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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2014  |  Volume : 25  |  Issue : 4  |  Page : 814-818
Co-administration of ketoconazole and tacrolimus to kidney transplant recipients: Cost minimization and potential metabolic benefits


Renal Unit, Ahmed Gasim Cardiac Surgery and Kidney Transplant Center, Khartoum, Sudan

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Date of Web Publication24-Jun-2014
 

   Abstract 

To evaluate the effects of the co-administration of tacrolimus and ketoconazole to a group of kidney transplant recipients, we studied 30 kidney transplant recipients with stable kidney function who were maintained on tacrolimus-based immunosuppression. They were pres­cribed ketoconazole (100 mg/day) with a concomitant reduction in daily tacrolimus dose to maintain its level within the therapeutic range. The study included 19 males and 11 females with a mean age of 36 ± 12 years. All patients were at least three months post-transplant and had tacrolimus trough levels within the therapeutic range of 5-7 ng/mL. Desired tacrolimus trough levels could be achieved in 29/30 patients after the addition of ketoconazole. This resulted in a significant reduction of the median tacrolimus dose from 5 mg/day (range 3-20 mg/day) at baseline to 2 mg/day (range 1-4 mg/day) (P = 0.00). The median reduction in the tacrolimus dose was 63% (range 50-83%). The median monthly tacrolimus cost dropped from 375 US$ per patient (range 225-1440 US$) to 150 US$ per patient (range 120-300 US$). There were no reported adverse drug effects during the study period. After one year of follow-up, there was a small but significant improvement in the estimated glomerular filtration rate (72 ± 18 versus 78 ± 20 mL/min, P = 0.01) and a significant reduction in serum uric acid levels (7.7 ± 1.7 versus 5.9 ± 0.8 mg/dL, P = 0.003). The co-administration of ketoconazole and tacrolimus to kidney trans­plant recipients is safe and significantly reduces the cost of immunosuppression. In addition, this combination appears to have a beneficial effect on kidney function.

How to cite this article:
Elamin S, El-Magzoub ARA, Dablouk N, Mahmoud F, Abbas M. Co-administration of ketoconazole and tacrolimus to kidney transplant recipients: Cost minimization and potential metabolic benefits. Saudi J Kidney Dis Transpl 2014;25:814-8

How to cite this URL:
Elamin S, El-Magzoub ARA, Dablouk N, Mahmoud F, Abbas M. Co-administration of ketoconazole and tacrolimus to kidney transplant recipients: Cost minimization and potential metabolic benefits. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2019 Jul 16];25:814-8. Available from: http://www.sjkdt.org/text.asp?2014/25/4/814/135033

   Introduction Top


Kidney transplantation is the best available treatment option for patients with end-stage renal disease (ESRD). It surpasses dialysis in terms of survival, patients' quality of life and cost-effectiveness. Compared with cyclospo-rine, tacrolimus reduces the risk of acute rejection and improves graft survival during the first year of kidney transplantation. The Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines suggest using tacrolimus as the first-line calcineurin inhibitor (CNI) for maintenance therapy of kidney transplant recipients. [1] The same guide­lines considered the addition of ketoconazole an appropriate strategy to minimize drug cost. [1]

Two important studies demonstrated the safety and efficacy of ketoconazole in redu­cing the tacrolimus dose for kidney transplant recipients. [2],[3] The magnitude of reduction was determined in comparison with a control group in the first study, [2] and in comparison with tacrolimus doses recommended in the litera­ture in the second study. [3]

Our aim from this study was to determine the magnitude of reduction in tacrolimus dose that can be achieved in kidney transplant reci­pients with the addition of ketoconazole. In this study, each patient served as his/her own control, allowing us to evaluate inter-patient variability. We also studied the effect of keto-conazole on patients' clinical and biochemical parameters after one year of follow-up.


