Once-a-day Administration of Everolimus, Cyclosporine, and Steroid
`After Renal Transplantation: A Review of the Rationale
`
`G. Corbetta and C. Ponticelli
`
`ABSTRACT
`The Evidence study (EVerolImus once-a-Day rEgimen with Neoral® versus Corticosteroid
`Elimination) sought to compare once-a-day administration with steroid withdrawal versus
`twice-daily administration among de novo kidney transplant recipients treated with
`everolimus, cyclosporine, and steroids. This article describes the study design and rationale
`of once-daily administration and steroid withdrawal among recipients of de novo kidney
`transplants treated with everolimus and cyclosporine.
`
`EVEROLIMUS (EVL) is an inhibitor of the mTOR1,
`the downstream effector of PIk-3,
`in response to
`various stimuli thereby providing a signal for proliferation
`of several cells, including T lymphocytes. Compared with its
`parent compound sirolimus, EVL shows increased solubil-
`ity in aqueous solvents and distinct pharmacokinetic (PK)
`characteristics.1,2 Two pivotal phase 3 studies in de novo
`renal transplant recipients showed that in combination with
`standard cyclosporine (CsA) exposure, EVL (0.75–1.5 mg
`b.i.d.) was as effective as mycophenolate mofetil (MMF) to
`prevent acute rejections episodes. However, the association
`of EVL with standard CsA exposure resulted in decreased
`renal allograft function as compared with MMF.3,4 This
`unexpected nephrotoxicity was likely due to the combina-
`tion of the 2 drugs prescribed at high dosages. In animal
`models of autoimmune diseases and in allotransplantation
`experiments, EVL has been shown to act synergistically
`with CsA, since the latter drug inhibits the synthesis of
`interleukin (IL)-2, whereas EVL inhibits the response to
`IL-2. This synergy results in a 10-fold reduction in EVL and
`a 3- to 4-fold reduction in CsA doses required to achieve
`equivalent effects of either drug alone in animal studies.5
`The pharmacological synergy1,2 allows reduction of the
`doses of both agents when administered together in clinical
`trials. To confirm this assumption, the relationship between
`EVL/CsA pharmacokinetics (C0) and clinical events has
`been explored.6,7 The results of a simulated scenario based
`on several prospective clinical trials8 showed that the risk of
`biopsy-proven acute rejection (BPAR) was inversely related
`to trough blood levels of EVL. The highest risk was
`observed when the blood levels of EVL were ⬍3 ng/mL.
`When EVL trough levels were ⬎3 ng/mL, the blood levels
`of CsA had little, if any, influence on the risk of BPAR. In
`contrast, the risk of developing graft dysfunction was strictly
`
`related to blood CsA levels while there was little influence
`of EVL blood levels on the risk of nephrotoxicity. Addi-
`tionally, in a randomized, exploratory, controlled trial in de
`novo kidney transplantation, it has been shown that re-
`duced CsA exposure in combination with EVL improved
`renal function in comparison with standard CsA exposure.9
`Recently 2 randomized trials combining EVL at reduced
`CsA exposure (A2306/A2307) showed excellent efficacy and
`safety.10,11 In a study with basiliximab (Simulect) induction
`and reduced CsA exposure, namely, mean C2 levels of 700
`ng/mL at month 1, reduced to 350 – 450 ng/mL by month 12,
`in combination with 1.5 or 3 mg/d of EVL, the BPAR rates
`at 12 months were 13.7% and 15.8%, respectively, and the
`graft loss rates were 1.7% and 5.0%, respectively. Median
`creatinine clearance level at 12 months was 64 mL/min in
`both groups.
