data.BMJ. 2005; 331: 810Crossref PubMed Scopus (443) Google Scholar After the publication of the Efficacy Limiting Toxicity Elimination (ELITE)–Symphony study, tacrolimus gradually took over from cyclosporine.5Ekberg H. Tedesco-Silva H. Demirbas A. et al.ELITE-Symphony StudyReduced exposure to calcineurin inhibitors in renal transplantation.N Engl J Med. 2007; 357: 2562-2575Crossref PubMed Scopus (1391) Google Scholar Two years later, the Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommended tacrolimus as the first-choice CNI in kidney transplant recipients.6Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work GroupKDIGO clinical practice guideline for the care of kidney transplant recipients.Am J Transplant. 2009; 9: S1-S155PubMed Google Scholar At present, the combined use of tacrolimus and MMF is the most frequently used maintenance treatment after solid organ transplantation. In the recent KDIGO clinical practice guideline on glomerular diseases, CNIs are suggested as treatment options in children with steroid-resistant nephrotic syndrome, and in adults with treatment-resistant membranous nephropathy, minimal change nephropathy, and focal segmental glomerulosclerosis.7Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Disease Work GroupKDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases.Kidney Int. 2021; 100: S1-S276Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar Although tacrolimus is the first-choice CNI in organ transplantation, cyclosporine is widely used in the treatment of several forms of glomerulonephritis. In January 2021, voclosporin was the first CNI to be approved by the US Food and Drug Administration for treatment of adult patients with active lupus nephritis. In the phase 2 and phase 3 studies, the addition of voclosporin on top of the standard of care (MMF and steroids) significantly increased renal response at 1 year.8Rovin B.H. Solomons N. Pendergraft 3rd, W.F. et al.AURA-LV Study GroupA randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis.Kidney Int. 2019; 95: 219-231Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar,9Rovin B.H. Teng Y.K.O. Ginzler E.M. et al.Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.Lancet. 2021; 397: 2070-2080Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar A comparison of the efficacy and safety of tacrolimus and cyclosporine, if combined with MMF, is not just a comparison of 2 CNIs. The exposure to the active metabolite of MMF, MPA, differs substantially between the 2 regimens. The higher MPA concentrations associated with the use of tacrolimus will certainly contribute to the overall success of the combined treatment. There is a clinically relevant drug–drug interaction between MMF and the CNIs. With new treatment options entering the market, this mini review aims to highlight the existence of this drug–drug interaction, with emphasis on the underlying molecular mechanism and the clinical consequences. In 1997, a study in kidney transplant patients reported that MPA concentrations differed between tacrolimus and cyclosporine cotreatment.10Zucker K. Rosen A. Tsaroucha A. et al.Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings.Transpl Immunol. 1997; 5: 225-232Crossref PubMed Scopus (200) Google Scholar Besides higher MPA concentrations in the tacrolimus-treated patients, significantly lower levels of the glucuronide metabolite of MPA (MPAG) were also found. The authors suggested that tacrolimus had an inhibitory effect on the glucuronidation of MPA. A couple of years thereafter, it was shown that it was not tacrolimus that increased MPA exposure, but in fact cyclosporine that caused a decrease in MPA concentrations.11van Gelder T. Klupp J. Barten M.J. et al.Comparison of the effects of tacrolimus and cyclosporine on the pharmacokinetics of mycophenolic acid.Ther Drug Monit. 2001; 23: 119-128Crossref PubMed Scopus (278) Google Scholar Increasing cyclosporine daily doses are associated with lower MPA concentrations, whereas discontinuation of cyclosporine leads to an increase in MPA trough concentrations.12Gregoor P.J. de Sévaux R.G. Hené R.J. et al.Effect of cyclosporine on mycophenolic acid trough levels in kidney transplant recipients.Transplantation. 