In kidney and other types of solid organ transplantation, lifelong immunosuppression is required to preserve graft function (1). Therefore, medication nonadherence is a major risk factor for graft failure (2, 3). Kidney transplant recipients (KTRs) are more prone to medication nonadherence than other solid organ recipients, possibly because of the nonvital nature of the graft (4, 5). One of the reasons for nonadherence is a massive pill burden (5, 6). Therefore, the availability of once-daily (OD) formulations of immunosuppressive drugs could improve adherence and, by inference, graft survival.
Tacrolimus (Tac), a calcineurin inhibitor that prevents T-cell activation, was first developed as an oral twice-daily (BID) formulation (Prograf; Astellas Pharma Europe Ltd, Staines, United Kingdom; hereafter referred to as Tac-BID). In 2008, Astellas designed an OD-extended release Tac formulation that could contribute to improve nonadherence (Advagraf; Astellas Pharma Europe Ltd; hereafter referred as Tac-OD). Because Tac exhibits a narrow therapeutic index and highly variable inter- and intrapatient pharmacokinetics, regular assessment of plasma trough levels (C0) is required for both formulations. Of note, changes in the shape of the exposure-time curve with different formulations such as Tac-BID and Tac-OD may have an effect on exposure due to the timing of meals or different drug interactions. However, there are solid data showing that C0 correlates well with Tac AUC0–24 (area under the plasma concentration time curve that reflects Tac exposure) for both Tac-OD and Tac-BID formulations (see below). For logistic reasons, Tac C0 is more often used in clinical settings than AUC0–24, which are mainly performed for research purposes.
Phase I and II studies showed that pharmacokinetic parameters (C0 and AUC0–24) of Tac-OD and Tac-BID are equivalent according to the criteria specified by most regulatory agencies (7, 8). This was demonstrated in healthy controls, de novo KTRs, and stable KTRs after switch (3). Initial experience in stable solid organ recipients showed that both formulations were effective and safe during short-term follow-up (9, 10). Accordingly, a 1:1 conversion from Tac-BID to Tac-OD formulation was recommended by both the European Medicines Agency and the Canadian Society of Transplantation (3, 8). Measurement of trough levels before and within 2 weeks after conversion was also recommended (8). Following these recommendations, several studies in de novo and stable solid organ recipients have shown similar efficacy, tolerance, and safety of Tac-OD versus Tac-BID formulations (3, 9 – 17). Nearly 70% to 80% of stable renal and liver transplant recipients did not require dose adjustments upon conversion from Tac-BID to Tac-OD, and patients were maintained in the preset target ranges (15, 17). This optimism was fueled by preliminary, uncontrolled reports suggesting that Tac-OD could improve compliance (18) and graft function of stable KTRs (19).
In 2008, Astellas launched a campaign targeted at transplant physicians, to convince them to switch their patients from Tac-BID to Tac-OD. Three years later, how does daily life experience with unselected transplant patients match the initial expectations? Several recent reports indicate that the use of Tac-OD in de novo or stable transplant recipients is associated with a considerable lower tacrolimus exposure (19 – 23). First, Wlodarczyk et al. have reported that the AUC0–24 with Tac-OD in comparison to Tac-BID for de novo KTRs was 30% lower at day 1 and 15% lower at 6 weeks, despite doses adjustments. Second, among de novo liver or KTRs, the dose of Tac-OD had to be increased by 20% to 40% during the initial 6 months to match the exposure achieved with Tac-BID. Third, two independent studies (n=284 and 55, respectively) of switching stable KTRs from Tac-BID to Tac-OD showed that approximately 30% of switched KTRs experienced a sustained decrease of tacrolimus C0 over time, that reached a mean of 10% to 20% at 6 months. This occurred despite repetitive dose adjustments (21, 23). In one study, at 6 months, the mean dose of Tac-OD had to be increased by 50% to achieve stable tacrolimus exposure (23). Although no severe adverse events (i.e., graft rejection) were reported on conversion from Tac-BID to Tac-OD, long-term effects of this unexpected decrease in trough levels are unknown. Indeed, the absence of acute events does not preclude subclinical graft damage that could compromise lifelong survival. On the other hand, the lower blood tacrolimus peak levels achieved with Advagraf might help to reduce nephrotoxicity. Longer follow-up and more data are required to unambiguously establish the equivalence or potential superiority of Tac-OD over Tac-BID.
Are there obvious reasons for these discrepancies in the evolution of Tac exposure between the early trials and daily life experience? Patients enrolled into early studies had to be free of several actual or potential gastrointestinal conditions that may affect the absorption of Tac, such as diarrhea, vomiting, peptic ulcer disease, any gastrointestinal tract motility disorder, and diabetes mellitus. They also needed to be compliant. In addition, there was a long list of prohibited concomitant medications, including omeprazole and most calcium antagonists (13). Therefore, it is no surprise that inclusion of unselected KTRs suffering from the above-mentioned conditions, and/or taking the prohibited medications, may lead to reduced Tac-OD absorption. Moreover, careful analysis of preliminary scientific data in healthy volunteers (n=5 studies, 82 subjects) revealed that MR4 (current formulation is Tac-OD) resulted in a systematic 10% lower AUC0–24 in comparison to Tac-BID (8). Studies in stable KTRs failed to find any major clinical, therapeutic (i.e., drugs interacting with CYP3A4 or P-glycoprotein) or genetic determinants (i.e., CYP3A5) that could predict decreased exposure after Tac-OD intake (21, 23). Therefore, patients at risk for a major decrease in Tac exposure after switching to Tac-OD could not be identified preemptively to provide closer clinical follow-up.
Although it has been clearly reported for many drugs that a once-daily formulation improves adherence, one other important point relevant to transplantation deserves to be mentioned. In patients who are not perfectly compliant, missing an identical number of Tac-OD pills has a more serious impact on Tac exposure as compared to Tac-BID pills. Indeed, in the course of 1 week, missing four daily doses of Tac-OD would result in a decrease of nearly 45% of the required weekly dose, whereas four missed doses of Tac-BID would limit the decrease of the weekly dose to only 30%. Therefore, the assumption that the once-daily formulation improves overall adherence remains to be thoroughly investigated and validated in patients already on a high pill burden.
The Tac-BID story has in our opinion serious implications with regards to generics used for immunosuppression. It must be acknowledged that, for many countries and patients, the availability of low-cost Tac might outweigh the potential advantage of a once-daily intake. However, of concern is that the observed lack of pharmacokinetic equivalence in a routine clinical practice setting occurred with a drug developed by Astellas, a pharmaceutical company that has excellent records and a long-standing commitment to transplantation medicine. Less attention and experience might be expected from nondedicated manufacturers of generic drugs. Furthermore, in spite of their narrow therapeutic index, immunosuppressants have to fulfill only loose criteria to establish bioequivalence (24). For instance, the Food and Drug Administration considers a generic as bioequivalent if the confidence interval of both the trough level and the AUC falls within a margin of −20% to +25% in comparison to the original drug in healthy volunteers (24). Therefore, we support the recent policy of the European Medicines Agency and Health Canada that have reduced their margins for AUC ratios from −10% to +11% (7, 25) for all drugs with narrow therapeutic index. According to these latter criteria, trough levels of Tac-OD were not bioequivalent to Tac-BID in our cohorts of KTRs (21, 23).
In conclusion, Tac-OD is not bioequivalent to Tac-BID in a routine clinical transplant setting. Therefore, close supervision is needed after switching from Tac-BID to Tac-OD. Similarly, we recommend a high level of caution during conversion from any original drug to its generic formulation, especially when the therapeutic index is critical.
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. Accessed December 20, 2010.