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NDT Advance Access published online on October 23, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm632
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Cinacalcet's Effect on the Pharmacokinetics of Tacrolimus, Cyclosporine and Mycophenolate in Renal Transplant Recipients

Pål Falck1, Nils Tore Vethe2, Anders Åsberg1, Karsten Midtvedt3, Stein Bergan2, Jan Leo Egge Reubsaet4 and Hallvard Holdaas3

1 Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway 2 Department of Medical Biochemistry, Rikshospitalet Medical Center, Oslo, Norway 3 Department of Internal Medicine, Rikshospitalet Medical Center, Oslo, Norway 4 Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, Norway

Correspondence and offprint requests to: Correspondence and offprint requests to: Pål Falck, Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, 0316 Oslo, Norway. Tel: +47-22857578; Fax: +47-22854402; E-mail: pal.falck{at}farmasi.uio.no



   Abstract
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 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. The calcimimetic drug cinacalcet offers a novel therapeutic option to treat post-transplant hypercalcemia and hyperparathyroidism; however, the interaction with calcineurin inhibitors and mycophenolate has not been evaluated.

Methods. In the present study the effects of cinacalcet on the pharmacokinetics of cyclosporine A (CsA), tacrolimus (Tac) and mycophenolate were investigated in 14 renal transplant recipients with stable renal function (mean creatinine 126.4 ± 45.3 µmol/L). The patients were treated with either CsA (n = 8) or Tac (n = 6) in combination with mycophenolate/azathioprine and steroids. Twelve-hour pharmacokinetic investigations to measure CsA and its six main metabolites, Tac and mycophenolate concentrations were performed before and after 1-week treatment with 30 mg cinacalcet once daily.

Results. Cinacalcet treatment induced a significant 14.3 ± 12.1% decrease in Tac AUC0–12 (P = 0.039). Tac Cmax, Tmax and T1/2 also tended to decrease. The pharmacokinetics of CsA and mycophenolate were not significantly affected by concomitant treatment with cinacalcet. However, the secondary CsA metabolite, AM19, showed a significant increase of 9.0 ± 9.5% during cinacalcet treatment (P = 0.040). Renal function decreased significantly from 78 ± 11 to 72 ± 12 mL/min (P = 0.019) and correlated with the increased levels of metabolite AM19 in the CsA group. Renal function was unchanged in the Tac group.

Conclusion. Cinacalcet treatment showed a moderate effect on the Tac, but not CsA or mycophenolate, pharmacokinetics after 1-week concomitant treatment. This interaction appears to have minor clinical relevance. However, it is advisable to monitor renal function in CsA-treated patients due to the observed decrease in renal function.

Keywords: cinacalcet; cyclosporine; interaction; renal function; renal transplantation; tacrolimus



   Introduction
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 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Hyperparathyroidism (HPT) is a common complication in patients with reduced renal function and end-stage renal disease. Restoring renal function by renal transplantation often normalizes HPT [1]; however, 15–50% of the renal transplant recipients may experience persistent HPT [2–5]. The main contributing factors associated with persistent post-transplant HPT are time on dialysis and severity of pre-transplant HPT [6]. Traditional medical therapy (e.g. active vitamin D, calcium and phosphate binders) might be inadequate for the management of HPT after transplantation. The calcimimetic drug cinacalcet offers a novel therapeutic option to treat post-transplant hypercalcemia and HPT [7–9].

Calcineurin inhibitors are still widely used as part of immunosuppressive regimens. Both calcineurin inhibitors on the market, cyclosporine A (CsA) and tacrolimus (Tac), undergo extensive intestinal and hepatic metabolism, primarily via CYP3A [10]. Over 30 metabolites of CsA have been described so far [11]. Cinacalcet also undergoes rapid and extensive hepatic metabolism via CYP3A [12], and a pharmacokinetic interaction between these drugs can therefore not be ruled out. Some earlier reports measuring only trough levels of CsA, have hypothesized that cinacalcet does not interact with CsA [8,13–17]. However, it has been shown in numerous publications that trough concentrations of CsA are poorly associated with systemic exposure of the drug, and therefore give marginal pharmacokinetic information [18–20]. The interaction between cinacalcet and immunosuppressive treatment has not been completely evaluated [21], and the aim of the present study was to investigate the potential effects of cinacalcet treatment (30 mg once daily) on CsA, Tac and mycophenolate pharmacokinetics in stable renal transplant recipients.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Patients
Fourteen stable renal transplant patients (11 men and 3 women), with a median age of 59 (range 23–75) either on CsA (n = 8) or Tac (n = 6) plus mycophenolate (n = 12) or azathioprine (n = 1) and steroid-based (n = 14) immunosuppression, were enrolled in this single-centre, open label study. Demographic data of the patients are shown in Table 1. The patients were included in an early phase after transplantation, except two patients in the Tac group, who were 8 and 12 years post-transplant respectively. The study was performed in accordance with the Declaration of Helsinki and all the patients signed a written informed consent before the study started. The study was evaluated by the Regional Committee for Medical Research Ethics and approved by the Norwegian Medicines Agency. The enrolled patients were all recipients of a single renal transplant at a median of 1.9 (range 0.7–150) months prior to the study, and their general medical condition (including graft function) had to be stable for at least the last 3 weeks prior to inclusion. Other inclusion criteria were stable therapeutic CsA C2 concentration (2-h post-dose concentration) within the range of 1200–1800 µg/L or Tac trough concentrations within the range of 5–10 µg/L, calcium concentration >2.2 mmol/L, plasma creatinine <444 µmol/L and transaminase levels ≤2 times upper normal level. None of the patients had hypercalcemia (defined as >2.6 mmol/L). Elevated PTH levels were not mandatory for inclusion. The patients were not treated with vitamin D sterols, calcium supplementation, bisphosphonates or fluoride.


