Tolerability and steady-state pharmacokinetics of everolimus in maintenance renal transplant patients
Klemens Budde1,
Hans-Hellmut Neumayer1,
Gustav Lehne2,
Michael Winkler3,
Ingeborg Anni Hauser4,
Arno Lison5,
Lutz Fritsche1,
Jean-Paul Soulillou6,
Per Fauchald2 and
Jaques Dantal6 on behalf of the RADW 102 Renal Transplant Study Group
1 Charité, Berlin, 3 Medizinische Hochschule Hannover, 4 Universitätsklinikum Frankfurt, 5 Zentralkrankenhaus, Bremen, Germany, 2 Rikshospitalet, Oslo, Norway and 6 Nephrology Service, CHU Hotel Dieu Nantes, France
Correspondence and offprint requests to: Dr Klemens Budde, Department of Nephrology, Charité University Hospital, Schumannstrasse 2021, D-10117 Berlin, Germany. Email: klemens.budde{at}charite.de
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Abstract
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Background. Current immunosuppressant regimens need to be improved to prevent acute and chronic graft rejection. The novel macrocyclic immunosuppressant everolimus (CerticanTM, RAD) is currently in clinical development to address this issue.
Methods. The primary objective of this multicentre, randomized, double-blind, placebo-controlled, dose-escalating phase 1 study was to evaluate the safety and tolerability of everolimus at four dose levels (0.75, 2.5, 5 and 10 mg/day) in maintenance renal transplant patients receiving cyclosporin and steroids. The secondary objective was to assess the pharmacokinetic profile of two different formulations (capsule and tablet) of everolimus.
Results. Fifty-four subjects were randomized for 4 weeks treatment with everolimus (n = 44) or placebo (n = 10). Dose levels of everolimus between 0.75 and 5 mg daily were well tolerated, permitting dose escalation to the highest everolimus dose of 10 mg daily. At this dose, everolimus was associated with a higher incidence and severity of adverse events, most notably thrombocytopenia. Pharmacodynamic assessment showed a relationship between drug exposure and thrombocytopenia. Notable reversible elevations of cholesterol were also observed at the 10 mg/day dose. Other changes in laboratory evaluations, including triglycerides, were minor, reversible and did not appear to be dose dependent. The bioavailability of the tablet formulation was 2.6-fold higher compared with the capsule, with evidence for dose proportionality over the dose range tested. Within-subject pharmacokinetic variability was low (coefficient of variation: 1019%); however, between-subject variability ranged from 34 to 60% for AUC and Cmax.
Conclusions. These results indicate that up to 5 mg/day everolimus results in a dose-proportional exposure, and is adequately well tolerated in renal transplant recipients receiving cyclosporin and steroids.
Keywords: everolimus; pharmacodynamics; pharmacokinetics; renal transplantation
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Introduction
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The novel macrocyclic immunosuppressant everolimus (CerticanTM, RAD) [40-O-(hydroxy)ethyl-rapamycin] is a promising candidate for a potent adjunctive immunosuppressant. Everolimus belongs to the same drug class as sirolimus, but structural differences between the two agents confer different pharmacokinetic characteristics [14]. Everolimus targets the signal transduction pathway involved in cell cycle progression, and leads to inhibition of interleukin (IL)-2-induced T-cell proliferation as well as inhibition of general growth factor-dependent proliferation of haematopoietic and non-haematopoietic cells, including vascular smooth muscle cells [3,4]. In pre-clinical models, everolimus has been shown to prevent allograft rejection effectively and even to reverse ongoing rejection [510]. Pertinent to its potential for prevention of chronic rejection, everolimus has been found to prevent development of vascular changes following allogeneic rat aorta transplantation [11]. These vascular changes are reminiscent of pathological changes (graft vessel disease) seen in chronic rejection in clinical transplantation, providing a basis for the hypothesis that everolimus may be able to affect the progression of chronic rejection in clinical practice [12].
