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Keywords:

  • Cyclosporine;
  • everolimus;
  • immunosuppressants;
  • pharmacokinetics

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The pharmacokinetics of everolimus were characterized over the first 6 months post transplant in 731 patients receiving either 0.75 or 1.5 mg bid everolimus in addition to cyclosporine and corticosteroids. Pharmacokinetic data consisted of 4014 everolimus trough concentrations (Cmin) obtained in all patients and 659 area under the concentration-time curve (AUC) -profiles obtained at months 2, 3, and 6 in a subset of 261 patients. Cmins averaged 4.3 ± 2.4 and 7.2 ± 4.2 ng/mL at 0.75 and 1.5 mg bid, indicating a 20% under-proportionality at the upper dose level. Cmins were 19–34% lower in the first month compared with months 2 through 6-values. AUC was dose-proportional and stable over time, averaging 77 ± 32 and 136 ± 57 ng·h·mL−1 at the two dose levels. Within- and between-patient variability in AUC were 27% and 31%, respectively. There was no influence of sex, age (16–66 years), or weight (42–132 kg) on AUC. Everolimus exposure was significantly lower by an average 20% in blacks. Everolimus exposure was relatively stable over the first 6 months post transplant, with no major departure from dose-proportionality over the therapeutic dose range. Weight-adjusted dosing (mg/kg) does not appear warranted. Black patients may have lower bioavailability and/or higher clearance of everolimus compared with white patients.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Everolimus (Certican, Novartis Pharmaceuticals) is a proliferation signal inhibitor intended for immunoprophylaxis of allograft rejection. Two international phase 3 trials were conducted in de novo kidney transplantation with a follow-up of 3 years. In these trials, everolimus was compared with mycophenolate mofetil as part of triple immunosuppressive therapy combined with cyclosporine and corticosteroids (1, 2). Pharmacokinetic blood sampling for both everolimus and cyclosporine was prospectively included in the study protocols, extending from the de novo setting in months 1–2, through the metastable period in months 3–5, into the stable phase in month 6 after transplantation.

The first 6 months post transplant are a period in which it is especially important to properly adjust immunosuppression. Characterizing the disposition of everolimus was therefore deemed important so as to detect temporal trends in exposure which may influence the safety–efficacy balance during this period, and may need to be taken into account in dosing regimens. Furthermore, both everolimus and cyclosporine undergo extensive biotransformation via the CYP3A isozyme located in enterocytes and in the liver. Both are also substrates for the countertransporter P-glycoprotein located in enterocytes and biliary canaliculi. Consequently, these two drugs may influence each other's absorption, metabolism, or biliary clearance via these shared disposition pathways. Proper dosing of both agents therefore requires that potential drug–drug interactions be assessed.

Against these background considerations, the specific pharmacokinetic objectives were to characterize: (a) longitudinal patterns in predose everolimus trough concentrations; (b) dose-proportionality and temporal stability in everolimus pharmacokinetic profiles; (c) the correlation between everolimus trough concentrations and area-under-the-curve; (d) everolimus intra- and interindividual pharmacokinetic variability; (e) the contribution to pharmacokinetic variability from the demographic covariates age, weight, sex, and ethnicity, and (f) the longitudinal influence of everolimus on cyclosporine pharmacokinetics. The overall intent of this evaluation was to provide a basic population description of everolimus and cyclosporine exposure over time post transplant as an aid in the use of this immunosuppressant combination in transplant medicine.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study design and immunosuppressive regimens

Two randomized, double-blind, international efficacy trials were performed in kidney transplantation. One study was conducted in North and South America and one in Europe, Australia, and South Africa. The protocols were reviewed by investigational review boards at the individual study centers and patients gave written informed consent to participate. A total of 1171 de novo renal allograft recipients (583 and 588 from the two separate studies) were enrolled from 98 clinical centers. Patients were randomized to receive either everolimus 0.75 mg bid (n = 387), everolimus 1.5 mg bid (n = 393), or mycophenolate mofetil 1 g bid (n = 391) in addition to cyclosporine and corticosteroids. Everolimus was begun post transplant, administered as a tablet formulation (Certican, Novartis Pharmaceuticals, Basel, Switzerland) given simultaneously with cyclosporine (Neoral, Novartis) according to a twice-daily schedule. Cyclosporine was begun at the time of transplantation with subsequent dose titration to bring trough concentrations in the range 150–400 ng/mL in the first month post transplant and then 100–300 ng/mL thereafter. Corticosteroids were dosed based on a protocol-specified taper.