1999; 68: 1603-1606Crossref PubMed Scopus (148) Google Scholar,13van Hest R.M. van Gelder T. Vulto A.G. Mathot R.A. Population pharmacokinetics of mycophenolic acid in renal transplant recipients.Clin Pharmacokinet. 2005; 44: 1083-1096Crossref PubMed Scopus (90) Google Scholar In a pharmacokinetic substudy of the ELITE–Symphony study, the effect of cyclosporine on MPA concentrations was observed as well.14Grinyó J.M. Ekberg H. Mamelok R.D. et al.The pharmacokinetics of mycophenolate mofetil in renal transplant recipients receiving standard-dose or low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus: the Symphony pharmacokinetic substudy.Nephrol Dial Transplant. 2009; 24: 2269-2276Crossref PubMed Scopus (78) Google Scholar The pharmacokinetics of MPA are complex, and involve enterohepatic recirculation.15Staatz C.E. Tett S.E. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients.Clin Pharmacokinet. 2007; 46: 13-58Crossref PubMed Scopus (423) Google Scholar In the liver, MPA is glucuronidated to MPAG, which is then excreted into bile. The bile subsequently reaches the gut, where it is deglucuronidated by bowel flora and is again reabsorbed as MPA (Figure 1). This enterohepatic recirculation contributes significantly to overall MPA exposure. Interruption of the enterohepatic recirculation leads to a decrease in area under the curve (AUC) of ≈40%.16Cremers S. Schoemaker R. Scholten E. et al.Characterizing the role of enterohepatic recycling in the interactions between mycophenolate mofetil and calcineurin inhibitors in renal transplant patients by pharmacokinetic modelling.Br J Clin Pharmacol. 2005; 60: 249-256Crossref PubMed Scopus (75) Google Scholar The enterohepatic recirculation leads to a second peak in the concentration-time profile of MPA at approximately 8 to 12 hours after the administration of MMF.17Bullingham R.E. Nicholls A.J. Kamm B.R. Clinical pharmacokinetics of mycophenolate mofetil.Clin Pharmacokinet. 1998; 34: 429-455Crossref PubMed Scopus (708) Google Scholar In this review, the focus is on the impact of cyclosporine on the pharmacokinetics of MPA. An external bile drain (not unusual after liver transplantation) or broad-spectrum antibiotics (eliminating the glucuronidase activity on the gut flora) can also interrupt the enterohepatic recirculation and lead to a decrease in MPA concentrations.18Bergan S. Brunet M. Hesselink D.A. et al.Personalized therapy for mycophenolate: consensus report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.Ther Drug Monit. 2021; 43: 150-200Crossref PubMed Scopus (25) Google Scholar The biliary excretion of MPAG into bile is an active process, in which the transporter protein multidrug resistance-associated protein (mrp)–2 (currently also known as ABCC2) is involved.19König J. Nies A.T. Cui Y. et al.Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance.Biochim Biophys Acta. 1999; 1461: 377-394Crossref PubMed Scopus (686) Google Scholar In the past, this protein was also referred to as canalicular multispecific organic anion transporter. This name refers to its role in the biliary excretion of glutathione conjugates, glucuronides, and other organic anions. The mrp-2 transporter protein, present in the hepatobiliary membrane, is responsible for the excretion of MPAG into bile. The mrp-2 transporter protein is inhibited by cyclosporine, resulting in interruption of the recirculation.20Kobayashi M. Saitoh H. Kobayashi M. et al.Cyclosporin A, but not tacrolimus, inhibits the biliary excretion of mycophenolic acid glucuronide possibly mediated by multidrug resistance-associated protein 2 in rats.J Pharmacol Exp Ther. 2004; 309: 1029-1035Crossref PubMed Scopus (172) Google Scholar,21Westley I.S. Brogan L.R. Morris R.G. et al.Role of Mrp2 in the hepatic disposition of mycophenolic acid and its glucuronide metabolites: effect of cyclosporine.Drug Metab Dispos. 2006; 34: 261-266Crossref PubMed Scopus (90) Google Scholar Evidence that this is the mechanism by which cyclosporine causes its effect comes from an experimental study performed in rats deficient for this transporter protein.22Hesselink D.A. van Hest R.M. Mathot R.A. et al.Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2.Am J Transplant. 