   Subjects and Methods Top


We recruited 30 kidney transplant recipients from the outpatient clinic of Ahmed Gasim Kidney Transplant Center, Khartoum, Sudan during August and September 2009. The se­lected patients were maintained on tacrolimus (Prograf ® ) prescribed in two divided doses per day. They received their kidney transplants at least three months prior to the initiation of the study and had tacrolimus trough levels within the therapeutic range of 5-7 ng/mL. We ex­cluded patients with known liver disease, those with serum creatinine level exceeding 2 mg/dL and those on less than 3 mg of tacro-limus per day.

The purpose of the study was explained to the patients and informed consents were ob­tained. We instructed the patients on the im­portance of adherence to the prescribed keto-conazole dose and its effect on tacrolimus levels. They were prescribed 100 mg of keto-conazole daily with a concomitant 50% reduc­tion in daily tacrolimus dose, rounded down to the closest integer. Tacrolimus levels were measured by the enzyme-linked immunosorbent assay (ELISA). Serum creatinine and trough tacrolimus levels were checked twice per week and tacrolimus doses were indivi­dually titrated to achieve the required levels. Tablets containing 0.5 mg of tacrolimus were only used for patients who required less than 1 mg of tacrolimus per dose. The keto-conazole dose was reduced to 50 mg/day in patients who experienced high levels of tacrolimus despite reducing the tacrolimus dose to 0.5 mg/12 h. After achieving the therapeutic target, trough levels were checked every one to three months. For the purpose of this study, the patients were followed for one year.


   Statistical Analysis Top


Analysis was performed using the Statistical Package for Social Sciences (SPSS), version 19.0 (SPSS Inc., Chicago, IL, USA). Tacro-limus trough levels were summarized using the mean and standard deviation. Tacrolimus doses were summarized by median value. Paired measurements of tacrolimus trough levels were compared using paired Student's "t" test. Paired tacrolimus doses were com­pared using the Wilcoxon signed ranks test. Values of P <0.05 were considered statistic-cally significant.


   Results Top


The study included 30 Sudanese kidney trans­plant recipients, 19 males and 11 females. Their mean age was 36 ± 12 years (range 16- 55 years). Thirteen patients (43.3%) were in their first post-transplant year and the remain­ders were more than one year post-transplant.

Twenty-nine patients received their kidney transplants locally from live related donors. They were maintained on tacrolimus, azathio-prine and prednisolone, except for two pa­tients. One of these two patients was off steroids because of avascular necrosis of the hip joint and the other patient was off azathio-prine because of recurrent drug-induced ane­mia. Only one patient received her kidney transplant abroad from a live unrelated donor and was maintained on tacrolimus, mycophe-nolate mofetil (MMF) and prednisolone. The same patient was the only one with a second transplant.

Eight (27%) patients were diabetic, seven of whom were insulin dependent. Seventeen (57%) patients were hypertensive and one patient had sickle cell trait. All patients were sero-negative for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, and none of them had clinical or biochemical evidence of liver disease. The prevalence of overweight and obesity was 12% and 29%, respectively.

Nine patients (30%) were on ranitidine. No patient was on diltiazem, verapamil or rifam-picin. All patients were at least three months post-transplant. All patients had stable serum creatinine levels ranging from 0.8-1.8 mg/dL. All patients had trough tacrolimus levels with­in the therapeutic range of 5-7 ng/mL.

The desired tacrolimus trough levels could not be achieved in one patient despite re­ducing the tacrolimus dose to the minimum. She was a female patient 11 months post-transplant who was originally maintained on 5 mg of tacrolimus per day. Her tacrolimus trough levels remained elevated at 8.2 ng/mL despite reducing the tacrolimus dose to 0.5 mg BD and ketoconazole dose to 50 mg OD. Ketoconazole was withdrawn and the original tacrolimus dose was resumed.

All remaining 29 patients achieved tacro-limus trough levels within 30% of their base­line levels, and 71% of the patients achieved tacrolimus trough levels within 20% of their baseline levels. In two patients, this required reducing the ketoconazole dose to 50 mg OD. There were no significant differences between the mean trough tacrolimus levels at baseline and the mean trough tacrolimus levels after the addition of ketoconazole (6.2 ± 0.6 versus 6.0 ± 1.0 ng/mL, P = 0.3).