Assessments

Pharmacokinetic visits took place on day 2, weeks 1 and 2, and months 1, 2, 3, and 6 after transplantation. At each visit blood samples were obtained for determination of the everolimus and cyclosporine morning trough concentration. In a subset of 261 patients, pharmacokinetic profiles of both analytes were obtained at the month 2, 3, and 6 visits over the morning dose interval with a blood sample predose and 1, 2, 5, and 8 h post dose. The everolimus concentration at 12 h post dose was estimated by log-linear regression based on the measured concentrations at 5 and 8 h post dose. This then allowed the calculation of the full 12-h steady-state AUC (3).

Bioanalytics

Everolimus concentrations were determined in blood by validated liquid chromatography methods at two central laboratories, one for each study. The lower limit of quantification was 0.2 and 0.4 ng/mL at the two laboratories. Cyclosporine blood concentrations were determined by liquid chromatography in one trial and by commercially available monoclonal-specific bioassays in the other trial. The lower limits of quantification were 5 and 30 ng/mL, respectively.

Pharmacokinetic and statistical evaluations

Steady-state pharmacokinetic parameters included the trough concentration (Cmin), the peak concentration (Cmax), the time to reach the peak (tmax), the area under the concentration-time curve (AUC), the average concentration (Cavg = AUC/12), and the per cent peak-trough fluctuation (PTF = [Cmax – Cmin]/Cavg).

Pharmacokinetic parameters were log-transformed for statistical evaluation. To investigate dose-proportionality and temporal stability in exposure, a linear mixed-effects model was used consisting of the fixed effects Dose, Visit, and Dose-by-Visit interaction and the random effects Subject and Residual. Provided that the Dose-by-Visit interaction was not significant, dose-proportionality and stability across visits was examined by testing the significance of Dose- and Visit-effects, respectively. The clinical relevance of a significant Dose- or Visit-effect was assessed by conventional equivalence testing whereby a parameter-ratio between dose levels or visits whose 90% confidence interval (90% CI) fell outside the range 0.80–1.25 was considered clinically notable (4). Based on the mixed-effects model, the inter- and intraindividual coefficients of variability were estimated by calculating the square root of the estimated covariance parameters for Subject and Residual, respectively. The influence of demographic factors on everolimus mean AUC were explored by two-tailed unpaired t-test for the categorical variables sex and ethnicity and by linear regression for the continuous variables age and weight. Cyclosporine parameters were evaluated in a similar statistical model with Dose replaced by Treatment which referred to the three treatment groups in the trials. Data are presented as mean ± standard deviation unless otherwise indicated.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study population

Pharmacokinetic data were evaluable from a total of 1068 patients: 363 received mycophenolate mofetil, 354 received 0.75 mg bid everolimus, and 351 received 1.5 mg bid everolimus. The total population was 63.6% men, the average age was 44.3 ± 12.1 years and the average weight was 73.9 ± 15.7 kg. Demographics were similar across the three treatment arms.

Everolimus dosing and trough concentrations

The study protocols provided guidelines for everolimus dose reduction in cases of thrombocytopenia, leukopenia, or hyperlipidemia. There was a total of 4014 pharmacokinetic visits at which an evaluable everolimus trough concentration was obtained. At the majority of these visits (3765 or 93.8%), the patient was receiving the initially assigned dose. At the remaining 249 visits (6.2%), the patient was taking a reduced dose of everolimus. Overall, 20% of patients had dose reductions at one or more pharmacokinetic visits over the course of the trial. Nonetheless, the average dose over 6 months remained close to the protocol-specified dose: 0.73 ± 0.07 mg bid in patients randomized to the lower dose group and 1.45 ± 0.18 mg bid in those randomized to the upper dose group.