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  		Table 1. Baseline patient characteristics

 
Study design and analysis of immunosuppressants
The study design is outlined in Figure 1. On days 1 and 8, a 12-h pharmacokinetic investigation was performed to measure whole blood concentrations of CsA (including the six main metabolites) or Tac and plasma concentration of mycophenolate. Patients were treated with the lowest recommended oral cinacalcet, 30 mg once daily for 7 days to achieve the steady state condition. During this period, the CsA, Tac or mycophenolate doses were not changed and no concomitant drugs with potential interacting properties were allowed during the study. Patients fasted for at least 10 h prior to the pharmacokinetic investigation. After the trough sample was drawn, the patients received their usual morning dose of CsA/Tac and mycophenolate on both days. Samples for the pharmacokinetic profile were collected in addition at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10 and 12 h after drug administration. A standard hospital breakfast was given 2 h after drug intake.


Figure 1
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  		Fig. 1.  Study design. Patients started with 12-h pharmacokinetic profile of CsA/Tac and mycophenolate (MPA) on Day 1. From day 2 to day 8 cinacalcet (30 mg once daily) was administrated each morning. On day 8 a 12-h pharmacokinetic profile was repeated for both CsA/Tac and mycophenolate.

 
Whole blood samples (heparine vacutainers) for CsA analysis were immediately frozen and stored at –30°C until analyzed with a validated HPLC-MS/MS method [22]. In brief, after protein precipitation with methanol and centrifugation, the supernatants were subjected to solid phase extraction using Oasis® HLB cartridges. CsA and the six metabolites AM19, AM1c9, AM1, AM9, AM1c, AM4N were all separated chromatographically before MS/MS detection. The method had a linear range of 2.5–3000 ng/mL for CsA and metabolites. The lower limit of quantification was 2.5 ng/mL for CsA and the six metabolites. Inter- and intra-day precision, accuracy and stability were all within the limit of acceptance in accordance with the FDA guidelines for the bioanalytical method [23]. For Tac analysis, EDTA whole blood samples were stored in cryo-tubes at –20 °C until determination by the MEIA-based Tac II Assay on an IMx-system (Abbott Laboratories, Abbott Park, IL). Plasma was separated from EDTA whole blood samples by centrifugation at 1800 g for 10 min and stored at –20°C until determination of the mycophenolate total plasma concentrations by HPLC-UV (HP Series 1100 and HP Chemstation, Agilent Technologies, Palo Alto, CA) in accordance with the method described by Svensson et al. [24].

Genotyping was performed with previously reported polymerase chain reaction-restriction fragment length polymorphism assays on deoxyribonucleic acid (DNA), extracted from EDTA blood by QIAamp (Qiagen, Valencia, CA, USA), using specific primers and separation on 3% agarose gels [25–27]. All patients were screened for relevant polymorphisms in CYP3A5*2 [C27289A, Thr398Asn] and *3 [A6986G, splicing defect] and MDR1 (G1199A, C1236T, G2677A/T and C3435T). Positive controls were kindly supplied by Dr D. Katz, Abbott Laboratories, Abbott Park, Ill (MDR1) and Dr R. van Schaik, Department of Clinical Chemistry, Erasmus MC, The Netherlands (CYP3A5).

Calculations
The peak concentration (Cmax) and time to Cmax (Tmax) are given as actual observed values. The area under the whole blood/plasma concentration versus time curve from time zero to 12 h post-dose (AUC0–12) was calculated in accordance with the log-trapezoidal rule. The terminal half-life (T1/2) was calculated from the slope (kel) of the semi-logarithmic plot of at least the last three time points (T1/2 = ln 2/kel). Renal function refers to estimated creatinine clearance using Nankivell formula B [28]. Results are expressed as mean ± standard deviation, unless otherwise specified.

