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DRUG INTERACTIONS |
From the University Clinic Charité, Berlin, Germany (Dr Budde, Dr Fritsche, Dr Neumayer); Nephrology Service, CHU Hotel Dieu, Nantes, France (Dr Soulillou, Dr Dantal); Rikshospitalet, Oslo, Norway (Dr Lehne, Dr Fauchald); Medizinische Hochschule, Hannover, Germany (Dr Winkler); Universitätsklinikum Kiel, Germany (Dr Renders); and Zentral-krankenhaus, Bremen, Germany (Dr Lison).
Address for reprints: Klemens Budde, University Clinic Charité, Schumannstr. 20/21, Berlin 10098, Germany.
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ABSTRACT |
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 TOP ABSTRACT MATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Cyclosporine • everolimus • pharmacokinetics • renal transplantation
Sirolimus and everolimus have potent immunosuppressive activity and have a mode of action different from that of CsA and other classes of immunosuppressants.1,11 They target the signal transduction pathway involved in cell-cycle progression by inhibiting the mammalian target of rapamycin (mTOR), thus leading to subsequent inhibition of interleukin-2 (IL-2)-induced T-cell proliferation as well as inhibition of general growth-factor-dependent proliferation of hematopoietic and nonhematopoietic cells, including vascular smooth muscle cells.11,12 Chronic rejection has been attributed to proliferation of vascular smooth muscle cells.12 Therefore, improved immunosuppression and a direct effect of these drugs on smooth muscle cell proliferation may have an impact on long-term outcomes.12
Sirolimus, the first drug of the class of mTOR inhibitors, is primarily metabolized through the hepatic cytochrome P450 (CYP) 3A4 enzyme system, which is shared with CsA mutual microsomal metabolism.7-10 In addition, both drugs are substrates for p-glycoprotein countertransport.7-10 Not surprising, several studies have demonstrated a strong pharmacokinetic interaction between sirolimus and CsA.13-20 Interestingly, CsA pharmacokinetics is unaffected by sirolimus in renal transplant recipients.13,14 In contrast, CsA administration resulted in markedly (1.8- to 2.3-fold) elevated sirolimus exposure20; even the timing of CsA dosing affected sirolimus pharmacokinetics. Whole-blood trough levels increased by about 30% with concomitant dosing; the time to peak levels was also shorter (1.8 vs 2.5 hours) compared to timely separated administration.20 As a consequence, sirolimus should be given 4 hours after CsA according to the dosing recommendations. No such effect of timing of drug administration, however, could be found on CsA pharmacokinetic parameters.20
Since everolimus is intended to be used with CsA and both compounds are metabolized in part by CYP3A4,9,10 the potential influence of everolimus on CsA pharmacokinetics needs to be investigated. This is the first study to investigate the tablet formulation of everolimus across a wide range of doses, unlike the previously reported phase I single-dose study5 and a multiple-dose study that used in development a service capsule formulation6 that will not be commercially available. This is of particular importance as the tablet has a 2.6-fold higher bioavailability compared to the service capsule.21 The aim of the present study was to assess the effect of steady-state everolimus coadministration over a wide dose range on detailed steady-state pharmacokinetics of CsA in stable renal allograft recipients. Unlike previously reported studies,22-26 complete 12-hour CsA pharmacokinetics in stable renal allograft recipients receiving the microemulsion formulation of CsA was assessed, as it is well known that CsA exposure varies over time22 and trough levels are a poor indicator of CsA exposure.27
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MATERIAL AND METHODS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Study Design
This was a randomized, double-blind, placebo-controlled, dose-escalation study conducted at 6 centers. Subjects fulfilling the entry criteria were randomly assigned in a 3:1 ratio to either 1 of 4 everolimus dose groups or placebo. This comprised 7 treatment groups to examine the effect of dose level, dosing frequency (once daily [QD] or twice daily [BID]), and formulation (capsule and tablet at 0.75 mg QD). Dose groups (0.75, 5, and 10 mg/d) 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, un-blinded Safety Monitoring Board constituted specifically for this study. An additional dose group (2.5 mg QD, open label) was added toward the end of the study. In addition, 4 patients were added in an open-label fashion to the 2.5-mg-BID group to further