2005; 5: 987-994Crossref PubMed Scopus (267) Google Scholar Clinical evidence, among others, comes from a population pharmacokinetic model published in this journal in 2014, which showed how increasing cyclosporine trough concentrations gradually cause more and more inhibition of the enterohepatic recirculation of MPA.23Colom H. Lloberas N. Andreu F. et al.Pharmacokinetic modeling of enterohepatic circulation of mycophenolic acid in renal transplant recipients.Kidney Int. 2014; 85: 1434-1443Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar The elevated MPAG concentrations in patients cotreated with cyclosporine may be due to accumulation of MPAG in the liver, where it is formed in the hepatocytes, but not excreted into bile. However, the mrp-2 protein is not only present in the canalicular membrane of hepatocytes but also in the luminal membrane of proximal renal tubular cells.24Masereeuw R. Notenboom S. Smeets P.H. et al.Impaired renal secretion of substrates for the multidrug resistance protein 2 in mutant transport-deficient (TR-) rats.J Am Soc Nephrol. 2003; 14: 2741-2749Crossref PubMed Scopus (67) Google Scholar Inhibition of the renal mrp-2 may also play a role in the accumulation of MPAG in plasma, due to reduced renal clearance.25El-Sheikh A.A. Koenderink J.B. Wouterse A.C. et al.Renal glucuronidation and multidrug resistance protein 2-/ multidrug resistance protein 4-mediated efflux of mycophenolic acid: interaction with cyclosporine and tacrolimus.Transl Res. 2014; 164: 46-56Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar As MPAG is an inactive metabolite, such high MPAG concentrations do not result in additional toxicity. Voclosporin is a novel CNI, structurally similar to cyclosporine except for a modification of a functional group on amino acid 1 of the molecule. This modification has changed the binding of voclosporin to calcineurin and has been shown both in vitro and in vivo to increase the potency by 2-fold to 5-fold compared with cyclosporine.26Kuglstatter A. Mueller F. Kusznir E. et al.Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin).Acta Crystallogr D Biol Crystallogr. 2011; 67: 119-123Crossref PubMed Scopus (33) Google Scholar In January 2021, the US Food and Drug Administration approved voclosporin, in combination with a background immunosuppressive therapy regimen consisting of steroids and MMF, for treatment of lupus nephritis. In view of the frequent coadministration of voclosporin and MMF in the lupus nephritis patient population, a formal drug–drug interaction study was performed. This study showed that adding voclosporin to MMF does not change MPA AUC (40.8 vs. 39.1 μg∗h/L).27van Gelder T. Huizinga R.B. Lisk L. Solomons N. Voclosporin: a novel calcineurin inhibitor without impact on mycophenolic acid in patients with SLE [e-pub ahead of print].Nephrol Dial Transplant. 2021; : gfab022Crossref PubMed Scopus (7) Google Scholar More evidence for lack of a drug–drug interaction between voclosporin and MMF comes from a phase 2 study in renal transplantation, where MPA exposure was found to be similar in voclosporin- and tacrolimus-treated patients.28Busque S. Cantarovich M. Mulgaonkar S. et al.The PROMISE study: a phase 2b multicenter study of voclosporin (ISA247) versus tacrolimus in de novo kidney transplantation.Am J Transplant. 2011; 11: 2675-2684Crossref PubMed Scopus (58) Google Scholar Apparently, with the registered voclosporin, 23.7 mg bid, dose found to be effective in the treatment of lupus nephritis, no clinically relevant inhibition of the enterohepatic recirculation of MPA is observed. Enteric-coated mycophenolate sodium (EC-MPS) and MMF are both prodrugs, producing the active drug K. P. F. et of the immunosuppressant mycophenolate 2004; 5: PubMed Scopus Google Scholar An dose of MMF and and mg bid, a similar MPA The of will result in more trough concentrations and more to the van Gelder T. P. et pharmacokinetics of mycophenolic acid: a comparison between mycophenolate sodium and mycophenolate mofetil in renal transplant recipients.Clin Pharmacokinet. 47: PubMed Scopus Google Scholar Also, for is an enterohepatic recirculation of MPA, and the drug–drug interaction with cyclosporine can be There are several studies that this P. et calcineurin inhibitor over study to the pharmacokinetics of mycophenolate Transplant. 2005; PubMed Scopus Google H. A. et of mycophenolic acid and its glucuronide and glucuronide in kidney transplant recipients from cyclosporine to Drug Monit. 