Statistics
The primary statistical analyses were performed in accordance with EMEA guidelines for bioequivalence studies [29]. The 90% confidence interval for the ratio of the population mean (with/without cinacalcet) of the AUC0–12 and Cmax should be within the 80 to 125% boundaries in order to be considered bioequivalent. The Wilcoxon signed rank test on untransformed data was used to evaluate the effect on Tmax. In addition the effect of cinacalcet treatment was evaluated using paired Student's t-test on ln-transformed data. The statistical significant difference was considered for P-values <0.05. A sample size of at least six patients was calculated to provide 80% power of detecting a 40% difference in AUC0–12 of CsA/Tac. All statistical analyses were performed using SPSS version 13.0.



   Results
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 Abstract
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 Subjects and methods
 Results
Discussion
 References
 
Tac pharmacokinetics
Co-medication of cinacalcet induced a moderate, but significant, decrease in Tac systemic exposure, and Tac pharmacokinetics did not fulfil the bioequivalence criteria when co-administered with cinacalcet (Figure 2, Table 2). The mean AUC0–12 of Tac decreased by 14.3 ± 12.1% (P = 0.039) from 133.8 ± 42.6 to 116.3 ± 42.4 ng h/mL. The other pharmacokinetic variables, Cmax, Tmax and T1/2, also showed decreasing tendencies (0.102 > P > 0.075). However, trough concentrations of Tac did not change during the study period, 6.3 ± 3.7 ng/mL before and 6.4 ± 1.6 ng/mL after cinacalcet treatment (P = 0.56).


Figure 2
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  		Fig. 2.  Tac concentration versus time curve without and with concomitant cinacalcet administration. Data are presented as population mean ± SEM.

 

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  		Table 2. Tac pharmacokinetic variables before and during concomitant oral treatment with 30 mg cinacalcet per day. All variables except Tmax were ln-transformed before statistical analysis with Student's t-test. Tmax was analysed with the Wilcoxon method

 
CsA pharmacokinetics
CsA pharmacokinetics fulfilled the bioequivalence criteria upon cinacalcet co-administration. The mean whole blood concentration versus time curve of CsA before and after cinacalcet co-administration is shown in Figure 3. The AUC0–12 of AM19, however, showed a significant increase from 720.0 ± 389 ng h/mL to 793.7 ± 431 ng h/mL (P = 0.040) when cinacalcet was co-administered. No other CsA metabolites AM1, AM9, AM1c9, AM1c and AM4N changed significantly during cinacalcet treatment.


Figure 3
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  		Fig. 3.  CsA concentration versus time curve without and with concomitant cinacalcet administration. Data are presented as population mean ± SEM.

 
Mycophenolate pharmacokinetics
Mycophenolate pharmacokinetics were not affected by co-administration of cinacalcet. The pharmacokinetics of the 10 patients treated with mycophenolate mofetil are summarized in Table 4. The two patients treated with enteric-coated mycophenolate sodium tended to have longer Tmax and higher Cmax, AUC0–12 and C0 levels compared to the mycophenolate mofetil treated patients, although this was not of clinical relevance.


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  		Table 4. Mean mycophenolate (MPA) pharmacokinetic variables following administration of MMF (n = 10) before and during concomitant oral treatment with 30 mg cinacalcet per day. All variables except Tmax were ln-transformed before statistical analysis with Student's t-test. Tmax was analysed with the Wilcoxon method

 
Genotyping
Two of the patients in the Tac group were CYP3A5 heterozygous (*1/*3). Numerically these patients metabolized Tac more rapidly compared to the non-expressors (*3/*3) and showed AUC0–12 of 68% compared to the non-expressors. For MDR-1 genotypes there were no differences observed between patients having a possible TTT haplotype and the other patients (data not shown).

Safety parameters
Cinacalcet was well tolerated and the only adverse effect observed during the study was a minor decrease in renal function in CsA-treated patients. The mean decrease in the glomerular filtration rate was 5.7 ± 4.5 mL/min (P = 0.019) in the CsA-treated patients, from 78 ± 11 to 72 ± 12 mL/min. The decrease in renal function was observed to correlate to the amount of the metabolite AM19 level in the whole blood. Of the six of eight patients that experienced a decrease in renal function, all showed an increase in AM19 levels. The one patient with increased renal function had a decrease in AM19 levels, and the last patient with unchanged renal function had the smallest increase in AM19 levels. A regression analysis of changes in renal function compared to the change in AUC0–12 of AM19 showed a significant correlation ({Delta}CrCL = –0.063*{Delta} AUC0–12 AM19 – 1.0 mL/min, P = 0.039, r2 = 0.54). Renal function was not significantly affected by cinacalcet in Tac patients, 68 ± 15 before and 68 ± 12 mL/min after cinacalcet treatment (P = 0.92).