assess the safety and tolerability of the 5-mg daily dose, given concomitantly with cyclosporine in a BID dosing regimen. Treatment at each dose level was administered for 4 weeks. At the baseline visit (before administration of study drug, while the patients were hospitalized for the baseline CsA pharmacokinetic profile), creatinine clearance was determined from a 24-hour urine sampling period using the local laboratory at each center. Pneumocystis carinii prophylaxis with cotrimoxazole/sulfamethoxazole was mandated during the course of the study. This study was of an exploratory design; that is, the study was not powered to address a specific statistical hypothesis. The results of the safety and pharmacokinetic exploration of everolimus were published separately.21
Pharmacokinetic Assessment
Morning trough whole-blood levels (Cmin) of CsA were measured at 1- to 3-day intervals throughout the study. Steady-state CsA pharmacokinetic profiles over the 12-hour dosing interval were obtained at baseline in the absence of everolimus and on day 21 during everolimus coadministration when steady-state everolimus blood concentrations would have been attained. For CsA profiling, blood samples were drawn predose and after 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, and 12 hours. Full pharmacokinetic profiles of everolimus over a 12- or 24-hour dosing interval were obtained on days 1 and 21. For everolimus profiles, blood samples were obtained from a forearm vein via an indwelling cannula predose 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 hours thereafter. On profiling occasions, patients had an overnight fasting period of at least 12 hours, and after administration of the medication, they remained fasting for an additional 4 hours; only water was allowed in this period. All blood samples were drawn into EDTA-coated collection tubes, gently inverted several times, frozen at -20°C or below, and analyzed in a central laboratory.
Whole-blood everolimus concentrations were determined in duplicate by a validated enzyme-linked immunosorbent assay method.5,6 Assay performance was based on a 7-point calibration curve (1.6 to 100 ng/mL) and 5 quality control concentrations (2 to 80 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) ranged from -1.6% to -8.8%. The limit of quantification was 2 ng/mL. CsA was quantified in whole blood by a commercially available radioimmunoassay using a monoclonal antibody specific for the parent compound (INCSTAR Cyclo-Trac SP, Stillwater, Minn). Assay performance was based on a 7-point calibration curve (25-2500 ng/mL) and 5 quality control concentrations (30-1600 ng/mL). The precision of quality control samples (coefficients of variation) ranged from 5.1% to 13.5%, and the assay quantification limit was 25 ng/mL.
Statistical Evaluation
Standard noncompartmental pharmacokinetic parameters were derived including the peak concentration (Cmax) and the time of its occurrence (tmax), the area under the concentration-time curve over the dosing interval (AUC), and the percentage peak-trough fluctuation (PTF). Attainment of steady state for everolimus and CsA was assessed by linear regression analysis of the serial trough concentrations over time. A slope not significantly different from zero (a horizontal line) was taken as evidence for steady-state conditions. Serial CsA trough concentrations were plotted for each everolimus dosing group and inspected for trends over the study duration. Linear regression analysis was performed for each patient's troughs over time. A significant positive slope was interpreted as a rise in CsA exposure over the course of the study.
The influence of everolimus on CsA pharmacokinetics was explored by an analysis of variance (ANOVA) on dose-normalized CsA parameters from baseline (without everolimus) and day 21 (under steady-state everolimus). The ANOVA included terms for everolimus dose level (including placebo), patient nested within everolimus dose level, study day (days 0 and 21), and day by everolimus dose-level interaction. This model explored whether differences in CsA pharmacokinetic parameters between baseline in the absence of everolimus and day 21 during everolimus coadministration were different among the everolimus dose levels including placebo. Pharmacokinetic parameter ratios (coadministration on day 21/baseline on day 0) were also derived and compared among everolimus dosing levels in a 1-way ANOVA. Linear regression analysis was performed on everolimus AUC on day 21 versus the CsA AUC ratio. A slope not significantly different from zero was taken as evidence that everolimus had no influence on CsA pharmacokinetics.