There were 4014 evaluable everolimus Cmins averaging 5.5 ± 1.6 per patient. Cmins at the day 2 visit were 2.3 ± 1.6 ng/mL at 0.75 mg bid and 3.0 ± 2.1 at 1.5 mg bid as concentrations were rising to steady-state. Steady-state was reached on or before the week 1 (day 7) visit. The corresponding Cmin trajectories at the two everolimus dose levels are shown in Figure 1 from week 1 to month 6. Over the full 6-month observation period, Cmins averaged 4.3 ± 2.4 and 7.2 ± 4.2 ng/mL in the lower and upper dose groups, respectively. The Cmin temporal patterns in each treatment arm were similar inasmuch as there was no Dose-by-Visit interaction (p = 0.44). A significant Dose-effect was observed for dose-normalized troughs (p = 0.0001), indicating a statistical departure from dose-proportionality. Equivalence testing yielded a between-dose ratio of 0.80 (90% CI, 0.75–0.85) implying an average 20% underproportionality at the upper dose level relative to the lower dose level. A significant Visit-effect (p = 0.0001) was noted, which subsequent pairwise comparisons attributed to 19–34% lower Cmins in the first month relative to values in months 2–6. This confirms the visual impression from the trough trajectories in Figure 1.

image

Figure 1. Everolimus trough trajectories. Mean everolimus trough concentrations (Cmin) over 6 months post transplant at dose levels of 0.75 mg bid (circles) and 1.5 mg bid (squares). Bars represent 95% confidence intervals.

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Everolimus profiles

Blood sampling for steady-state AUC profiles was an optional part of the protocol; 33 centers volunteered to participate in this part. No particular center dominated the distribution, inasmuch as there was an average of seven patients per center with a range of 2–18 patients. A total of 659 profiles was evaluable in 261 patients. The North/South American study contributed 65% of the profiles and the global study contributed 35%. Patients were equally distributed between the two dose levels: 126 and 135 patients at the lower and upper dose, respectively. Patients provided 1–3 profiles each, with an average 2.5 ± 0.7 profiles per patient. The patients participating were reflective of the full study population with respect to age (mean 43 years), weight (mean 76 kg), sex (63% men) and ethnicity.

The derived pharmacokinetic parameters are summarized in Table 1. Steady-state peak concentrations were reached by 1–2 h post dose and were approximately 11 and 21 ng/mL at the two dose levels. Although a Dose-effect was detected (p = 0.0001), there was no clinically relevant departure from dose-proportionality insofar as the Cmax-ratio and 90% CI of 0.88 (0.82–0.95) did not transgress the equivalence boundaries. AUC also exhibited a significant Dose-effect (p = 0.0001) but no clinically relevant departure from dose-proportionality: AUC-ratio (90% CI), 0.93 (0.87–1.01). Neither Cmax nor AUC was significantly different across visits (p = 0.94 and 0.65), indicating consistency over time. There were no Dose-by-Visit interactions (p = 0.86 and 0.68).

Table 1.  Everolimus pharmacokinetics
 0.75 mg  bid1.5 mg  bid
ParameterMonth 2Month 3Month 6Month 2Month 3Month 6
  1. Values are mean ± standard deviation except for tmax which is median (range).

  2. N, number of patients at each visit; Cmin, trough concentration; tmax, time to reach peak exposure; Cmax, peak exposure, AUC, area under the curve over the dosing interval; Cavg, average concentration; PTF, peak–trough fluctuation.

N1161129912211496
Cmin (ng/mL)4.6 ± 2.14.7 ± 2.44.6 ± 2.07.5 ± 3.58.0 ± 4.38.2 ± 4.1
tmax (h)2 (1–5)2 (1–12)1 (1–5)1 (1–5)1 (1–5)1 (1–5)
Cmax (ng/mL)11.0 ± 4.511.2 ± 4.710.7 ± 4.319.8 ± 7.521.0 ± 8.921.1 ± 8.9
AUC (ng·h/mL)76 ± 3178 ± 3576 ± 31131 ± 51137 ± 67138 ± 55
Cavg (ng/mL)6.3 ± 2.66.5 ± 2.96.3 ± 2.610.9 ± 4.311.4 ± 5.611.5 ± 4.6
PTF (%)117 ± 49114 ± 40106 ± 37126 ± 47131 ± 58123 ± 51

Everolimus Cmin:AUC correlation

The correlation between Cmin and overall exposure (AUC) was determined from the 659 profiles. Cmins ranged from 1.0 to 25.9 ng/mL and AUCs from 23 to 437 ng·h·mL−1. There was a significant linear correlation with a coefficient (r-value) of 0.89 (p < 0.001). The corresponding coefficient of determination (r2 value) was 0.79. Concentrations at other time-points in the profile were either similar to Cmin (2-h concentration: r = 0.89, r2 = 0.80) or inferior to Cmin (1-h concentrations: r = 0.76, r2 = 0.58).