The primary objective of this first clinical study with everolimus tablets was to assess the multiple dose safety and tolerability of four dose levels of everolimus in renal transplant patients receiving steady-state cyclosporin A (CsA) therapy. A secondary aim was to determine the pharmacokinetic profile of everolimus. This is the first study to investigate the tablet formulation of everolimus across a wide range of doses, unlike the previously reported phase 1 single-dose study [2], and a recently reported multiple-dose study which used a service capsule formulation [13] used in development and which will not be commercially available.
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Materials and methods
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Patients
Stable recipients of a primary renal transplant (cadaveric or living donor) were eligible for inclusion in the study. Subjects were aged 1868 years, were at least 6 months post-transplant and had stable serum creatinine. For at least 3 months before enrolment into the study, all patients were receiving the Neoral® formulation of CsA sufficient to produce morning trough levels of 80200 ng/ml and prednisone doses (or equivalent) at
15 mg/day. Pneumocystis carinii prophylaxis with cotrimoxazole/sulfamethoxazole (480 mg/day) was also mandated. For inclusion in the study, females had to be practising an accepted method of birth control. All subjects gave written informed consent prior to inclusion. The study was conducted in accordance with Good Clinical Practice guidelines, and in line with the Declaration of Helsinki and European Economic Community (EEC) directives. The protocol was approved by the Ethics Committee at each centre.
Individuals were excluded from the study if they had evidence of graft rejection within 3 months prior to the start of the current study. Subjects were also excluded if they had any clinically relevant intercurrent medical conditions that might compromise safety evaluations or the objectives of the study. In addition, subjects were excluded if they received any other immunosuppressive drug (azathioprine was to be discontinued at least 4 weeks prior to study enrolment), if they had received antiplatelet agents within 2 weeks prior to the study; anti-T-cell monoclonal antibody treatment within 6 months prior to enrolment; any investigational immunosuppressive drug within 4 months; or any other investigational drug within 4 weeks of the start of the study.
Study design
This was a randomized, double-blind, placebo-controlled, dose-escalation study conducted at centres in Germany (four), France (one) and Norway (one). Subjects fulfilling the entry criteria were assigned randomly in a 3:1 ratio to either one of four everolimus dose groups or placebo. It was intended to enrol sequential cohorts of eight patients (six on everolimus, two on placebo) at different dose groups (0.75, 5 and 10 mg/day) and different dosing frequencies [once daily (qd) or twice daily (bid)]. In addition, capsule and tablet formulations were compared at the lowest dose level to test absorption. Two additional dose groups (2.5 mg qd, 2.5 mg bid) were added towards the end of the study in an open-label fashion to assess the pharmacokinetics of everolimus further, in a dose range that would be expected to be used in subsequent larger clinical trials. Thus everolimus was administered at the following seven dosing regimens: 0.75, 2.5, 5 and 10 mg qd tablet; 2.5 and 5 mg bid tablet; and 0.75 mg qd capsule. These regimens were administered for 28 days unless interrupted due to tolerability or safety concerns. The initial dose groups were initiated sequentially at weekly intervals so that a preliminary assessment of safety and tolerability could be made at each dose level prior to escalation to the next dose level. Safety and tolerability were monitored in an ongoing manner throughout the study by an independent, unblinded Safety Monitoring Board constituted specifically for this study. This study was of an exploratory design, i.e. the study was not powered to address a specific statistical hypothesis. The hard gelatin capsule formulation of everolimus and matching placebo at a dosage strength of 0.25 mg was used. The tablet market formulation of everolimus and matching placebos at dosage strengths of 0.25, 1, 5 and 10 mg were used. Doses were administered fasting with 250 ml of water at least 60 min prior to the next meal.
Safety and tolerability assessment
Information was collected on any adverse events (AEs) which occurred during the trial. Serious AEs (SAEs) were defined as AEs which were fatal or life threatening, required hospitalization or which caused other significant medical events.