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RESULTS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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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/d received study drug for the full duration of treatment, while only 1 patient (12.5%) of the 8 enrolled in the 10-mg dose group completed the study. If samples for pharmacokinetic analysis were obtained, these were included in the results, even if the patients discontinued the study. A total of 9 serious adverse events (AEs) were reported in 8 everolimus-treated patients, consisting of 2 viral infections and 1 case each of gastroenteritis, pneumonia, intestinal obstruction, myocardial infarction, stomatitis, increased creatinine, and thrombopenia, leading to 4 treatment discontinuations. Treatment discontinuations in the everolimus group were due to AEs in 11 subjects, and in a further 3 subjects, discontinuation was due to the decision of the Safety Monitoring Board to discontinue treatment at the 10-mg/d dose level. AEs leading to discontinuation were thrombocytopenia (n = 4), infection (n = 2), stomatitis and thrombocytopenia, hypertension and headache, increased serum creatinine, intestinal obstruction (each n = 1), and a patient with gastritis, atrial fibrillation, edema, and elevated lipids. Most AEs leading to discontinuation (especially thrombocytopenia) occurred in the highest dosage groups.21 The highest dosage group was therefore prematurely terminated by the Safety Monitoring Board. Neither treatment discontinuations nor serious AEs were reported for the placebo group. One (10%) subject in the placebo group withdrew because of a protocol violation.
Cyclosporine Dosing
Initial CsA doses were comparable in each of the everolimus dosing cohorts: in the placebo group, the mean dose was 107 ± 36 mg BID and among the patients receiving everolimus, the mean cohort doses ranged from 100 ± 50 (0.75 mg QD), 133 ± 44 (2.5 mg QD), 133 ± 17 (5 mg QD), 135 ± 45 (2.5 mg BID), to 137 ± 40 (0.75 mg QD capsule mg BID). At the end of the study, the mean CsA dose differed not significantly from starting doses (placebo: 107 ± 36; 0.75-mg capsule: 133 ± 33; 0.75 mg QD: 95 ± 48; 2.5 mg QD: 129 ± 51; 5 mg QD: 133 ± 17; 2.5 mg BID: 129 ± 47; 10 mg QD (n = 1): unchanged 150 mg BID).
Of the 52 patients providing CsA concentration-time data (profiles and/or troughs), 38 (73%) maintained the same dosage schedule throughout the trial. The remaining 14 patients had dose reductions of 20 mg (n = 1), 25 mg (n = 4), 50 mg (n = 8), and 75 mg (n = 1). These dose reductions were started roughly equally in each study week: 3 in week 1, 5 in week 2, 2 in week 3, and 4 in week 4. While no patient randomized to receive placebo had a CsA dose alteration, the 14 dose reductions were equally spread among the rising everolimus dose levels.
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Cyclosporine Profiles
Paired CsA profiles from day 0 (CsA alone) and day 21 (CsA + everolimus) were evaluable from 9 patients receiving placebo and 32 patients receiving everolimus. None of the patients randomized to receive 5 mg everolimus BID remained in the study to day 21; hence, paired CsA profiles were not available at this dose level. Pharmacokinetic parameters are summarized in Table II for 3 representative everolimus dose levels using the tablet formulation. The administration of the capsule formulation yielded similar results (not shown). The global ANOVA did not detect any group-by-day interactions; hence, the main effects comparison was used to assess differences in parameters between days. No differences in tmax or PTF were noted when CsA was coadministered with everolimus compared with administration alone (P = .60 and .17, respectively). Dose-normalized Cmin and AUC were significantly increased (P < .01 for both) across all dose groups (including placebo), while dose-normalized Cmax showed a similar trend (P = .06). Representative plots to examine the mean dose-normalized parameters across 3 dosing groups and the placebo group on the 2 profiling occasions are shown in Figure 2.
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Cyclosporine Parameter Ratios
An alternative approach to examine CsA changes across everolimus dose groups was based on the CsA parameter ratios (ratio coadministration/baseline). These data are summarized in Table III. Over the course of the study, CsA trough concentrations rose by 24% on average in patients receiving placebo and between 10% and 19% for the lower dose everolimus regimens (0.75-2.5 mg QD). Of the 2 regimens delivering the same total daily dose of 5 mg, there was a 58% increase for 5 mg QD but a 28% increase for 2.5 mg BID; this lack of an apparent dose relationship was due to individual variability. At the highest dose level of 10 mg QD (n = 1), no change in CsA trough was noted. Similar patterns were noted for dose-normalized Cmax and AUC. In the placebo arm, these parameters rose on average by 11% and 15%, respectively, with similar increases at all other everolimus dose levels with the apparent exception of 5 mg QD (38% and 43%). Nonetheless, ANOVA did not detect any differences in the magnitude of the Cmax or AUC increases (P = .17 and .13, respectively) across all dose levels including placebo. The plot of dose-normalized AUC ratios is reproduced in Figure 3. In agreement with the global ANOVA, CsA peak-trough fluctuation was not altered upon coadministration with everolimus (P = .17).