Everolimus pharmacokinetic variability and covariates

Coefficients of intraindividual variability for Cmin, Cmax, and AUC were 45%, 24%, and 27%, respectively. The corresponding interindividual coefficients of variation were 55%, 33%, and 31%, respectively. Dose-normalized AUCs were not different between men and women (p = 0.10). There was no correlation between AUC/Dose and age which ranged from 16 to 66 years (p = 0.58). Weight ranged from 42 to 132 kg and was significantly negatively correlated with AUC/Dose (p = 0.001). However, the slope was shallow (reduction of 0.5% in exposure per kg) and weight explained only 4.5% of the variability in AUC/Dose based on the r2-value. Hence, although statistically significant, weight was not a clinically relevant covariate.

Since the majority of black patients (65 of 78) were enrolled in the North/South American trial, ethnicity was explored in the context of that trial database. There was no bias in the randomization of blacks and whites to the two everolimus dose levels: 29 and 36 blacks compared with 136 and 125 whites to the lower and upper dose groups, respectively. At steady-state on day 7, Cmin/Dose was 20% lower in blacks: 4.1 ± 2.1 vs. 5.1 ± 4.0 ng/mL/mg (p = 0.01). At month 2, the everolimus profiles showed that Cmin/Dose was 14% lower in blacks (4.8 ± 2.4 vs. 5.6 ± 2.7, p = 0.05) and AUC/Dose was 19% lower in blacks (78 ± 35 vs. 96 ± 40, p = 0.03).

Cyclosporine troughs and dosing

There were a total of 5123 evaluable cyclosporine trough concentrations (Cmin) with an average of 4.8 ± 1.5 per patient. Average Cmin trajectories are shown in Figure 2 and remained in the protocol-specified target ranges. Cmins were slightly higher in the North/South American trial compared with the global trial in the first 2 months post transplant. Within each study, Cmins were similar in all three treatment arms: p = 0.87 in the North/South American trial and p = 0.74 in the global trial.

image

Figure 2. Cyclosporine trough trajectories. Mean cyclosporine trough concentrations (Cmin) over 6 months post transplant in patients receiving mycophenolate mofetil (circles), 0.75 mg bid everolimus (squares) and 1.5 mg bid everolimus (triangles). Data are from the North/South American trial (open symbols) and the global trial (filled symbols). Dashed lines demarcate the protocol-specified target Cmin ranges.

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Although Cmins were similar among the treatment arms, they were achieved with different doses of cyclosporine in the global trial. Specifically, cyclosporine doses were significantly lower in patients receiving everolimus compared with those receiving mycophenolate mofetil (p = 0.002); whereas, cyclosporine doses did not differ between the two everolimus groups (p = 0.85). Comparison of the time-averaged mean dose between each everolimus arm vs. the control arm indicated 9.9% (90% CI: 4.8%– 14.5%) and 9.3% (4.8%– 13.8%) lower cyclosporine doses in the 0.75 and 1.5 mg everolimus groups, respectively. Figure 3 combines both Cmin and dose data from the global trial. These trajectories indicated that the dose : Cmin relationship changes over the first post-transplant month and then stabilizes thereafter, as has been previously described (5). The plot confirms that dose-normalized Cmins were higher in everolimus-treated patients compared with mycophenolate mofetil-treated patients (p = 0.0007).

image

Figure 3. Cyclosporine dose-normalized trough trajectories. Mean cyclosporine dose-normalized trough concentrations (Cmin/Dose) over 6 months post transplant in patients receiving mycophenolate mofetil (open circles), 0.75 mg bid everolimus (filled squares) and 1.5 mg bid everolimus (filled triangles) in the global trial. Bars represent 95% confidence intervals.