`The possibility of obtaining excellent graft survival and a
`low rate of BPAR by combining EVL with even lower CsA
`exposure was recently confirmed by an Italian multicenter
`randomized trial (Everest study group).12 This group ex-
`plored the relationship between EVL/CsA blood levels and
`BPAR in the first 3 months after transplantation, showing
`that a simulated increase in EVL blood levels would have
`resulted in a further reduction of the BPAR rate, and a
`decrease of EVL blood levels would have led to an in-
`
`From the Medical Department (G.C), Novartis Farma SpA,
`Origgio (Va), and Nephrology Unit (C.P), Istituto Clinico Humani-
`tas, Rozzano (Mi), Italy.
`G.C. is a full-time employee of Novartis Farma Italy, SpA; C.P.
`is a consultant of Novartis Farma Italy, SpA.
`Address reprint requests to Giuseppe Corbetta, Medical De-
`partment, Novartis Farma SpA, L.go Boccioni, 1, I 21040 Origgio
`(Va), Italy. E-mail: giuseppe.corbetta@novartis.com
`
`© 2010 Published by Elsevier Inc.
`360 Park Avenue South, New York, NY 10010-1710
`
`0041-1345/–see front matter
`doi:10.1016/j.transproceed.2010.03.084
`
`Transplantation Proceedings, 42, 1303–1307 (2010)
`
`1303
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`1304
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`CORBETTA AND PONTICELLI
`
`creased risk of BPAR. In contrast, changes in CsA blood
`levels within the first 3 months after transplantation would
`not have affected the risk of BPAR.13
`In addition to the possibility of reducing the CsA dose to
`⬍50%, and thereby the CsA-related toxicity, EVL-based
`regimens may have further advantages: (1) in randomized
`double blind trials, transplant recipients given EVL showed
`a reduced risk of cytomegalovirus (CMV) infections com-
`pared with those receiving MMF3; (2) EVL has been shown
`to be an effective anticancer agent.14 After solid organ
`transplantation, patients receiving an immunosuppressive
`regimen containing EVL or sirolimus showed a lower risk
`of developing cancer compared with patients prescribed
`other immunosuppressive regimens15; (3) in a phase 3 heart
`transplantation trial, EVL was more efficacious than aza-
`thioprine to reduce the severity and incidence of cardiac-
`allograft vasculopathy, a leading cause of late graft loss and
`death16; and (4) recent investigations have demonstrated
`that mTOR inhibitors reduce lipid retention by increasing
`adipose-tissue lipase activity and decreasing lipoprotein
`lipase activity.17 Moreover, these agents would protect
`plaque from rupture by selectively clearing macrophages
`without affecting vascular smooth muscle cells.18 Thus,
`there is a rationale for implementing the use of EVL-based
`treatments in organ transplantation. However, further stud-
`ies are needed to maximize the therapeutic index of this
`agent.
`
`ONCE-A-DAY IMMUNOSUPPRESSIVE REGIMENS
`
`Low adherence to prescribed regimens19,20 is a major cause
`of long-term graft failure. Although psychosocial status is a
`factor that heavily influences adherence to prescription,21
`an important barrier to adherence is represented by the
`complexity of the treatment, in particular, by the number of
`pills to be taken every day.22 Among the possible interven-
`tions to improve adherence to prescriptions, simplification
`of the regimen with a reduced number of pills per day may
`play an important role. At present, most if not all available
`immunosuppressive regimens have to be given twice a day.
`
`Once-a-Day CsA
`
`CsA half-life is about 11 hours and the rate of drug
`absorption is formulation-dependent. The old formulation
`of CsA (Sandimmun) was usually given once daily, even if
`high dosages (up to 15 mg/kg/d at transplantation) were
`normally used. The absorption of CsA from this formula-
`tion was slow and highly variable, especially among liver
`transplant recipients. The new microemulsion formulation,
`Sandimmun Neoral (CsA-ME) improved absorption and
`reduced pharmacokinetic variability with clinically relevant
`improvements to prevent BPAR. However, as the new
`formulation produced higher and earlier Cmax, CsA-ME
`was given twice daily to avoid side effects linked with high
`blood CsA peaks levels.