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An additional analysis of the impact of everolimus exposure on CsA disposition was based on linear regression of everolimus AUC versus the coadministration/baseline CsA AUC ratios (day 21/0). As shown in Figure 4, the slope of the relationship was not significantly different from that of a horizontal line (P = .24).
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DISCUSSION |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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No CsA dose reductions were performed in the placebo arm, and 28 of 44 patients (64%) randomized to receive everolimus maintained the same CsA dose throughout the study. The remaining 14 patients had generally small dose reductions of 
50 mg, probably reflecting the improved compliance during the course of the study. Only 1 patient had a reduction of 75 mg. Since these patients were evenly distributed across all everolimus dose levels, increasing everolimus exposure did not appear to have a strong influence on CsA exposure based on CsA-dosing histories. This observation extends the previous report on 24 patients receiving the service capsule formulation of everolimus.6 No dose changes under everolimus treatment were reported in this smaller study, suggesting no major impact on CsA pharmacokinetics under steady-state conditions. However, the fact that all patients who received CsA dosage adjustments were on active everolimus and none on placebo and that all were CsA dosage reductions might suggest that there was indeed a minor interaction occurring. Unfortunately, even the analysis of 2 large prospective trials with more than 580 patients each could not solve this question as the mean CsA dose was about 9% lower in everolimus-treated patients, but this reached statistical significance only in the global trial, not in the American trial.22 In this regard, it is important to note that smaller drug interactions cannot be detected based on CsA-dosing histories alone, mainly because CsA dose changes depend on the fluctuating CsA trough levels (with a coefficient of variation in this study of 14%-20%), which precludes the detection of smaller pharmacokinetic interactions.
We next analyzed CsA trough concentrations in greater detail. To avoid any additional interassay variability, all CsA concentrations were determined in a central laboratory. CsA trough concentration trajectories demonstrated a general rise in troughs over the study duration in the majority of patients receiving placebo, suggesting better patient compliance during the course of the clinical trial. In cohorts of patients receiving everolimus, a similar or even lower proportion of patients had significant increases in trough levels. Again, this observation is in line with the previously reported North American study, in which 29% of patients had increasing CsA trough levels over the course of the study.6 Furthermore, even large studies in de novo renal allograft recipients failed to demonstrate a clear effect of low everolimus doses (1.5-3 mg/d) on CsA trough level.22 Although dose-normalized Cmin was approximately 10% higher in everolimus-treated patients, this difference reached statistical significance only in the global trial and failed to reach statistical significance in the American trial. Using a population pharmacokinetic approach, it was found that everolimus-treated patients had similar CsA trough levels compared to mycophenolate mofetil-treated patients, and there was only a weak correlation between everolimus exposure and CsA trough levels, suggesting congregation of high absorber status and/or poor clearance for both drugs.25 In addition, 3 de novo trials could not demonstrate a significant impact of everolimus dosing (0.5-4 mg) on CsA levels24,28,29; however, these trials had no control group of patients not receiving everolimus. The detailed analysis in our European cohort of stable maintenance patients provided further evidence that everolimus, assessed over a wide dosing range, has no major impact on CsA trough levels, which would be expected to have a clinical meaningful effect. Important to note is the rather large coefficient of variation (14%-20%) in consecutive CsA trough level determinations, even in this closely monitored, selected, and compliant study population. This probably reflects the highly variable CsA pharmacokinetics and makes the detection of smaller changes of CsA exposure based on trough level monitoring difficult.27