There was a statistically significant reduction of the median tacrolimus dose from 5 mg/day (range 3-20 mg/day) at baseline to 2 mg/day (range 1-4 mg/day) after the addition of keto-conazole (P = 0.00). The addition of ketoconazole allowed the tacrolimus dose to be reduced by a median of 63% (range 50-83%) while maintaining equivalent tacrolimus trough levels. The tacrolimus dose was reduced by at least 50% for all patients, and one-third of the patients required more than 75% reduction in their baseline tacrolimus doses.

The patients who were on ranitidine required significantly more reduction in their median tacrolimus doses than other patients (79% vs. 60%, P = 0.01). The patients in their first post-transplant year required more reduction in their median tacrolimus doses compared with other patients, but the difference was not statistically significant (69% vs. 61%, P = 0.2). The reduction in the tacrolimus doses was paralleled by a significant reduction in the cost of immunosuppression. The median monthly tacrolimus cost dropped from 375 US$ per patient (range 225-1440 US$) to 150 US$ per patient (range 120-300 US$) by the addition of ketoconazole.

One patient died during the study. She was a 49-year-old diabetic female with sickle cell trait in her 4 th post-transplant year. She pre­sented with clinically diagnosed acute rejec­tion 10 months after initiation of the study while maintaining therapeutic tacrolimus trough levels. Her serum creatinine dropped to 1.9 mg/dL after a course of pulse steroids, but she presented one month later with sepsis and multi-organ failure that resulted in her death. Another patient suffered from recurrent cys­titis while maintaining trough tacrolimus le­vels within the therapeutic range of 5-7 ng/mL. She was maintained on tacrolimus 0.5 mg BD and ketoconazole 50 mg OD. Keto-conazole was withdrawn after eight months with the aim of reducing the overall level of immunosuppression. Her serum creatinine le­vel was 1.3 mg/dL. Three patients were not compliant on ketoconazole and stopped it three and eight months after the initiation of the study. This caused their tacrolimus trough levels to fall below the therapeutic range, but none of them developed rejection. When asked about the reason for stopping ketoconazole, they merely complained of "too many medications."

There were no reported adverse drug effects during the study period. Twenty-four patients completed one year of follow up. Their renal function tests and other biochemical para­meters are presented in [Table 1]. There was no difference between tacrolimus trough levels at baseline and tacrolimus trough levels after one year on ketoconazole. The study patients had a small but statistically significant im­provement in their estimated glomerular filtration rate after one year of follow-up (72 ± 18 vs. 78 ± 20 mL/min, P = 0.01). They also had significantly lower serum uric acid levels (7.7 ± 1.7 vs. 5.9 ± 0.8 mg/dL, P = 0.003).
Table 1: Clinical and biochemical parameters of patients who were maintained on tacrolimus and ketoconazole for 1 year (n = 24).

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   Discussion Top


This study confirms previous observations that the co-administration of tacrolimus and ketoconazole to kidney transplant recipients significantly reduces the tacrolimus dose and cost. The magnitude of reduction is consistent with the values reported by El-Dahshan et al, who observed a 59% reduction in tacrolimus doses and a 57% reduction in its cost after the addition of ketoconazole. [2] Soltero et al esti­mated the reduction in tacrolimus dose after the addition of ketoconazole by 78%, but they used tacrolimus doses recommended in the literature for comparison rather than actual patients. [3] Accordingly, the figures observed by Soltero et al are likely to be an overesti-mation.

Tacrolimus is a substrate for cytochrome P450 (CYP) 3A5. Enzyme activity is de­termined by a single nucleotide polymorphism (*1/*3) in the CYP3A5 gene. Kidney trans­plant recipients with the CYP3A5*1/*1 geno­type require higher daily tacrolimus doses compared with those with the CYP3A5*3/*3 genotype to maintain the target trough levels. [4] Ketoconazole retards metabolic degradation of tacrolimus through its effect on the cytochrome P450 enzyme system. The CYP3A5*1/*3 polymorphism is an important determinant of the response to inhibition of tacrolimus metabolism by ketoconazole, with a 30% greater inhibition in those lacking the *1 allele. [5]

Genetic heterogeneity may explain the varia­bility of patients' responses to ketoconazole. However, we found that the minimum dose reduction required by any patient was 50%. It seems prudent to reduce the tacrolimus dose by at least one-half upon the addition of keto-conazole in order to avoid inducing dange­rously high drug levels.

