Co-administration of ketoconazole and tacrolimus to kidney transplant recipients: cost minimization and potential metabolic benefits.

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 trans-plant recipients is safe and significantly reduces the cost of immunosuppression. In addition, this combination appears to have a beneficial effect on kidney function.

Pityriasis versicolor: avoiding pitfalls in disease diagnosis and therapy.

Pityriasis versicolor is common among young active duty members with overactive sweat glands working in humid environments and results in pigmentary changes that can be profound in those with darker skin. This article addresses several issues related to making the correct diagnosis and providing appropriate treatment, as well as the specific challenges military providers may face in these cases.

Effectiveness and cost of replacing a calcineurin inhibitor with sirolimus to slow the course of chronic kidney disease in renal allografts.

Renal grafts suffer a progressive decrease in glomerular filtration rate (GFR) because of several factors including calcineurin inhibitor (CNI) nephrotoxicity. Switching CNIs to sirolimus may improve this adverse prognosis. We performed a prospective, open-label clinical trial among 18 kidney transplant patients with more than 12 months of evolution (range, 385-1826 days), showing progressive GFR decreases and biopsies with interstitial fibrosis and tubular atrophy (IFTA). Immunosuppressive treatment included cyclosporine, ketoconazole, and steroids associated with azathioprine or mycophenolate mofetil. After signing an Institutional Review Board-approved written consent, cyclosporine was switched to sirolimus seeking to achieve a trough blood sirolimus concentration of 6-15 ng/mL. Wilcoxon and Student's t-tests were used to compare the values in the annual periods before and after the switch. GFR was estimated by the Modification of Diet in Renal Disease formula. There were no acute rejection episodes. Estimated GFR on the day of the switch was 38.0 +/- 12.1 mL/min. After CNI switch, the slope of the estimated GFR significantly improved from -6.5 +/- 9.2 to 8.1 +/- 14.0 mL/min/year (P < .01). The estimated GFR 1 year after the switch was 47.2 +/- 16.9 mL/min (P = .003 vs baseline). Total expenditures increased. The ratio of post-switch versus baseline total expenditures was 1.93 (95% confidence interval, 1.54-2.31) and the ratio of sirolimus to CNI cost was 2.16 (95% confidence interval, 1.53-2.78). Switching from CNI to sirolimus for kidney transplants with decreasing GFR and a biopsy with IFTA changes, suggesting progressive graft nephropathy, almost doubled total expenses. It is necessary to conduct trials using clinical end points to definitively validate this therapeutic intervention.

Impact of the cyclosporine-ketoconazole interaction in children with steroid-dependent idiopathic nephrotic syndrome.

BACKGROUND: Children with steroid-dependent nephrotic syndrome experience serious side effects from steroid therapy. Cyclosporine A (CsA), which is an effective agent in the treatment of steroid-dependent nephrotic syndrome, is expensive and, consequently, often unaffordable in developing countries. Many studies have documented the benefit of ketoconazole administration in transplant adults treated with CsA. We have conducted a retrospective study with the objective of addressing cost-savings, safety, and the efficacy of the co-administration of ketoconazole and CsA to children with steroid-dependent nephrotic syndrome. METHODS: This study included 102 nephrotic patients who were steroid-dependent and who received cyclosporine therapy. The commonest pathologic lesions were focal segmental glomerulosclerosis (64 patients) and minimal change disease (36 patients). Among the patients participating in the study, 78 received daily ketoconazole therapy (ketoconazole group) in the form of a 50-mg dose accompanied by an initial one-third decrease in the CsA dose, while 24 received CsA alone (non- ketoconazole group). All of the patients were children (below 18 years), and the male-to-female ratio was 3:1. The mean duration of treatment was 22.9 months. The characteristics of both groups were comparable. RESULTS: Co-administration of ketoconazole significantly reduced mean doses of CsA by 48% with a net cost savings of 38%. It also resulted in a significant improvement in the CsA response and a more successful steroid withdrawal as well as a decrease in the frequency of renal impairment. Liver function tests remained normal in both groups up to and including the final follow-up (mean of 33.6 months). CONCLUSIONS: The co-administration of ketoconazole to CsA in children with idiopathic steroid-dependent nephrotic syndrome safely results in a significant reduction in CsA cost, which causes great concern in developing countries. It may also improve CsA response.

Co-administration of cyclosporine and ketoconazole in idiopathic childhood nephrosis.

The concomitant use of cyclosporine (CsA) and ketoconazole (keto) in children with nephrotic syndrome (NS) has never been reported in the literature. This retrospective cohort study was conducted to investigate cost saving, safety, and efficacy of co-administration of keto and CsA in children with NS. The study included 186 nephrotic children receiving CsA therapy. Most were steroid dependent or resistant, and the most common pathology was focal segmental glomerulosclerosis (62%). Among our patients, 137 received daily keto therapy (keto group) 50 mg/day in addition to CsA, while 49 received CsA alone (non-keto group). The characteristics of both groups were comparable and the mean (+/-SD) duration of treatment was 22.9 +/- 8.1 months. Co-administration of keto significantly reduced the mean dose of CsA with an overall net cost saving of 37%. It also resulted in a significant improvement of CsA response, more successful steroid withdrawal, and decreased the frequency of renal impairment. Keto was generally well tolerated and safe. We conclude that co-administration of low-dose keto with CsA in children with idiopathic NS is safe, significantly reduces the cost of CsA therapy, and may improve the patient outcome.