Because CsA trough levels do not adequately reflect CsA drug exposure,27 individual CsA pharmacokinetic parameters from the full profiles were compared between baseline and coadministration with everolimus across different everolimus dose groups. ANOVA detected higher CsA exposure during coadministration with everolimus; however, this was also detected in the placebo arm. To more specifically address potential differences among everolimus dose levels, the CsA AUC ratios (coadministration/baseline) were compared across groups. The mean ratio was 1.15 for placebo and did not significantly differ in the everolimus dose groups in which the ratios ranged from 1.08 to 1.43. Finally, the above approaches categorize each patient's everolimus exposure into the nominal everolimus regimen they received, which may down-play interindividual variation in the systemic everolimus exposure. By contrast, linear regression analysis incorporates everolimus exposure (AUC on day 21) as a continuous variable. When regressed against the change in CsA exposure, the relationship was not different from a horizontal line over the full range of everolimus AUCs achieved in this study. Using abbreviated pharmacokinetic profiles from 256 de novo patients, Kovarik et al22 could not find differences between everolimus-treated patients and patients receiving mycophenolate mofetil with regard to CsA AUC and Cmax. In 953 paired observations, they observed only a weak correlation (r = 0.38) between everolimus exposure and CsA exposure and only a modest rise in dose-adjusted Cmin. The effect of everolimus on CsA exposure was clearly much less pronounced than the intra- and interindividual variability of CsA.22
Within the limitations of the study, our comprehensive and thorough evaluations over a broad range of everolimus exposures suggest that steady-state CsA pharmacokinetics was not influenced by steady-state coadministration of everolimus to a significant degree that would be expected to have a clinical effect, based on what is known about CsA pharmacokinetics. This conclusion is in agreement with preclinical pharmacokinetic studies in rats and monkeys9,30 and with previous clinical studies6,22,24,26 in which steady-state coadministration of 0.5 to 7.5 mg everolimus with CsA did not affect the pharmacokinetics of the latter. In addition, single-dose administration of everolimus to renal transplant patients5 or healthy volunteers23 resulted in no interaction with CsA pharmacokinetics. Kirchner and colleagues31,32 performed a detailed analysis of CsA metabolites in a small number of patients. They could not detect an impact of everolimus on CsA metabolites after single-dose and multiple-dose administration,31,32 which excluded a significant influence of everolimus on the time-concentration relationship and the metabolism of CsA under steady-state conditions. Finally, the single and multiple oral administration of sirolimus did not reveal any pharmacokinetic interaction on CsA blood concentrations13-15,20 in renal transplant recipients. Because both drugs are structurally closely related and share most metabolic pathways, this observation provides further evidence that there is no significant drug interaction of everolimus on CsA pharmacokinetics, but this cannot rule out pharmacodynamic interactions of both drugs.
Similar to tacrolimus and CsA, sirolimus and everolimus are metabolized to some extent in the small intestine and extensively in the liver via cytochrome P450 3A4 enzymes and are countertransported in the gut lumen by the multidrug efflux pump, p-glycoprotein; these processes account for low bioavailability and high pharmacokinetic variability.2,4,13 As a consequence of this wide interpatient variability, it is not possible to rule out that some patients have an interaction to everolimus. This has been described for other drugs interacting with CsA, in which some patients are more sensitive to the interaction than are others (eg, serial metabolic inhibition studies with diltiazem33). Larger, specifically designed studies are needed to further explore this issue.
As immunosuppressive doses and concentrations of CsA in humans are usually 100-fold higher than those of everolimus, the competition between both drugs for elimination pathways would favor an influence of CsA on everolimus compared with the reverse situation. This indeed has been shown in animal models, in which CsA increased the systemic exposure to everolimus. Similarly, CsA seems to exert rather strong effects on everolimus exposure in humans, as demonstrated in a single-dose study.23 The effect of CsA seems to be dependent on the CsA formulation, as Neoral exhibited much stronger effects on everolimus exposure (168% increase) compared with the previous CsA formulation (Sandimmun; 74% increase). Because everolimus was added to patients already receiving CsA, there was no opportunity to examine the possible effect of CsA on everolimus pharmacokinetics in this study. Similar to everolimus, in preclinical models, sirolimus increased the bioavailability of CsA by 2- to 3-fold,19 with an approximately 2-fold increase in the CsA concentrations in rat tissues.9,16,18 From these studies, it was suggested that the pharmacokinetic interaction between both drugs might contribute to the observed in vivo synergism. However, this pharmacokinetic interaction with increased drug concentrations in renal tissue might be responsible for the aggravation of CsA-induced renal dysfunction, as has been suggested by Podder et al.16 Whether these data derived from experimental models transfer to humans is yet unclear.