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Although there was a trend toward slightly lower cyclosporine doses in everolimus-treated patients in the North/South American trial, this did not reach statistical significance (p = 0.08). The corresponding dose-normalized Cmins (Cmin/Dose) were not different among treatments (p = 0.42).

Cyclosporine profiles

A total of 634 steady-state profiles were evaluable from 256 patients evenly distributed among the three treatment groups in the North/South American trial. The parameters are summarized in Table 2. Consistent with cyclosporine dose reduction over time post transplant, AUC decreased in parallel over time in all three treatment arms (no Treatment-by-Visit interaction, p = 0.49). AUCs also did not differ among treatments on any profiling occasion (p = 0.73). Similar conclusions were made from the Cmax data (p = 0.83).

Table 2.  Cyclosporine pharmacokinetics
VisitTreatmentNCmin (ng/mL)tmax (h)Cmax (ng/mL)AUC (ng·h·mL−1)
  1. Values are mean ± SD except for tmax which is median (range).

  2. N is number of patients, Cmin is trough concentration, tmax is time to peak concentration, Cmax is peak concentration, AUC is area under the curve.

Month 2:MMF88216 ± 1361 (1–5)1325 ± 4225859 ± 1774
 Everolimus 0.75 mg  bid78242 ± 1662 (1–5)1380 ± 4916214 ± 2439
 Everolimus 1.5 mg  bid74244 ± 1382 (1–5)1369 ± 4796146 ± 2260
Month 3:MMF85201 ± 962 (1–5)1271 ± 3875632 ± 1690
 Everolimus 0.75 mg  bid68225 ± 1772 (1–5)1298 ± 4935651 ± 2415
 Everolimus 1.5 mg  bid68196 ± 1162 (1–5)1240 ± 4855424 ± 2025
Month 6:MMF81179 ± 811 (1–8)1106 ± 4224765 ± 1683
 Everolimus 0.75 mg  bid44168 ± 1172 (1–8)1089 ± 4304627 ± 1893
 Everolimus 1.5 mg  bid48197 ± 1352 (1–6)1019 ± 4444405 ± 1874

Relationship between concurrent everolimus and cyclosporine exposures

Figure 3 indicates that the presence of everolimus was associated with an elevated cyclosporine Cmin/Dose compared with the absence of everolimus (control treatment group). However, within the everolimus-treated subpopulation, there did not appear to be a marked difference in cyclosporine Cmin/Dose despite a 2-fold difference between the lower vs. higher dose of everolimus. To examine this on a more refined level with respect to everolimus systemic exposure, paired measurements of everolimus Cmin and cyclosporine Cmin/Dose from both trials were assembled from the month 1–6 visits when both parameters were stable over time. The resulting plot is shown in Figure 4 from 953 paired observations which were subjected to curvilinear regression to explore for potential nonlinear trends in the data. The average cyclosporine Cmin/Dose in the absence of everolimus (that is, in patients in the control arm of the study) was 1.18 ± 0.44 ng/mL per mg which corresponds to the y-axis intercept of the curvilinear regression line. Although the data are sparse in the range of 0.2–2 ng/mL everolimus, there did not appear to be abrupt changes or discontinuities in the relationship in the presence of low everolimus concentrations. Everolimus Cmins from 2 to 15 ng/mL were associated with a modest rise in cyclosporine Cmin/Dose. Excluding the data from the control group (everolimus Cmin = 0 ng/mL) yielded a similar curvilinear regression line (not shown). The trend noted by curvilinear regression was confirmed statistically with conventional linear regression on the data of everolimus-treated patients which yielded a significant positive, albeit weak, correlation (r = 0.38, p = 0.0001). When data from each trial were analyzed separately, similar conclusions were obtained.

image

Figure 4. Relationship between everolimus and cyclosporine troughs. Paired everolimus and dose-normalized cyclosporine trough concentrations (Cmin) from month 1 to 6. Superimposed is the curvilinear regression line. Data are pooled from both trials.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Serial pharmacokinetic assessments were an integral component of the everolimus pivotal trials in kidney transplantation. The general goals were to describe the longitudinal disposition of everolimus and cyclosporine in renal allograft recipients from the de novo through the stable period after transplantation and to explore for exposure-response relationships. As reported separately, there were clear relationships between everolimus trough concentrations vs. efficacy and safety parameters in these trials (6), which testifies to the practical implications of characterizing and understanding the pharmacokinetics of everolimus in this population. Likewise, because cyclosporine is a critical-dose immunosuppressant, it is important to determine whether its disposition is influenced by coadministration of other agents which share biotransformation or transport pathways.