`Many studies, however, have continued to explore once-
`daily regimens with CsA-ME. Tarantino et al showed that
`
`twice-daily and once-daily regimens of CsA-ME were
`equally effective and safe in de novo kidney transplant
`recipients.23 In a clinical-pharmacokinetic, randomized
`study in stable maintenance liver transplant recipients,
`Kovarik et al showed that conversion from twice-daily to
`once-daily CsA-ME was feasible and well tolerated, main-
`taining a good graft function with no increased risk of
`rejection.24 The 24-hour CsA-ME dose could be reduced
`by 25%–30% to maintain the same exposure to drug
`(AUC0 –24h). Nighttime CsA exposure was reduced, and
`the nighttime mean arterial blood pressure also decreased
`among a large proportion of patients receiving CsA once-
`a-day (67%–73%) versus b.i.d. (43%). This finding may be
`relevant, as it has previously been shown that the absence of
`a decrease in blood pressure during the nighttime is a
`strong predictor of cardiovascular morbidity and mortality
`after renal transplantation.25 Thus, in addition to improved
`adherence to immunosuppressive therapy and reduced
`daily doses, once-daily administration of CsA-ME in main-
`tenance renal transplant recipients may reduce long-term
`cardiovascular risk.
`
`Once-a-Day EVL
`
`Although the elimination half-life of EVL is 28 hours,
`which is appropriate for once-daily administration, the drug
`was developed in a twice-daily regimen in combination with
`CsA-ME, mainly because of the EVL-CsA pharmacokinetic
`interactions.6 Pharmacokinetics of
`twice-a-day EVL in
`combination with CsA-ME were measured in kidney trans-
`plant recipients treated with 0.9 –1.4 mg of EVL b.i.d.26
`Depending on the time since transplantation, the exposure
`to CsA varied largely from C2 values ⬎1000 ng/mL to ⬍500
`ng/mL. The AUC of EVL was strictly proportionate to the
`dose, with a 12-hour AUC ranging from 83–100 ng*h/mL
`per milligram of EVL administered.
`The pharmacokinetics of once-a-day EVL were docu-
`mented by Kahan et al.27 Stable renal transplant recipients
`treated with CsA-ME b.i.d. were also given EVL (0.75, 2.5,
`and 7.5 mg/d) once a day for 28 days. At steady state, the
`24-hour AUC, C0, and Cmax increased proportionate to the
`administered dose. The AUC0 –24h adjusted for the EVL
`dose was 84 at 2.5 mg/d, and varied between 62 and 90
`ng*h/mL at the extremes of the dose range. After admin-
`istration of 2.5 mg EVL, the C0 was 4.4 ng/mL. The
`relationship between C0 and AUC after once-daily admin-
`istration was excellent, confirming that C0 blood levels are
`useful predictors of EVL exposure even with once-daily
`administration.
`A comparison of pharmacokinetic data after once versus
`twice-daily EVL administration in kidney transplant recip-
`ients treated with CsA-ME indicated that the exposure to
`EVL over the 24 hours appeared to be proportionate to the
`EVL daily dose,
`independent
`from the administration
`schedule (Table 1). Furthermore, the EVL trough blood
`levels (C0) were dose-proportional for both once- and
`twice-daily administration. Last but not least, the dose-
`adjusted AUC was proportionate to the dose, independent
`
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`EVL, CSA, AND STEROID
`
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`
`Table 1. EVL PK in Renal Transplant Recipients Receiving
`CsA-ME
`
`EVL mg
`Twice a
`Day
`
`Time After
`Transplantation
`
`CsA C2
`ng/mL
`(Estimated)
`
`EVL AUC
`(0–12)
`ng*h/mL
`
`EVL
`Ratio
`AUC/mg
`
`EVL C0
`ng/mL
`
`0.9
`1
`1
`0.9
`1.4
`1.3
`1.4
`1.4
`
`Wk 2
`Mo 2
`Mo 3
`Mo 6
`Wk 2
`Mo 2
`Mo 3
`Mo 6
`
`1100
`900
`680
`590
`1150
`850
`750
`580
`
`84.00
`87.00
`82.00
`84.00
`124.00
`130.00
`135.00
`130.00
`
`93.33
`87.00
`82.00
`93.33
`88.57
`100.00
`96.43
`92.86
`
`3.9
`4.3
`4
`4.3
`5.9
`6.6
`6.6
`6.4
`
`the possibility of avoiding steroids in renal transplant
`recipients treated with EVL and CsA.34 The results were
`encouraging, with 95% of patients assigned to stop steroids
`at 1 week after transplantation still being alive with kidneys
`functioning after 3 years; however, the risk of BPAR during
`the study increased from 18%–32%. Older and more recent
`meta-analyses of randomized trials35–37 clearly indicated
`that the risk of BPAR was significantly higher among
`patients assigned to eliminate than those who continued
`steroids. However, this increased risk did not affect patient
`or graft survivals, which were similar among patients with or
`without steroid withdrawal.
