The problem with generic immunosuppressants

According to the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) and other national databases, mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is the most widely prescribed immunosuppressive agent used to prevent rejection following kidney transplantation in many countries 1, 2. In 2009, 59.6% of patients received MMF therapy 2. Innovator drugs face ever-decreasing patent protection, normally granted for 20 yr from the filing of the application to the Food and Drug Administration (FDA). Extensive and drawn-out licensing processes and the enactment of the 1984 Hatch–Waxman Act, which generated the Abbreviated New Drug Application (ANDA) and entices generics manufacturers not to wait but to immediately pursue drugs with “weak” patents in the legal realm 3, have been two significant contributors to this phenomenon. This is especially true for blockbuster drugs, which are highly profitable and disproportionately targeted by generic companies 4, leading to extreme competition 5. This competition can be advantageous as it decreases drug costs, resulting in a savings of approximately $1 trillion for the US healthcare system from 2002 to 2011 6. Rather than requiring preclinical and clinical data to establish safety and efficacy, the FDA requires that a generic company demonstrates that the generic drug is bioequivalent to the existing innovator drug in normal healthy subjects 7. To demonstrate that a generic drug is interchangeable with its corresponding innovator drug, this bioequivalence testing is based on “essential similarity,” which requires that the generic drug has the same amount and type of active principle, the same route of administration, and the same therapeutic effectiveness as the original drug. However, bioequivalence and therapeutic effectiveness are not necessarily the same 8, and this criterion may be insufficient for MMF and for most immunosuppressants, which are critical dose drugs and may require special considerations 9. As such, this concept may be particularly important in transplant settings. For example, different formulations of a critical dose drug may lead to unintended consequences. Critical dose antirejection drugs include calcineurin inhibitors (ciclosporin and tacrolimus) and mTOR inhibitors (sirolimus and everolimus). Switching patients from ciclosporin to microemulsified ciclosporin in one study resulted in acute rejections and even graft loss 10, and a consensus statement by leading European and North American transplant and pharmacokinetic specialists highlighted data showing that the use of generic cyclosporine A formulation may result in reduced graft survival at one yr 11. This consensus statement recommended that any switch between ciclosporin formulations in a particular patient should only take place in a controlled setting with adequate pharmacokinetic monitoring. Current literature supports the notion that companies producing both innovator and generic critical dose drugs should be required to perform replicate studies measuring intrasubject variability and subject–treatment interactions to establish that the two are truly bioequivalent 8. Not only should these studies be performed in human subjects, but they should include the pharmacokinetics of concomitant drugs to mimic real-life clinical treatment scenarios. For example, the bioequivalence of MPA exposure when switching from regular tacrolimus to modified release tacrolimus should be tested 12. MPA can either be administered intravenously or orally, and oral formulations are available either as the prodrug mycophenolate mofetil (MMF) or as mycophenolate sodium. It is available as intravenous mycophenolate mofetil (Cellcept®; Roche, Basel, Switzerland), as oral MMF (originally marketed as Cellcept®; Roche) and now in non-innovator generic formulations (Tevacept® or Myfenax®; Teva, Petah Tikva, Central District, Israel) 13. It is also available as EC-MPS (marketed as Myfortic®; Novartis, Basel, Switzerland). Although there are substantial inter- and intrapatient variabilities in patient responses to the drug, MPA has not traditionally been viewed as a critical dose drug. In fact, despite the substantial amount of evidence supporting this variability 14, 15, manufacturer guidelines endorse fixed dosing. Considering this paucity of pediatric data, we are delighted to read about a sizeable pediatric study from Mexico 16. To avoid the challenges associated with administering immunosuppressants to pediatric patients at risk of losing their grafts, the authors studied 18 children receiving peritoneal dialysis prior to transplantation and performed a proper 12-h pharmacokinetic profile with MPA measurements. Eight patients received the innovator MMF and 10 received generic MMF. The group found no significant differences between the two patient cohorts. The dose-normalized MPA area under the time–concentration curves (AUC) were not significantly different, and the authors concluded that the two drugs could be used interchangeably without any safety concerns. This echoes findings from a couple of small studies comparing generic and innovator MMF in healthy and post-transplant adults, which have seen good clinical results with both drugs 17, 18. A considerable strength of the study is the inclusion of proper MPA pharmacokinetic profiles. Still, omitting the use of standard concomitant drugs used in renal transplantation in study patients is a limitation. The highly variable pharmacokinetics of MMF in patients who have received a transplant 14, 15, the ontogeny of drug disposition 19, variable degrees of renal impairment 20, and drug–drug interactions (DDIs) all significantly contribute to the substantial interpatient variability, which can reach 100%. For example, there is good evidence that an AUC >30 mg × h/L is required to prevent organ rejection 21. DDIs that contribute to the variability include those between MMF and both of the calcineurin inhibitors (ciclosporin or tacrolimus 22) and steroids 23: Ciclosporin increases MPA clearance 24, whereas tacrolimus may reduce it. As a result, recent consensus guidelines have based dosing recommendations on the concomitant calcineurin inhibitor being administered to avoid under-dosing 14, 15. The upper therapeutic window of MPA is not as well defined, and limited sampling strategies are necessary to determine AUC as there is poor correlation between the trough level and the AUC 25. Despite this evidence and underlying concerns, MMF therapy is not usually subject to pharmacokinetic monitoring. We strongly advocate for MPA monitoring. Pharmacokinetic monitoring is widely available, either through immunologic assays such as the EMIT 2000 MPA assay from Siemens Healthcare Inc. (Erlangen, Germany), through the high-performance liquid chromatography (HPLC) reference method, or through mass spectrometry, the most cost-effective method. While we agree with the authors that the dose-normalized MPA exposure in the patients in their study was equivalent in the innovator MMF and the generic MMF and that they can be used interchangeably, further studies are necessary to prove that this still holds true following transplantation – particularly in pediatrics. Given the substantial variability, ongoing MPA pharmacokinetic monitoring is required to prevent under- or overdosing. Monitoring guidelines can be found in the consensus paper by Tönshoff et al. 14. We would like to congratulate the authors of the recent manuscript published in Pediatric Transplantation once more for their important work. The manuscript provides pediatric evidence for the bioequivalence of both formulations of MPA and may form the basis for initial therapy with the generic formulation, or conversion from the innovator drug to the generic, which may lead to substantial cost savings. Given the substantial interpatient variability of the drug, a double cross-over trial design with patients who have undergone transplantation would provide stronger support for the authors' main message. Regardless of the formulation used, the necessity of pharmacokinetic monitoring during MPA therapy should be emphasized. None.

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