In the current study, three patients of 30 stopped taking ketoconazole on their own accord. Adherence to prescribed medication is a major challenge for patients with chronic medical conditions. In a cross-sectional study of outpatient kidney transplant recipients, 8.4% of patients were non-adherent to immu-nosuppressive medications, whereas 44.9% of patients were non-adherent to non-immuno-suppressive medication. [6] Regular follow-up with repeated emphasis on the importance of adherence to medication is vital in this setting.

This study also demonstrates the safety of ketoconazole when co-administered with tac-rolimus to kidney transplant recipients, in sup­port of other reports. [2],[3] Moreover, there was a slight but statistically significant improvement in patients' estimated GFR after one year of follow-up. A similar finding was reported by El-Dahshan et al. [2] This improvement was not due to changes in tacrolimus trough levels, which remained stable throughout the follow-up period, and was accompanied by a signi­ficant reduction in serum uric acid levels. El-Dahsahn et al also reported that patients on ketoconazole had less fungal skin infections, gastrointestinal episodes and hospitalizations compared with controls. [2] However, these va­riables were not included in the current study protocol.

The economic advantage of adding ketoco-nazole to the standard immunosuppression regimens for kidney transplant recipients in developing countries is evident. This study highlights the possibility of ketoconazole ha­ving additional metabolic benefits in this setting. Additional long-term, large-scale con­trolled studies are required to confirm these findings.


   Conclusion Top


We conclude that the co-administration of ketoconazole and tacrolimus to kidney transplant recipients is safe and significantly re­duces the cost of immunosuppression. In addi­tion, this combination appears to have a bene­ficial effect on kidney function.

 
   References Top

1.Kasiske BL, Zeier MG, Chapman JR, et al; Kidney Disease. Improving Global Outcomes. KDIGO clinical practice guideline for the care of kidney transplant recipients: A summary. Kidney Int 2010;77:299-311.  Back to cited text no. 1
    
2.el-Dahshan KF, Bakr MA, Donia AF, Badr Ael-S, Sobh MA. Co-administration of ketoc-onazole to tacrolimus-treated kidney trans­plant recipients: A prospective randomized study. Nephrol Dial Transplant 2004;19:1613-7.  Back to cited text no. 2
    
3.Soltero L, Carbajal H, Rodríguez-Montalvo C, Valdés A. Coadministration of tacrolimus and ketoconazole in renal transplant recipients: Cost analysis and review of metabolic effects. Transplant Proc 2003;35:1319-21.  Back to cited text no. 3
    
4.Tsuchiya N, Satoh S, Tada H, et al. Influence of CYP3A5 and MDR1 (ABCB1) polymer-phisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation 2004;78:1182-7.  Back to cited text no. 4
    
5.Chandel N, Aggarwal PK, Minz M, Sakhuja V, Kohli KK, Jha V. CYP3A5*1/*3 genotype influences the blood concentration of tacro-limus in response to metabolic inhibition by ketoconazole. Pharmacogenet Genomics 2009; 19:458-63.  Back to cited text no. 5
    
6.Terebelo S, Markell M. Preferential adherence to immunosuppressive over nonimmunosup-pressive medications in kidney transplant recipients. Transplant Proc 2010;42:3578-85.  Back to cited text no. 6
    

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Correspondence Address:
Sarra Elamin
Renal Unit, Ahmed Gasim Cardiac Surgery and Kidney Transplant Center, P. O. Box 363, Khartoum
Sudan
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DOI: 10.4103/1319-2442.135033

PMID: 24969193

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    Abstract
   Introduction
   Subjects and Methods
   Statistical Analysis
   Results
   Discussion
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