Despite their structural similarity and identical mode of action, sirolimus and everolimus clearly differ in their pharmacological metabolism.17 Although CYP 3A4 is mainly responsible for the metabolism of both sirolimus and everolimus, the total intrinsic clearance of the CYP-dependent formation of everolimus metabolites is 3-fold lower than for sirolimus, and some of the main metabolic rate constants are drastically (up to 15-fold) reduced.17 In contrast to sirolimus, everolimus decreased CsA concentration in rat brain mitochondria.9 Furthermore, sirolimus enhances CsA toxicity on rat brain; everolimus, however, had no effect on CsA toxicity and even improved some deleterious effects of CsA on high-energy phosphate metabolism.9
Taken together, our data provide further evidence that everolimus coadministration exhibits no relevant effect on pharmacokinetics and CsA exposure in Caucasians that would be expected to have a clinical effect, based on what we know today about CsA pharmacokinetics. This observation clearly extends our knowledge on this interesting new immunosuppressive compound, suggesting that everolimus could be used concomitantly with the microemulsion formulation of CsA using either QD or the standard BID dosage. However, the present study did not address the question of pharmacodynamic interactions, which might be responsible for the increased incidence of calcineurin-related toxicity, seen in clinical studies, when everolimus or sirolimus were coadministered with CsA.1,3,10,16,28,29 Because of limitations of the present study, which do not allow us to detect smaller changes or changes in subpopulations (eg, black patients; patients who differ in their expression of CYP 3A or p-glycoprotein), this finding will, however, need to be confirmed over longer periods of coadministration in broader patient populations.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Nashan B. Review of the proliferation inhibitor everolimus. Expert Opin Investig Drugs. 2002;11: 1845-1857.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
2. Kovarik JM. Everolimus: a proliferation signal inhibitor targeting primary causes of allograft dysfunction. Drugs Today. 2004;40: 101-109.
3. Nashan B. Early clinical experience with the novel rapamycin derivative. Ther Drug Monit. 2002;24: 53-58.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. Kirchner GI, Meier-Wiedenbach I, Manns MP. Clinical pharmacokinetics of everolimus. Clin Pharmacokinet. 2004;43: 83-95.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Neumayer H-H, Paradis K, Korn A, et al. Entry-into-human study with the novel immunosuppressant SDZ RAD in stable renal transplant recipients. Br J Clin Pharmacol. 1999;48: 694-703.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
6. Kahan BD, Wong R, Carter C, et al. A phase I study of a 4-week course of SDZ-RAD (RAD) in quiescent cyclosporine-prednisone-treated renal transplant recipients. Transplantation. 1999;67: 1100-1106.
7. MacDonald A, Scarola J, Burke JT, Zimmermann JJ. Clinical pharmacology and therapeutic drug monitoring of sirolimus. Clin Ther. 2000;22: B101-B121.
8. Gallant-Haidner HL, Trepanier DJ, Freitag DG, Yatskoff RW. Pharmacokinetics and metabolism of sirolimus. Ther Drug Monit. 2000;22: 31-35.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
9. Serkova N, Jacobsen W, Niemann CU, et al. Sirolimus, but not the structurally related RAD (everolimus), enhances the negative effects of cyclosporine on mitochondrial metabolism in the rat brain. Br J Pharmacol. 2001;133: 875-885.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Jacobsen W, Serkova N, Hausen B, et al. Comparison of the in vitro metabolism of the macrolide immunosuppressants sirolimus and RAD. Transplant Proc. 2001;33: 514-515.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Kahan BD, Chang JY, Sehgal SN. Preclinical evaluation of a new potent immunosuppressive agent, rapamycin. Transplantation. 1991;52: 185-191.[Web of Science][Medline] [Order article via Infotrieve]
12. Nashan B. The role of Certican (everolimus, Rad) in the many pathways of chronic rejection. Transplant Proc. 2001;33: 3215-3220.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
13. Ferron GM, Mishina EV, Zimmerman JJ, Jusko WJ. Population pharmacokinetics of sirolimus in kidney transplant patients. Clin Pharmacol Ther. 1997;61: 416-428.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. Zimmerman JJ, Kahan BD. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol. 1997;37: 405-415.[Abstract]
15. Brattstrom C, Sawe J, Tyden G, et al. Kinetics and dynamics of single oral doses of sirolimus in sixteen renal transplant recipients. Ther Drug Monit. 1997;19: 397-406.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
16. Podder H, Stepkowski SM, Napoli KL, et al. Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations. J Am Soc Nephrol. 2001;12: 1059-1071.