Cyclosporine and ketoconazole for the treatment of perianal fistulas in dogs.

OBJECTIVE: To evaluate efficacy and cost of using cyclosporine and ketoconazole for the treatment of perianal fistulas in dogs. DESIGN: Clinical trial. ANIMALS: 12 dogs with perianal fistulas. PROCEDURE: Dogs received cyclosporine and ketoconazole orally (target whole blood trough cyclosporine concentrations of 400 to 600 ng/ml). Study endpoints were resolution of clinical signs, remission, and recurrence of disease. Adverse effects and cost of medications were reported. Results were compared with those from previous studies in humans and in dogs in which single agent cyclosporine treatment for perianal fistulas was used. RESULTS: All dogs had resolution of clinical signs. Eight dogs went into remission; however, 5 of those 8 had recurrence of fistulas. Adverse effects of treatment were minimal and well tolerated. Cost of treatment was comparable to traditional surgical options and less than single agent cyclosporine treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of cyclosporine with ketoconazole is an effective and cost-comparable treatment for perianal fistulas in dogs.

Coadministration of ketoconazole and cyclosporine for kidney transplant recipients: long-term follow-up and study of metabolic consequences.

In a prospective randomized study including 100 kidney transplant recipients, we previously reported on the safety and financial benefits of the coadministration of ketoconazole (keto) to cyclosporine (CsA)-treated kidney transplant recipients. In this study, we report on the long-term follow-up of these patients and their control group, as well as possible metabolic consequences of this drug combination. Evaluation of 51 keto-treated patients and their control group (49 patients) included graft function, lipogram, fasting blood glucose, liver function tests, serum calcium, phosphorus, and radiological and histopathologic assessments. Follow-up of these patients for 54 months showed that the CsA dose reduction was 72.9% at 12 months, decreased to 69.3% at the last follow-up. We also found that the mean keto dose required for CsA dose reduction decreased to 82.8 +/- 24.1 mg/d compared with the starting dose (100 mg/d). Diagnosis of acute rejection episodes was similar in both groups. However, in the control group, rejection episodes were more recurrent, with poorer response to treatment. Acute CsA nephrotoxicity was more common in the keto group, but this was encountered more at keto induction and was rapidly reversed on further reduction of CsA doses. Chronic graft dysfunction was statistically significantly less in the keto group during the first year. However, by the end of the study, the difference was not statistically significant. In this study, hepatotoxicity was similar in the two groups. On studying the metabolic consequences, we found that serum cholesterol, low-density lipoprotein, and triglyceride levels were lower in the keto group. Bone mineral contents in both groups were less than the mean values for age- and sex-matched healthy controls. From this study, we conclude that long-term use of low-dose keto in CsA-treated kidney transplant recipients is safe and cost-saving and may induce better graft function. Bone mineral contents, vitamin D blood levels, and lipid profiles are not affected by long-term keto coadministration in CsA-treated kidney transplant recipients.

Nondermatologists are more likely than dermatologists to prescribe antifungal/corticosteroid products: an analysis of office visits for cutaneous fungal infections, 1990-1994.

BACKGROUND: Dermatologists have greater accuracy than nondermatologists for diagnosis of skin disease. However, it is not clear whether this affects medical outcome. OBJECTIVE: We tested the hypothesis that nondermatologists would be more likely than dermatologists to prescribe combination products for the treatment of common fungal skin infections. METHODS: We analyzed office-based physician visits for fungal skin infections recorded in the 1990-1994 National Ambulatory Medical Care Survey. RESULTS: There were 4.1 million visits for cutaneous fungal disease of which 82% were to nondermatologists. Nondermatologists were more likely to prescribe combination agents (34.1%) than dermatologists (4.8%, p=0.001). If the percentage of combination agents used by nondermatologists was reduced to that of dermatologists, an estimated $24.9 million or $10.3 million would be saved if clotrimazole or ketoconazole, respectively, were the substituted drug for the combination agent clotrimazole/betamethasone dipropionate. CONCLUSION: Nondermatologists are more likely to use a more expensive, less effective regimen than are dermatologists, suggesting that dermatologists are more cost-effective than nondermatologists in the treatment of common fungal skin disorders.

The use of other drugs to allow a lower dosage of cyclosporin to be used. Therapeutic and pharmacoeconomic considerations.