Baseline measurements of vital signs, haematology and biochemistry were recorded, and a viral screening was performed. Treatment was initiated on day 1. Scheduled on-treatment assessments of vital signs, haematology and clinical biochemistry were made every 13 days up to day 28 (treatment end-point), and one post-treatment assessment was performed on day 42 (study end-point). An electrocardiogram (ECG) was performed every 13 days up to day 16, and on days 21 and 28. All patients who received at least one dose of study drug and underwent at least one assessment were evaluated. AEs of those patients participating in the open-label groups were recorded separately.
Pharmacokinetic assessment
Full pharmacokinetic profiles of everolimus over a 12 or 24 h dosing interval were obtained on days 1, 15 and 21. On profiling occasions, patients had an overnight fasting period of at least 12 h and, after administration of the medication, they remained fasting for an additional 4 h; only water was allowed. Blood samples were obtained from a forearm vein via an indwelling cannula pre-dose and then 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16 and 24 h thereafter. Blood samples (1.5 ml) were drawn into EDTA-coated collection tubes, gently inverted several times, frozen at 20°C or below, and analysed in a central laboratory.
Standard non-compartmental pharmacokinetic parameters were derived including the peak concentration (Cmax) and the time of its occurrence (tmax), the area under the concentrationtime curve over the 24 h dosing interval for once-daily regimens (calculated by trapezoidal summation; AUC24), and the percentage peaktrough fluctuation (PTF = [(Cmax Cmin)/Cavg] x 100).
Whole-blood everolimus concentrations were determined in duplicate by a validated enzyme-linked immunosorbent assay (ELISA) method [6]. Assay performance was based on a 7-point calibration curve (1.6 to 100 ng/ml) and five quality control concentrations (280 ng/ml) determined with each assay run. Assay precision (coefficients of variation) ranged from 11.2 to 26.3%, and accuracy (deviation from nominal value) from 1.6 to 8.8%. The limit of quantification was 2 ng/ml.
Statistical evaluation
Everolimus dose proportionality for Cmax and AUC24 was assessed by two approaches: (i) a one-way analysis of variance (ANOVA) with dose level as the source of variation performed on dose-normalized parameters separately for days 1, 15 and 21; and (ii) linear regression of Cmax and AUC24 vs dose level. To quantify everolimus inter- and intra-patient pharmacokinetic variability, the replicate steady-state parameters from days 15 and 21 were dose normalized and assessed in a two-way ANOVA with patient and replicate as sources of variation. The coefficient of inter-patient variability was derived from the patient mean square term, and the intra-patient variability from the error mean square term. The respective coefficients of variation were derived from the standard deviation (square root of the respective mean square term) divided by the global mean of the parameter.
Relative bioavailability of everolimus tablet vs capsule
Pharmacokinetic parameters on day 1 were log-transformed and compared between formulations by unpaired t-test. Tlag and tmax were compared untransformed by MannWhitney U-test. Replicate steady-state parameters from days 15 and 21 were log-transformed and compared in an ANOVA with the following model:
where response is a pharmacokinetic parameter. Potential formulation effects were tested using subject(formulation) as the error term. The model explored whether the differences between formulations were the same over time (day x formulation interaction term) or differed between days.
Relative bioavailability was calculated separately for days 15 and 21 as the ratio of the mean tablet AUC24 divided by mean capsule AUC24. In the absence of a day x formulation interaction and a day effect, the average AUC24 for each patient from days 15 and 21 was calculated and the above-mentioned ratio derived from the respective formulation means.
Everolimus pharmacodynamics
Laboratory parameters of interest for this evaluation were platelets, cholesterol, triglycerides and leukocytes. The everolimus pharmacokinetic metric was the AUC24 from day 21 in the present study and from day 28 from Study RADB154 in which stable renal transplant recipients receiving the service capsule [20] were assessed at steady state.
The relationship between everolimus AUC24 vs the minimum platelet and leukocyte counts and the maximum cholesterol and triglyceride levels was assessed by Spearman rank correlation. Logistic regression was used to determine the probability of a laboratory parameter abnormality given the everolimus AUC24. Clinically relevant abnormalities for this analysis were defined as: platelet count <100 x 109/l; platelet decrease >50 x 109/l from baseline; leukocyte count <3 x 109/l; cholesterol >10 mmol/l; and triglycerides >5 mmol/l.