34: PubMed Scopus (7) Google Y. et al.Cyclosporine A and tacrolimus combined with mycophenolate sodium the mycophenolic acid a randomised controlled trial in kidney transplant J Clin 2014; : PubMed Scopus Google Scholar More in a population pharmacokinetic study in kidney transplant patients with it was shown that MPA AUC was significantly lower in patients cotreated with cyclosporine compared with tacrolimus and K. An et pharmacokinetics and of mycophenolic acid exposure in renal allograft recipients after administration of Clin Pharmacol. 2019; Google Scholar The between the MPA concentrations and the AUC is poor in patients with MMF, and in on van Gelder T. P. et pharmacokinetics of mycophenolic acid: a comparison between mycophenolate sodium and mycophenolate mofetil in renal transplant recipients.Clin Pharmacokinet. 47: PubMed Scopus Google Scholar In kidney transplant it has been shown that the of acute rejection is higher if MPA AUC is the of 30 to Nicholls A.J. R.E. et al.The for mycophenolate mofetil in renal Pharmacol Ther. 1998; PubMed Scopus Google Gelder T. H. de et al.Renal transplant patients at high of acute rejection from exposure to mycophenolic PubMed Scopus Google Scholar The evidence for this is for the combined treatment of MMF and cyclosporine, but this of MPA exposure is used also for treatment. Although MMF was introduced as a the in MPA AUC between and that the 1000 mg dose may not be the dose for all Y. Cantarovich M. et on of MPA. report on drug of mycophenolic acid in solid organ J Am Soc Nephrol. 5: PubMed Scopus Google Scholar With the 1000 mg MPA AUC in kidney transplant patients cotreated with cyclosporine is more the compared with patients with tacrolimus or N. A. A. et comparison of the effect of ciclosporin and on the of mycophenolate in renal transplant J Clin Pharmacol. 2006; PubMed Scopus Google Gelder T. de et mycophenolate mofetil for de novo renal transplant recipients: the PubMed Scopus Google A. et and for mycophenolic acid area under the curve in renal transplant patients with ciclosporin or Pharmacokinet. 2009; PubMed Scopus Google Scholar et showed in patients, dose to mg are to the MPA and that this in a lower of Y. M. A. et mycophenolate mofetil on drug exposure significantly patient after renal transplantation.Am J Transplant. 2007; PubMed Scopus Google Scholar A group recommended the first after P. et and pharmacodynamics of versus standard of mycophenolate sodium in renal transplant J Am Soc Nephrol. 5: PubMed Scopus Google Scholar with standard with an group more patients an MPA AUC of in the first MMF has been at a dose without MPA and of MMF or is not recommended in treatment Disease: Improving Global Outcomes (KDIGO) Transplant Work GroupKDIGO clinical practice guideline for the care of kidney transplant recipients.Am J Transplant. 2009; 9: S1-S155PubMed Google Scholar similar MPA exposure in maintenance the dose will be lower in compared with treatment regimens. patients cotreated with tacrolimus or voclosporin, a dose of 1000 mg MMF to be the with dose after the first 2 to on either drug or Gelder T. R. N. et al.The optimal MMF dose in tacrolimus J Transplant. 2014; 14: PubMed Scopus Google Scholar clinical of the interaction is after discontinuation of cyclosporine, the MPA concentrations will increase and can cause adverse such as the MMF dose was not This has been observed in patients with a in due to renal it was to cyclosporine M. et Study of cyclosporine on mycophenolic acid pharmacokinetics in kidney transplant recipients with renal Drug Monit. 2001; 23: PubMed Scopus Google Scholar In patients in the MMF dose has been for years, the emergence of adverse effects may then not be to MMF, if MPA drug concentrations are not In the treatment of organ transplant recipients and of patients with lupus nephritis, combination therapy with a CNI and is daily In to tacrolimus and voclosporin, is a decrease in the MPA AUC cyclosporine and are inhibition of the enterohepatic recirculation of MPA is the mechanism this drug–drug to similar MPA exposure, the dose of will to be higher if combined with cyclosporine. Furthermore, discontinuation of cyclosporine, or from cyclosporine to CNI, may cause adverse an

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