`
`Modified from Kovarik JM et al.26
`Note: EVL was administered twice a day.
`
`of CsA blood concentrations as shown by the similar values
`obtained in patients tested at various times after transplan-
`tation.
`
`Once-a-Day Steroid
`
`The endogenous cortisol blood concentration peaks around
`8 AM with a nadir around 12 PM. Therefore, a glucocorticoid
`given in a single morning dose produces only slight adrenal
`suppression; in contrast, the same glucocorticoid dose given
`at midnight will nearly completely suppress the adrenal
`glands for about 24 hours.28 For this reason a single
`morning dose between 7 and 9 AM is strongly recommended
`for chronic steroid administration.
`
`STEROID WITHDRAWAL
`
`Steroids are routinely used to reduce the risk of early and
`late renal transplant rejections. However, steroids have
`frequent side effects that can impair the quality of life of
`transplant recipients and also exert life-threatening compli-
`cations. In addition to the long list of side effects that are
`usually dose- and time-dependent, glucocorticoids can in-
`duce or impair known risk factors for cardiovascular dis-
`eases, the main cause of death in renal transplant recipi-
`ents: hypertension, glucose intolerance, hyperlipemia,
`obesity, hyperuricemia, and so on.29 –31 In a large retrospec-
`tive study, only 47% of surviving patients at 15 years after
`transplantation had not experienced cardiovascular events,
`the risk of such complications being 5-fold less frequent
`among patients who had withdrawn steroids.31 Other
`studies reporting, long-term follow-ups have shown sig-
`nificantly lower risks of death or cardiovascular complica-
`tions among patients who had withdrawn glucocorti-
`coids.32,33 There is, therefore, a rationale for eliminating
`the use of steroids in renal transplantation. Recently, there
`has been a significant increase in the use of steroid avoid-
`ance regimens as the initial treatment for kidney transplant
`recipients. These studies are often small with usually short
`follow-up. Apparently, the results seem to be influenced by
`the clinical and immunological characteristics of the recip-
`ients as well as by the medications. To the best of our
`knowledge, only 1 randomized controlled trial evaluated
`
`THE EVIDENCE STUDY: RATIONALE FOR THE STUDY
`DESIGN AND CONCLUSIONS
`
`In the Evidence study, the following immunosuppressive
`regimens are compared among recipients of kidney trans-
`plantation: (1) EVL, CsA, and steroids once-daily; (2) EVL,
`and CsA twice-daily with steroid withdrawal; and (3) EVL
`and CsA twice-daily and continuous steroids. The once-
`daily immunosuppressive regimen is started when the pa-
`tient is stabilized, that is, at 3 months after transplantation.
`In fact, the drug dosages in the immediate posttransplan-
`tation setting are higher, therefore, administration as a
`single morning dose may lead to increased adverse events.
`As a more reasonable approach, we decided to switch to a
`once-daily regimen when the drug dosages were lower and
`stable.