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Results
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Subjects
A total of 54 subjects were randomized for treatment with everolimus (n = 44) or placebo (n = 10). Due to safety concerns, the highest dosage group (10 mg qd) was prematurely terminated by the Safety Monitoring Board. The following seven dose regimens were assessed: 0.75 mg (everolimus n = 6; placebo n = 2), 2.5 mg (everolimus n = 6), 5 mg (everolimus n = 6; placebo n = 2) and 10 mg (everolimus n = 2; placebo n = 1) tablet given orally once daily (qd); 2.5 mg (everolimus n = 12; placebo n = 2) and 5 mg (everolimus n = 6) tablet given orally twice daily (bid); and 0.75 mg (everolimus n = 6; placebo n = 2) capsule given orally qd. Demographic data and background medical characteristics (including prior non-immunosuppressant medications, kidney transplant and rejection history) were comparable across treatment groups (Table 1). Initial cyclosporin doses were comparable in each of the everolimus dosing cohorts: in the placebo group, the dose was 107±36 mg bid and among the patients receiving everolimus, the mean cohort doses ranged from 100±50 to 137±40 mg bid.
Eight (80%) of the 10 patients in the placebo group and 29 (80.5%) of the 36 patients in the everolimus dose group up to 5 mg/day received study drug for the full duration of treatment, while only one patient (12.5%) of the eight enrolled in the 10 mg dose group completed the study. Treatment discontinuations in the everolimus group were due to AEs in 11 subjects, and in a further three subjects was due to the decision of the Safety Monitoring Board to discontinue treatment at the 10 mg/day dose level. One (10%) subject in the placebo group was withdrawn because of a protocol violation (not meeting the inclusion/exclusion criteria). If samples for pharmacokinetic analysis were obtained, these were included in the results, even if the patients discontinued the study.
Evaluation of safety and tolerability
Adverse events
Overall, AEs were reported by a similar proportion of subjects in the everolimus treatment group (96%), the placebo group (90%) and in unblinded patients (90%). Thus the AEs for unblinded patients are included in the overall safety analysis (Table 2). A higher proportion of AEs was reported for the higher everolimus dose groups.
Only a few of these events, however, were considered severe AEs in everolimus daily dose groups up to 5 mg (n = 9, 25% of patients) compared with one severe AE (10%) in the placebo group. In seven out of 36 patients, treatment was discontinued due to an AE: in three cases of the blinded treatment groups [pneumonia (0.75 mg qd); fever, elevated C-reactive protein (CRP) and oedema (5 mg qd); and anaemia and thrombocytopenia (5 mg qd)], and in four patients in the open-label group (2.5 mg bid: hypertension and headache; increased serum creatinine; intestinal obstruction; and a patient with gastritis, atrial fibrillation, oedema and elevated lipids). A total of five SAEs were reported in everolimus dosage groups up to 5 mg daily, consisting of one case each of gastroenteritis, pneumonia, influenza-like symptoms, intestinal obstruction and myocardial infarction. Neither treatment discontinuations nor SAEs were reported for the placebo group.
In contrast to the lower dose groups, the SAEs and discontinuations for AEs observed in the everolimus 10 mg daily dose group frequently represented events typically associated with this macrolide class of immunosuppressants, especially thrombocytopenia (n = 4; in two cases associated with haematoma and epistaxis, respectively). Two out of three SAEs constituted thrombocytopenia and stomatitis, respectively (one case each). This highest dosage group was therefore prematurely terminated by the Safety Monitoring Board.