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
The main finding of the present study was that 1 week of cinacalcet treatment in maintenance renal transplanted patients induced a moderate, but a significant decrease in systemic exposure of Tac while CsA and mycophenolate pharmacokinetics were unaffected. Cinacalcet might also impair glomerular filtration in the short term in renal transplant patients on CsA-based regimen. Cinacalcet did not influence the trough levels of Tac and CsA, nor the C2 level of CsA.

The finding of decreased AUC of Tac has not been reported earlier to our knowledge. Interestingly, Tac trough concentration was not altered during cinacalcet treatment. Even though Tac trough levels correlate better to AUC than CsA do, the correlation is still poor [30,31]. If the observed non-correlation between trough level and AUC0–12 is confirmed in a larger study, it would indicate that Tac should, as CsA, be monitored 2 h post-dose. No rational explanation of the decreased AUC of Tac in short-term cinacalcet treatment was found. Cinacalcet is known to be an inhibitor of CYP 2D6 [32]; however, no available data so far support an inductive effect on CYP3A4, which metabolizes Tac. Unchanged elimination is supported by the observed parallel elimination phases of Tac with and without cinacalcet co-administration (Figure 2). However, the concentration versus time curve may indicate that there is an interaction in the absorption phase.

Even though there was no effect of cinacalcet on CsA pharmacokinetics, one of its secondary metabolites, AM19, increased significantly. This metabolite has previously been associated with nephrotoxicity [33,34] which is in concordance with the findings of the significantly decreased renal function in the CsA group. Not only was the decrease in renal function significantly correlated with increases in AM19 levels, but the absolute level of AM19 was also low in the two patients without renal function impairment. There are no data available in the literature supporting an effect of cinacalcet on AM19 production. It is most likely that cinacalcet reduces the clearance of AM19, either via inhibition of its metabolism or via reduced renal excretion. These data support the hypothesis that the CsA metabolite AM19 is associated with renal impairment, but we cannot establish whether AM19 is a biomarker or there is a causal relationship. The study duration is too short to fully evaluate an eventual nephrotoxic effect of the co-administration of cinacalcet with CsA, but the fast onset of reduced renal function indicates a haemodynamic effect. Six-month treatment with cinacalcet has previously been shown to result in progressively decreasing renal function [35]; however, others have shown no effect on renal function [17].

Two Tac patients expressed functional CYP3A5 (*1/*3) and showed a tendency of more rapid metabolism than the non-expressors (*3/*3) as previously reported [36,37]. No difference with regards to the interaction with cinacalcet between the CYP 3A5 genotypes was however observed. The group of expressors was too small to produce any significant findings. Eight patients showed MDR-1 mutations in positions 1236, 2677 and 3435 that possibly indicate MDR-1 TTT haplotypes, which previously has been associated with the effects on the pharmacokinetics of several drugs [38]. No differences in the pharmacokinetics of CsA, Tac or mycophenolate were found in patients with possible TTT haplotypes in this study.

In conclusion, cinacalcet treatment showed a moderate, but significant, effect on the Tac, but not CsA or mycophenolate, pharmacokinetics after 1-week concomitant treatment. Even though this interaction appears to have limited clinical relevance, it would be advisable to intensify Tac monitoring when initiating cinacalcet therapy. For CsA and mycophenolate, no dose adjustment seems to be necessary upon cinacalcet initiation. However, it might be relevant to monitor renal function in CsA patients closely, with regard to the observed decrease in renal function that correlated with an increase of the potential nephrotoxic metabolite AM19. Further studies with more patients, longer follow-up and higher cinacalcet doses will be needed to better elucidate the pharmacokinetics for this therapeutic combination.


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  		Table 3. CsA pharmacokinetic variables before and during concomitant oral treatment with 30 mg cinacalcet per day. All variables except Tmax were ln-transformed before statistical analysis with Student's t-test. Tmax was analysed with the Wilcoxon method

 



   Acknowledgments
 
A special thanks goes to Siri Johannesen, Kirsten K. Lund, Janicke Narverud, Jean Stenstøm and Laila Gjerdalen and colleagues for their skilled help during the pharmacokinetic investigations.

Conflict of interest statement. None of the authors has any conflict of interests.

Copyright statement. The results presented in this paper have not been published previously in whole or part, except in abstract form, at the International Society of Nephrology meeting in Rio de Janeiro in April 2007 and the American Transplantation Congress in May 2007 in San Francisco.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 5. 6.07
Accepted in revised form: 20. 8.07


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