Everolimus trough concentrations were relatively stable, on average, over the first half year after transplantation, as shown in Figure 1. The only exception appeared in the first month when troughs exhibited a slight rise over time. The reason for this trend in everolimus exposure is unclear inasmuch as the kidney does not contribute significantly to everolimus elimination. Slight instability in exposure in the first month was also noted in a phase 2 study in de novo renal transplant patients (3), but not in a month-long phase 1 study in maintenance kidney transplant patients (7). Hence, the early weeks after transplantation surgery during which patients may be clinically unstable and during which concomitant medications are frequently altered (prednisone taper, for example) may have contributed to this pattern in everolimus pharmacokinetics. Regardless of the exact causes, the 20–30% lower everolimus concentrations in the first month compared with months 2–6 observed in the present study is a relatively minor difference compared to the more pronounced changes in other immunosuppressants such as cyclosporine or mycophenolate mofetil which occur over this same period after transplantation (5, 8). From month 2 to 6, both trough concentrations in all patients and AUCs in a subset confirm the temporal stability of everolimus exposure.

The 20% underproportionality which was detected in everolimus troughs is relatively minor, and subject to the limitation that it was assessed at only two dose levels. A similar underproportionality in trough concentrations was evident from phase 3 data for sirolimus (9). Everolimus Cmax and AUC in the subgroup of patients from whom profiles were obtained were consistent with dose-proportionality inasmuch as they both satisfied equivalence criteria when dose-normalized and compared between dose levels. This is in agreement with previous Cmax and AUC data in kidney transplant patients which demonstrated dose-proportionality after single-dose administration from 0.25 to 15 mg (10) and after multiple-dose administration from 0.5 to 2 mg bid (3). Everolimus dose-proportionality should facilitate dose adjustment as exposure is titrated for the individual patient over the therapeutic dose range in response to clinical and/or blood level monitoring.

Moderate to high within- and between-patient variability in everolimus exposure was noted in the population as a whole over the 6-month observation period of this study. None of the conventional demographic factors, such as sex, age, or weight, contributed to a relevant extent in explaining the between-patient variability. With regard to ethnicity, however, black patients had an average 20% lower exposure to everolimus compared with white patients. This lower exposure likely contributes, in part, to the poorer efficacy outcome in the North/South American trial for blacks compared with non-blacks (11) and suggests that higher doses of everolimus may be needed in blacks. Whether the lower average exposure is a result of reduced bioavailability and/or higher clearance in blacks cannot be discerned from this study in the absence of parallel intravenous pharmacokinetic data. Both bioavailability and clearance appear to play a role, for instance, in the lower average exposure to cyclosporine observed in blacks (12); whereas, bioavailability may play the predominant role in the lower exposure to tacrolimus in this ethnic group (13). Pharmacokinetic differences in blacks have also been noted for methylprednisolone (14) and sirolimus (15).

A few features of everolimus identified in this study and in the corresponding exposure-response evaluations (6) indicate that therapeutic monitoring may be a beneficial adjunct for the use of this agent in transplant medicine. Firstly, there exist well-characterized relationships between everolimus trough blood levels vs. freedom from acute rejection and everolimus-associated adverse events such hyperlipidemia and myelosuppression in the first half-year post transplant (6). Accordingly, therapeutic monitoring could aid in individualizing exposure to properly balance efficacy and safety. Secondly, there is evidence of moderate to high between-patient pharmacokinetic variability. Initially, therapeutic drug monitoring would help to detect those patients receiving the recommended starting dose whose exposure is suboptimal and who may benefit from a dose adjustment. This may be particularly important for black patients. Some temporal instability in exposure was apparent, especially in the first month post transplant, but overall, the within-patient pharmacokinetic variability was generally moderate. This may indicate that, after targeting the appropriate exposure in an individual patient in the early post-transplant period, less frequent monitoring may be needed under clinically stable conditions over the long-term. In this context, steady-state trough blood levels were well correlated with overall exposure (Cmin vs. AUC) and may serve as a convenient monitoring parameter given the considerations mentioned above.

