CYCLOSPORINE AND LOW-DOSE KETOCONAZOLE IN RENAL TRANSPLANT RECIPIENTS: A SINGLE-CENTER EXPERIENCE

Abstract

Background. 

The high cost of cyclosporine A (CsA) is an impediment for low-income patients. Previous studies have used ketoconazole at doses between 200 and 400 mg/day to lower CsA consumption.

Methods. 

Ketoconazole and CsA were administered prospectively to renal transplant patients. Patients treated historically with CsA were used as a reference group. At different intervals posttransplant, clinical and laboratory data were recorded.

Results. 

The reference group (n=14) was treated with CsA from 1992 to 1997 and the CsA plus ketoconazole group (n=17) from 1998 to 2002. Follow-up was 76±22 and 29±14 months, respectively. CsA doses throughout the study were 4.0±1.3 and 1.6±0.6 mg/kg/day (a 60% reduction, P =0.00). Trough levels of CsA were 194±87 and 193±69 ng/mL, respectively. The ketoconazole dose was 54±17 mg/day. The monthly cost of CsA was reduced by 60%, including the cost of ketoconazole.

Conclusions. 

CsA with ketoconazole resulted in a substantial dose and cost reduction that proved safe and effective.

Calcineurin inhibitors form the mainstay of immunosuppression for renal transplant recipients. The majority of centers in Mexico base their regimens on cyclosporine A (CsA). The high cost of this medication continues to be an impediment for low-income patients and is a heavy tax burden for developing countries. During the early 1980s, transplant patients with mycotic infections suffered CsA toxicity when treated with ketoconazole. It was found that cytochrome P-450 3A4 (CYP3A4) enzymes in the liver as well as in the intestine metabolized CsA (¹). Further studies showed that ketoconazole is a potent microsomal inhibitor and, in addition, affects P glycoprotein, a calcineurin inhibitor efflux pump in the apical portion of intestinal cells (²). In this fashion, ketoconazole also affects the bioavailability and metabolism of tacrolimus and sirolimus (^{3, 4}).

CsA has been associated with clinically relevant side effects, including nephrotoxicity, hypertension, dyslipidemia, gingival hyperplasia, and hirsutism. Ketoconazole can produce an idiosyncratic drug reaction in the liver, with 10% to 20% of patients developing subclinical hypertransaminasemia; fulminant hepatitis is a relatively rare occurrence that can respond to timely drug discontinuation (⁵). In high doses, ketoconazole inhibits other CYP isoenzymes involved in steroid biosynthesis, and can reduce levels of vitamin D and sex hormones (^{6, 7}). Ketoconazole also reduces cholesterol biosynthesis through CYP-mediated 14-demethylase activity, a late step in the pathway that controls the conversion of lanosterol to ergosterol (⁸).

Previous trials with ketoconazole have used fixed daily doses ranging between 200 and 400 mg/day. The purpose of this study was to demonstrate that renal transplant patients treated with individually tailored doses of ketoconazole require smaller doses of CsA to reach therapeutic blood levels, thus reducing costs substantially. Another goal was to review the metabolic effects of this combination.

PATIENTS AND METHODS

Ketoconazole was administered prospectively to renal transplant patients treated with CsA starting in 1998. This group was compared with patients that had previously undergone transplantation receiving CsA. Forty-eight hours after surgery, ketoconazole was initiated at a dose of 200 mg/day, unless there was a clear contraindication (preexisting liver disease, hypertransaminasemia, or gastrointestinal tract intolerance). In the first weeks after transplant, the dose of ketoconazole and CsA was lowered according to CsA whole blood concentrations (Abbott monoclonal assay). At 0 to 1, 1 to 6, 6 to 12, 12 to 24, 24 to 36, and 36 to 48 months, clinical data and laboratory values were recorded. Costs were calculated on the basis of the mean daily dose of CsA in milligrams per kilogram. The local market value of CsA was $0.10 (U.S. dollars) per milligram and ketoconazole was $0.05 per milligram. Fisher’s exact, Mann-Whitney U, and Kaplan-Meier analysis were used to test hypotheses and calculate graft survival. A two-tailed value of P ≤0.05 was considered significant.