`The advantages versus disadvantages of early steroid
`avoidance versus steroid withdrawal have been debated;
`although early steroid avoidance may enhance benefits, it
`also carries an increased risk of BPAR. Furthermore,
`allowing more flexibility in the management of immunosup-
`pressive drugs, the initial use of steroids may be of benefit
`in elderly patients and in recipients of a kidney from an
`extended criteria deceased donor. In the Evidence study,
`steroids will be gradually withdrawn starting at 3 months
`after transplantation, when kidney function is established
`and the patient is stable.
`The available data on EVL support a 1:1 switch from
`twice-daily to once-daily; in other words, the total daily dose
`given in the 2 daily administrations should be given in the
`morning. According to Kahan et al,27 the C0 after once-
`daily EVL administration should be 30% lower to maintain
`the same AUC0 –24h. For example, for a range 8 –12 ng/mL
`when given twice-daily, the range after once-daily adminis-
`tration should be 5– 8 ng/mL.
`According to the available PK data, the conversion of
`CsA-ME from twice-daily to once-daily should be per-
`formed 1:1, followed by a 25%–30% reduction of the total
`daily dose of CsA-ME. The once-daily administration will
`result in C2 levels about 30%–50% higher than those
`observed after twice-daily administration. If monitored
`using blood C2 levels, the targeted range selected for b.i.d.
`administration (eg, 250 – 400 ng/mL) should be increased by
`50%– 69% (400 – 600 ng/mL).
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`CORBETTA AND PONTICELLI
`
`It appears, therefore, worthwhile to evaluate feasibility,
`efficacy, and tolerability of the following: (1) a once-daily
`triple regimen, and (2) a steroid-withdrawal regimen, both
`based on the EVL/CsA-ME combination in a clinical
`confirmatory study in kidney transplant recipients. In fact
`the possibility to explore once-daily and steroid-withdrawal
`regimens in the same study, by making use of the same
`control arm, is attractive as it may answer 2 relevant clinical
`questions in a relatively short time-span. The primary
`endpoint of the study should be to demonstrate noninferi-
`ority of the 2 experimental arms (steroid withdrawal arm
`and once-daily arm) compared with the standard b.i.d.
`regimen using the main endpoint of treatment failure
`rate—the composite of death, graft loss, and BPAR.
`There has been much debate about the use of noninferiority
`studies. According to Garattini et al38 “non-inferiority trials
`are unethical because they disregard patients’ interests” and
`should therefore be avoided. These authors argue that
`these studies might allow approval for drugs that are not as
`efficacious as the standard of care, in the end even leading
`to approval of drugs that are not different from the placebo.
`The same opinion was mentioned in an official document of
`the “Consulta” of the Italian Ministry of Health.39 They
`argue that “non-inferiority studies are not justified because
`they do not offer any advantage to the present or future
`patients.” The European Medicine Agency (EMEA) also
`express the same concerns for confirmatory registration
`trials, but, in the document “Determination of the non-
`inferiority limit,”40 they define the areas “where a non-
`inferiority trial might be performed as opposed to, or in
`addition to, a superiority trial.” These cases include studies
`where “the use of a placebo arm is not possible and an
`active control trial is used to demonstrate the efficacy,” or
`where “products with a potential safety advantage over the
`standard might require an efficacy comparison to the stan-
`dard to allow a risk-benefit assessment to be made,” or,
`most importantly, “cases where no important loss of efficacy
`compared to the active comparator would be acceptable.”
`In this document, the EMEA proposes guidelines on how to
`compute the noninferiority margin in a clinical trial to
`minimize the risk of approval of new drugs with lower
`efficacy than the standard.
`The Evidence study fulfills the situations mentioned
`above. For this reason we believe that a noninferiority trial
`is not only feasible, but mostly recommended. In fact, only
`an adequately sized noninferiority trial will allow strict
`control of the efficacy of the “experimental” in comparison
`with the control regimens.
`
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