Twenty-nine AEs coded as infections occurred during the course of this study, the majority of them of mild to moderate severity. The overall rate was found to be higher in the everolimus-treated patients (43%) as compared with placebo-treated patients (20%). Five infections in the everolimus dose groups were reported as SAEs, three of them in the 0.75 mg dose group (one case of gastroenteritis, one case of pneumonia and sepsis resulting in discontinuation of study medication, and one case of influenza-like symptoms) and two of them in the 10 mg total daily dose group (one patient with viral infection and fever, one patient with stomatitis resulting in discontinuation of study medication). While the overall incidence of infections may reflect the augmented immunosuppression within this study (in particular in the 10 mg dose group), no distinct pattern of infections or dose relationship was apparent.
No patient died during the course of the study. However, one patient randomized for treatment with 10 mg/day everolimus (5 mg bid) died due to intracerebral haemorrhage (ruptured aneurysm) 23 days after treatment had been discontinued prematurely [due to thrombocytopenia (80 k/µl), spontaneous haematoma and mild epistaxis]. The subject's platelets had returned to normal prior to the event (290 k/µl). The cerebral haemorrhage was considered by the investigator to be unrelated to everolimus therapy.
No differences in vital signs (blood pressure, pulse rate, body weight and temperature) or physical examination were observed between the everolimus and placebo treatment groups during the present study. Frequent ECG monitoring over the course of the study did not reveal any increased incidence of ECG abnormalities on everolimus as compared with placebo treatment. Similarly, no clinically relevant changes were detected in echocardiograms performed during the study.
Laboratory evaluations
Haematology assessments showed that decreases in leukocytes and platelets were observed after 2 weeks (days 1216) on treatment with everolimus, compared with placebo (Figure 1). Notably, these changes improved while patients were still on treatment and reversed by the end of treatment. With respect to leukocyte numbers, there was no clear doseeffect relationship for doses up to 5 mg of everolimus daily. The trend towards a transient decrease in leukocyte counts appeared to be due primarily to a decrease in neutrophil counts, while peripheral lymphocyte counts appeared less or not affected. No differences in haemoglobin or haematocrit were observed between the everolimus treatment groups as compared with placebo. The decrease in platelet counts was more pronounced at the higher everolimus dose levels.
Measurements of biochemical variables showed abnormalities more than twice the upper normal limit for serum cholesterol (peak day 9) following treatment with everolimus [17 subjects (43%)], compared with placebo [one subject (14%)]. Elevation of cholesterol was greatest at the 10 mg/day dose level. Lesser differences were observed between everolimus and placebo in terms of elevations in triglycerides. A tendency to increase over time was observed, which was most pronounced at the 2.5 and 5 mg bid dose groups. After the end of the treatment phase (day 28), triglyceride values returned close to baseline values at the follow-up visit on day 42 (Figure 1). No notable changes were observed in any other measurements of renal, liver or metabolic function, nor in electrolytes, enzymes, markers of inflammation or urinalysis.
Everolimus pharmacokinetics
Relative bioavailability: tablet vs capsule
The pharmacokinetic parameters from the service capsule and tablet given in regimens of 0.75 mg qd are summarized in Table 3. The parallel group comparison of the capsule and tablet formulations of everolimus on day 1 (Figure 2) was characterized by much lower Cmax and AUC24 for the capsule (P<0.02). Concentrations were generally no longer quantifiable after 6 h (range 216 h) following administration of the capsule, whereas they were quantifiable to 1224 h for the tablet. The replicate profiles on days 15 and 21 were comparable within patients as indicated by lack of a significant day effect in the ANOVAs. Differences between the formulations were consistent on both assessment days as supported by the absence of day x formulation interactions. Although there was no apparent difference in tmax, the rate of absorption was slower for the capsule, with a 2-fold lower Cmax on both study days (P<0.01). PTF was not significantly different between formulations (P = 0.14). The relative bioavailability of everolimus from the tablet vs the capsule formulation was 2.8 on day 15 and 2.3 on day 21. The relative bioavailability based on each patient's AUC24 averaged across study days was 2.6.