17. Kuhn B, Jacobsen W, Christians U, Benet LZ, Kollman PA. Metabolism of sirolimus and its derivative everolimus by cyctochrome P450 3A4: insights from docking, molecular dynamics, and quantum chemical calculation. J Mol Chem. 2001;44: 2027-2034.
18. Napoli KL, Wang ME, Stepkowski SM, Kahan BD. Relative tissue distributions of cyclosporine and sirolimus after concomitant peroral administration to the rat: evidence for pharmacokinetic interactions. Ther Drug Monit. 1998;20: 123-133.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
19. Stepkowski SM, Napoli KL, Wang ME, Qu X, Chou TC, Kahan BD. Effects of the pharmacokinetic interaction between orally administered sirolimus and cyclosporine on the synergistic prolongation of heart allograft survival. Transplantation. 1996;62: 986-994.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
20. Kaplan B, Meier-Kriesche HU, Napoli KL, Kahan BD. The effect of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent. Clin Pharmacol Ther. 1998;63: 48-53.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
21. Budde K, Neumayer HH, Lehne G, et al. Tolerability and steady state pharmacokinetics of everolimus in maintenance renal transplant patients. Nephrol Dial Transplant. 2004;19: 2606-2614.
22. Kovarik JM, Kaplan B, Silva HT, et al. Pharmacokinetics of an everolimus-cyclosporine immunosuppressive regimen over the first 6 months after kidney transplantation. Am J Transplant. 2003;3: 606-613.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
23. Kovarik JM, Kalbag J, Figueiredo J, Rouilly M, Frazier OL, Rordorf C. Differential influence of two cyclosporine formulations on everolimus pharmacokinetics: a clinically relevant pharmacokinetic interaction. J Clin Pharmacol. 2002;42: 95-99.[Abstract]
24. Kovarik JM, Kahan BD, Kaplan B, et al. Longitudinal assessment of everolimus in de novo renal transplant recipients over the first year: pharmacokinetics, exposure-response relationships and influence on cyclosporine. Clin Pharmacol Ther. 2001;69: 48-56.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
25. Kovarik JM, Kaplan B, Tedesco Silva H, et al. Exposure-response relationships for everolimus in de novo kidney transplantation: defining a therapeutic range. Transplantation. 2002;73: 920-925.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
26. Kovarik JM, Hsu CH, McMahon L, Berthier S, Rordorf C. Population pharmacokinetics of everolimus in de novo renal transplant patients: impact of ethnicity and comedications. Clin Pharmacol Ther. 2001;70: 247-254.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
27. Jorga A, Holt DW, Johnston A. Therapeutic drug monitoring of CsA. Transplant Proc. 2004;36: 396S-403S.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
28. Vitko S, Tedesco H, Eris J, et al. Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies. Am J Transplant. 2004;4: 626-635.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
29. Kahan BD, Kaplan B, Lorber MI, Winkler M, Cambon N, Boger RS. RAD in de novo renal transplantation: comparison of three doses on the incidence and severity of acute rejection. Transplantation. 2001;71: 1400-1406.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
30. Serkova N, Hausen B, Berry GJ, et al. Tissue distribution and clinical monitoring of the novel macrolide immunosuppressant SDZ-RAD and its metabolites in monkey lung transplant recipients: interaction with cyclosporine. J Pharmacol Exp Ther. 2000;294: 323-332.
31. Kirchner GI, Mueller L, Winkler M, et al. Long-term pharmacokinetics of the metabolites of everolimus and cyclosporine in renal transplant recipients. Transplant Proc. 2002;34: 2233-2234.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
32. Kirchner G, Winkler M, Mueller L, et al. Pharmacokinetics of SDZ RAD and cyclosporine including their metabolites in seven kidney graft patients after the first dose of SDZ RAD. Br J Clin Pharmacol. 2000;50: 449-454.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
33. Jones TE, Morris RG, Mathew TH. Diltiazem-cyclosporine pharmacokinetic interaction: dose-response relationship. Br J Clin Pharmacol. 1997;44: 499-504.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
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) and with various everolimus regimens (
).
) and group means (
). A ratio of 1.00 implies no change in cyclosporine exposure with everolimus or placebo coadministration. All everolimus regimens are with the tablet formulation except 0.75 mg QD (capsule).