In the global trial, significantly lower cyclosporine doses were used in everolimus-treated patients in order to achieve similar cyclosporine troughs as in mycophenolate mofetil-treated patients. The difference, however, was small and amounted to an average 9% lower cyclosporine dose. In the North/South American trial, a similar trend toward lower cyclosporine doses in the everolimus treatment groups was noted; however, this was not statistically significant. An obvious difference between the trials was the bioanalytical methods used to measure cyclosporine blood concentrations – bioassays were used in the global trial and chromatography in the North/South American trial. While it is known that bioassays have some cross-reactivity with cyclosporine metabolites, this is unlikely to have had a major impact on the pharmacokinetic interpretation. Firstly, the bioanalytical determinations of cyclosporine in patient blood samples were accompanied by calibration standard and quality control samples (16) of known cyclosporine concentrations made from analytical-grade parent cyclosporine. It was against these standards that cyclosporine concentrations in patient blood samples were interpreted. Secondly, the metabolism of cyclosporine is not influenced by concomitant administration of single-dose or multiple-dose everolimus in renal transplant patients (17, 18). A more likely explanation for the different cyclosporine outcomes in the two trials is that everolimus can increase cyclosporine blood concentrations via a pharmacokinetic interaction, but the magnitude is slight or borderline inasmuch as it was detectable in one study and constituted only a trend in the other study. The modesty of this effect is also consistent with the fact that previous developments studies did not detect an influence of everolimus on cyclosporine in small-scale studies of various designs (3, 7, 10).

Having uncovered a modest influence of everolimus on cyclosporine, possible contributory factors were sought. Inspection of the two cyclosporine Cmin/Dose trajectories in everolimus-treated patients in Figure 3 suggests that there is no distinction between patients receiving the lower or upper everolimus dose. While no dose-effect between the everolimus treatment groups was evident, an everolimus concentration-effect on cyclosporine may have been present as shown in Figure 4. An inherent difficulty in assessing this plot is the inability to distinguish between an influence of rising everolimus concentration on cyclosporine vs. an underlying correlation between exposure for both agents due to their dependence on common absorption and elimination routes in humans. Because both drugs are substrates for CYP3A and P-glycoprotein, patients who are, for example, fast clearers or poor absorbers of one drug may also handle the other drug in a similar manner, yielding a positive correlation in exposure to both drugs. This phenomenon has been observed for cyclosporine and sirolimus in kidney transplant patients (19). With this limitation in mind, the modest but statistically significant correlation between everolimus and dose-normalized cyclosporine Cmin may reflect a pharmacokinetic interaction which manifests itself clinically by slightly lower cyclosporine doses being used in everolimus-treated patients. This relatively minor influence would likely be taken into account in the context of routine cyclosporine therapeutic drug monitoring.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  • 1
    Vitko S, Margreiter R, Weimar W et al. International, double-blind, parallel-group study of the safety and efficacy of Certican versus mycophenolate mofetil in combination with Neoral and steroids (Abstract). Am J Transplant 2001; 1(Suppl. 1): 474.
  • 2
    Kaplan B, Tedesco Silva H et al. North/South American, double-blind, parallel-group study of the safety and efficacy of Certican versus mycophenolate mofetil in combination with Neoral and corticosteroids (Abstract). Am J Transplant 2001; 1 (Suppl. 1): 475.
  • 3
    Kovarik JM, Kahan BD, Kaplan B et al. Longitudinal assessment of everolimus in de novo renal transplant recipients over the first posttransplant year: pharmacokinetics, exposure-response relationships, and influence on cyclosporine. Clin Pharmacol Ther 2001; 69: 4856.
  • 4
    Schuirmann DJ. Comparison of the two one-sided tests procedure and the power approach for assessing the bioequivalence of average bioavailability. J Pharmacokinet Biopharm 1987; 15: 657680.
  • 5
    Kovarik JM, Mueller EA, Richard F et al. Evidence for earlier stabilization of cyclosporine pharmacokinetics in de novo renal transplant patients receiving a microemulsion formulation. Transplantation 1996; 62: 759763.
  • 6
    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: 920925.
  • 7
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