Dose proportionality
The pharmacokinetic variables of the qd dosing regimens are summarized in Table 4. Dose proportionality in everolimus Cmax and AUC24 over the single dose range 0.7510 mg was indicated by lack of differences among dose-normalized parameters (P = 0.46 and 0.27, respectively) and significant regressions with y-axis intercepts not significantly different from zero. Because the 10 mg once-daily regimen was discontinued, there were insufficient steady-state data to include this dose level in the evaluation. Therefore, steady-state dose proportionality was assessed from 0.75 to 5 mg once daily (Figure 3). Both ANOVA and linear regression demonstrated a dose-proportional rise in Cmax for days 15 and 21 as well as for combined data from both days. Both ANOVA and linear regression on AUCs indicated that values from the 2.5 and 5 mg once-daily regimens rose in a dose-proportional manner but that the data at 0.75 mg were slightly higher than expected for dose proportionality in this parallel-group assessment. Linear regression on combined data from days 15 and 21, however, provided evidence for dose proportionality over the range 0.755 mg once daily.
Intra- and inter-subject pharmacokinetic variability and covariates
Coefficients of pharmacokinetic variability at steady state were 1019% within patient and 3460% between patients. Statistical results comparing the replicate steady-state pharmacokinetic parameters from days 15 and 21 are summarized in Table 5, as are the pertinent data for deriving the coefficients of variation.
Pharmacodynamic evaluation
Plots showing the everolimus AUC24 vs the maximum/minimum laboratory parameter values are depicted in Figure 4. There was a moderate negative correlation between everolimus AUC24 vs decreases in platelet counts (r = 0.392, P = 0.005) as shown in Figure 4. Everolimus AUC24 was not predictive of abnormalities in white blood cell count (r = 0.161, P = NS), cholesterol (r = 0.006, P = NS) or triglycerides (r = 0.010, P = NS). It was a significant predictor of a decline in platelets >50 x 109/l from baseline (P<0.001) as shown in Figure 5 and of a platelet count <100 x 109/l (P = 0.003). These two regressions indicate that increasing everolimus exposure may result in a higher probability of a decline in platelets >50 x 109/l or of a platelet count <100 x 109/l. Linear regression for a decrease in leukocyte count <3 x 109, elevation of cholesterol >10 mmol/l or triglycerides >5 mmol/l yielded no significant results.

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Fig. 4. Relationship between everolimus AUC and important laboratory parameters. Scatterplot of everolimus AUC and (A) minimum platelet count, (B) minimum leukocyte count, (C) maximum cholesterol and (D) maximum triglycerides over the study course. The horizontal line identifies the critical value as defined in Materials and methods.
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Fig. 5. Logistic regression of showing the probability of a drop in platelets by 50 x 109/l from baseline.
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Discussion
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Here we report the results of the first, multiple oral dose clinical study of everolimus tablets. Everolimus (or placebo) was administered as add-on therapy to maintenance renal transplant patients on a double immunosuppressive regimen consisting of Neoral® and steroids. In this study, a wide dose range of everolimus was assessed, from 0.75 mg daily up to 10 mg daily. Further, everolimus tablets and capsules were compared at the lowest dose. No clinically relevant differences with respect to tolerability and AEs of the two galenical formulations were observed. Oral absorption of everolimus from the tablet formulation was rapid and consistent (low intra-subject, inter-occasion variability) and showed dose proportionality across the dose range studied. In comparison with the trials in de novo renal transplant patients [1820], the patients on cyclosporin maintenance therapy in this study had higher everolimus drug exposure. It seems conceivable that these differences are due in part to the strict laboratory conditions for the pharmacokinetic sampling in this study, due to differences in patient disposition or due to better absorption in maintenance patients. Between-subject variability for everolimus was high (3160%), a finding also reported for sirolimus [1417]. This observation suggests the requirement for therapeutic drug monitoring in the routine use of this drug.