RESULTS

The CsA reference group (n=14) was treated from January 1992 until April 1997, and the CsA with ketoconazole group (n=17) was treated from January 1998 until April 2002. Table 1 presents demographic and clinical characteristics. The maintenance dose range of each agent in both groups was azathioprine, 50 to 100 mg/day; mycophenolate mofetil, 500 to 1,000 mg/day; and prednisone, 5 to 10 mg/day. Throughout the study, CsA trough levels in both groups remained in the therapeutic range: 194±87 and 193±69 ng/mL (P =0.26). The mean CsA dose throughout the study was 4.0±1.3 and 1.6±0.6 mg/kg/day in each group (a 60% reduction, P =0.00). At the end of follow-up, the mean monthly cost of CsA in the ketoconazole group was $335 versus $854 in the reference group (60% reduction including the cost of ketoconazole). The average dose of ketoconazole was 54±17 mg/day. Calcium channel antagonists (verapamil-diltiazem) were used to treat hypertension in 71% and 76% of the patients. Laboratory parameters (Table 2) did not show any significant alterations, although there was a tendency for total cholesterol levels to be lower in the ketoconazole group (P =0.07). Two patients in the reference group and four in the ketoconazole group presented slight elevations of aspartate aminotransferase and alanine aminotransferase in the first month posttransplant, which were not clinically significant and resolved by adjusting the treatment regimen. Two patients in the reference group presented surgical complications: urinary bladder hemorrhage and ureteral necrosis. Four patients in the ketoconazole group presented a surgical complication: perirenal hematoma, postincisional hernia, urologic hemorrhage, and superficial wound bleeding. Cytomegalovirus (CMV) disease was absent in the ketoconazole group compared with five reported cases in the CsA group (P =0.01). Three cases of CMV disease in the CsA reference group were mild cases consisting of fever, malaise, and lymphopenia with a concomitant titer increase in immunoglobulin M anti-CMV; two cases of invasive CMV (esophagitis and colitis) were confirmed by histopathologic evaluation. The incidence of acute rejection was 14% in the CsA group versus 12% in the ketoconazole group (P =0.31). The 3-year graft survival was 100% in both groups (log-rank, 0.80).

Table 1: Demographic and clinical data

Table 2: Laboratory data^a

DISCUSSION

Ketoconazole has been used as a CsA-sparing agent in several studies (Table 3), achieving dose and cost reductions of 70% to 88% (^9–12). This protocol differs from some of the previous trials with ketoconazole because our center starts this agent within 48 hr posttransplant, while the patient is still hospitalized. This allows for tapering of the CsA dose with inpatient personnel and laboratory support. Experience has shown us that stabilizing the CsA and ketoconazole dose on an outpatient basis is more expensive and tedious because frequent consultations and assays are required to reach a steady state. Another difference is that our patients receive a much lower dose of ketoconazole (54±17 mg/day), and this probably accounts for the absence of azole-related side effects, which can include vomiting, diarrhea, flatulence, hepatotoxicity, and loss of libido. None of our patients required antacid therapy on a regular basis, which is important because ketoconazole requires an acid medium for optimal absorption.

Table 3: Previous ketoconazole and CsA studies

The subclinical hypertransaminasemia episodes seen in our patients seemed to be multifactorial in nature and cannot be attributed entirely to azole treatment. Moreover, these cases occurred in the first month posttransplantation, when immunosuppression and the risk of side effects are highest.

One of the pitfalls of using ketoconazole is the risk of CsA toxicity caused by inadequate CsA dose lowering according to whole blood concentrations. Trough levels in the first weeks posttransplant must be determined frequently (four to eight times per week). Also, some patients will respond more vigorously to ketoconazole, and this drug should be reduced as well. Most patients will reach a steady state within 1 month.

Patients receiving ketoconazole showed a trend toward lower cholesterol levels (statins were not used). Whether this reduction can translate into less future atherogenic disease requires a larger sample size and a more longitudinal study. Evidence by Moore et al. (¹³) suggests that hormone levels can be altered when using ketoconazole at a dose of 200 mg/day. However, a recent case control study by Sobh et al. (¹⁰) showed that ketoconazole can be safely administered at a dose of 50 to 100 mg/day without any clinical alterations significant enough to warrant its discontinuation (vitamin D and bone density also were assessed). Because of the low dose of medication used, we did not deem it necessary to assess testosterone and vitamin D levels.

Some of our patients received standard-dose antihypertensive treatment with calcium channel antagonists. Although ketoconazole is a more potent inhibitor of CYP3A4 (effects in 24 hr), diltiazem and verapamil can also reduce the dose of CsA up to 30% within 3 to 4 days (¹⁴). Although 71% and 76% of the patients in this study received nondihydropyridine calcium channel blockers, there remained a marked 60% CsA dose reduction in the ketoconazole group.

Most of the ketoconazole-treated patients received a kidney from a cadaveric donor, yet the incidence of acute rejection and 3-year allograft survival were excellent. Previous studies using CsA with ketoconazole have shown a similar if not lower incidence of acute rejection episodes (Table 3). It has been shown that ketoconazole may increase exposure to prednisone (¹⁵). Another beneficial factor might be that lower costs for therapy could be increasing patient compliance.

Previous studies have noted a lower incidence of infection among patients treated with CsA plus ketoconazole (^9–12). Not surprisingly, patients in our study that received ketoconazole had no mycotic infections. Although CMV disease was also absent in the ketoconazole group, it is our opinion that this is an incidental finding that would need to be reproduced in a larger and more controlled study to have external validity.

CONCLUSION

A major problem with transplant therapy continues to be the high cost of immunosuppressive drugs. The coadministration of CsA with ketoconazole results in a substantial reduction in expenditure. Low-dose ketoconazole proved free of side effects. By lowering CsA metabolism and increasing its bioavailability, ketoconazole functions as a CsA-sparing agent that can be titrated to an optimal dose for cost benefits and patient comfort. Also, the drug combination may have some beneficial lipid-lowering and antimicrobial properties that deserve further investigation. We conclude that the proper administration of CsA and low-dose ketoconazole in renal transplant recipients is safe and the immunosuppression is effective.