Overall, everolimus doses up to 5 mg daily were found to be adequately well tolerated. AEs frequently reported in everolimus-treated patients included the well known side effects of this class of macrolide immunosuppressants, with thrombocytopenia and hyperlipidaemia as the most prominent side effects [14,1317]. In the dosage groups up to everolimus 5 mg daily, few of these AEs were recorded as severe or serious AEs. In contrast, in the 10 mg everolimus daily dose groups, three out of seven patients needed to be discontinued from study medication due to severe thrombocytopenia, two of them with signs of bleeding. As a consequence, the 10 mg daily dosage group was prematurely discontinued. Over the entire everolimus dose range assessed, this study failed to reveal any new clinical relevant side effects attributed to everolimus that had not been observed with sirolimus [1,1417], or with everolimus previously [2,13,1820]. In summary, this dose-escalating phase I study provided evidence that everolimus up to 5 mg daily has an acceptable safety profile, while doses of 10 mg are beyond tolerability, thus extending our knowledge on this new immunosuppressive compound. As a consequence, everolimus daily doses of up to 4 mg are used in the ongoing phase II and III studies [1820].
Reductions in platelet counts appeared to be transitory, with the nadir reached by the second week of everolimus treatment. Thereafter, platelet counts tended to increase again, despite the continued administration of everolimus. Pharmacodynamic assessments further confirmed that increasing exposure with everolimus may result primarily in an increased frequency of thrombocytopenia, a result which was confirmed in other studies [3,13,1820]. It has been suggested that the reversible thrombocytopenia (and the less pronounced effects on leukocytes) may be related to a drug-induced inhibition of the transduction of cytokine signals necessary for the proliferation and differentiation of bone marrow elements. However, the exact molecular mechanisms (including the mechanisms behind the platelet count recovery during continued everolimus therapy) remain to be elucidated.
Serum creatinine remained stable over the entire course of the study, i.e. there was no indication that everolimus (over the dose range assessed) would potentiate CsA-induced renal dysfunction. However, the study was not designed to be able to draw any conclusions on nephrotoxicity, as seen with sirolimus and cyclosporin [5]. Other than those mentioned above, there was no consistent trend or finding with respect to the other biochemical assessments during the course of the study, in particular liver function tests. The most prominent effect on the safety laboratory values, besides thrombocytopenia, was the effect of everolimus on the lipid profile. This side effect has been well documented in other trials with everolimus [13,1820] and is a well-recognized side effect of sirolimus therapy [1,1417]. Analysis of the data and pharmacodynamic exploration, however, failed to demonstrate a clear dose relationship over the time course of this study; the incidence of hypertriglyceridaemia was even higher in the placebo group. In part, this might be due to the low exposure in the initial dosing cohorts and only a limited number of subjects receiving high everolimus exposure. Additionally, genetic factors and/or dietary behaviour in our well-educated study population may have contributed to the rather small effect in our study. Additional larger studies are needed to explore fully the effect of everolimus on lipid metabolism.
In conclusion, this study provides the first evidence that multiple daily dosing of everolimus, in doses up to 5 mg/day, is adequately well tolerated as add-on therapy in stable renal transplant patients receiving maintenance Neoral® immunosuppression. Further large-scale clinical studies of everolimus in de novo transplant recipients are underway to assess comprehensively the efficacy and safety of everolimus given concomitantly with Neoral®.
The RADW 102 Renal Transplant Study Group consists of the following additional members: L. Lerat (Nantes, France), K. Nordal (Oslo, Norway), L. Müller, R. Brunkhost (Hannover, Germany), L. Renders (Kiel, Germany), K. Burckhardt, M. Schreiber, H. G. Wullstein (Erlangen, Germany), R. Schötschel (Berlin, Germany), B. Charpentier (Safety Board Member, Le Kremlin Bicêntre, France), P. McMaster (Safety Board Member, Birmingham, UK), Albrecht-Georg Schmidt, Annette Jappe, Nathalie Cambon, Janet Von Fellenberg, Khazal Paradis, Silke Appel Dingemanse, Francois Legay (Novartis, Basel, Switzerland) and Christophe Gerbeau (Paris, France).
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Acknowledgments
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This study was supported by Novartis Pharma AG, Basel, Switzerland.
Conflict of interest statement. None declared.
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Received for publication: 2. 1.04
Accepted in revised form: 28. 4.04