Since its discovery in 1970, and introduction into clinical practice in 1978, cyclosporin has become the most important immunosuppressive drug used to prevent organ transplant rejection. This has been achieved by virtue of the improved graft survival rates and adverse effect profiles in patients when compared with that of the older agents. Cyclosporin is substantially more expensive (both to provide and to monitor) however, and the magnitude of these costs may preclude its use, particularly where the transplant recipient is required to pay. Cyclosporin has a complex pharmacokinetic profile with poor absorption, extensive metabolism to more than 30 metabolites and considerable inter- and intrapatient variability. Many transplant centres routinely use drugs ("cyclosporin-sparing agents') to allow a reduction in the dosage of cyclosporin while maintaining therapeutic blood cyclosporin concentrations. The use of a second drug to affect the pharmacokinetic profile of a primary drug is not new, but the use of cyclosporin-sparing agents is a departure from previous practices in that this coprescription is primarily for economic reasons. The decision to use these agents (and the choice of agent) is based upon economic and other factors including the extent of the cyclosporin-sparing effect, the potential for additional therapeutic benefit and/or adverse effects. The coprescription of cyclosporin-sparing agents is ethically more acceptable where the transplant recipient is the economic beneficiary but where the savings accrue to a third party it is more difficult. Benefits to the community at large must be balanced against the risk of adverse effects to the patient. The use of cyclosporin-sparing agents may reduce compliance and hence, jeopardise transplant and/or recipient outcomes. The transplant recipient must be informed about the reasons for their use and advised to consult an experienced physician or pharmacist before altering the established drug regimen.

Survey of cyclosporin-sparing agent use in Australasian transplant centres.

BACKGROUND: The co-prescription of drugs which elevate cyclosporin blood concentration has been advocated to reduce the costs associated with use of this expensive immunosuppressive drug. This is the first time that drugs have been widely prescribed for an economic purpose and while it is thought to be widespread, there are little published data on the extent of this practice in Australia and New Zealand. AIMS: To determine the extent to which cyclosporin sparing agents are used by Australian and New Zealand organ transplant centres, to determine which agents are used and why these agents are used by some but not all centres. METHODS: Organ transplant centres were surveyed via a questionnaire. RESULTS: Considerable variation in use of cyclosporin sparing agents exists both within and across organ transplant types by Australian and New Zealand transplant centres. Diltiazem use is more widespread than ketoconazole. CONCLUSIONS: Little of the variability in use of cyclosporin sparing agents can be explained by scientific considerations. While the central government benefits from the significant cost savings achieved by the use of cyclosporin sparing agents, individual transplant units may not. Transplant units may however be the major target in the event of litigation arising as a result of adverse effects. The availability of generic brands and improved formulations of cyclosporin may affect the viability of using cyclosporin sparing agents.

Pharmacoeconomic analysis of oral therapies for onychomycosis: a US model.

An evaluation of treatment practices in 13 countries, not including the United States, has shown oral terbinafine to be more cost-effective (from a government payer perspective) than griseofulvin, itraconazole, and ketoconazole in the treatment of onychomycosis of toenails and fingernails. The purpose of this study was to evaluate the clinical and economic effects of oral griseofulvin, itraconazole, ketoconazole, and terbinafine in the treatment of onychomycosis from the perspective of a third-party payer in the United States. A previously constructed decision-analytic model evaluating the costs of onychomycosis in 13 countries outside the United States was updated to determine the costs of treating onychomycosis in the United States. Clinical management patterns were assessed to identify and quantify physician visits, laboratory tests, and adverse drug reaction treatment components for patients with toenail and fingernail onychomycosis. A random-effects model meta-analysis of treatment efficacy (mycologic cure) and New York Metropolitan Medicare charge data for physician fees were used in the treatment model. A sensitivity analysis assessing alternative dosing regimens and a rank order stability analysis investigating the effects of length of treatment, success rates, relapse rates, and drug acquisition costs on overall results were also conducted. Terbinafine had the lowest cost per mycologic cure after one treatment regimen for onychomycosis in both toenail and fingernail infections ($791.00 and $454.00, respectively). The costs of treating toenail and fingernail infections were comparatively higher for therapy with itraconazole ($1535.00 and $767.00, respectively), griseofulvin ($2385.00 and $837.00, respectively), and ketoconazole ($10,025.00 and $1512.00, respectively). As a primary treatment choice, terbinafine also had the lowest overall expected cost per patient for both toenail and fingernail infections ($977.00 and $550.00, respectively). Griseofulvin had expected costs ($1543.00 and $822.00, respectively) similar to itraconazole ($1588.00 and $894.00, respectively), whereas ketoconazole was the most expensive primary treatment choice ($2359.00 and $1287.00, respectively). This study demonstrates that terbinafine is an economical and cost-effective treatment for patients with dermatophytic onychomycosis, supporting European and Canadian studies. Except for the rank order of griseofulvin and itraconazole, sensitivity analyses show that these results are fairly stable.

Ketoconazole to reduce the need for cyclosporine after cardiac transplantation.

BACKGROUND: Because ketoconazole can markedly reduce the need for cyclosporine and because it also has antimicrobial properties, it may offer benefits in the treatment of patients after cardiac transplantation. METHODS: We randomly assigned 43 patients at the time of cardiac transplantation to receive ketoconazole (200 mg per day) (23 patients) or no ketoconazole (20 patients). The main end points were the dose of cyclosporine required and the incidence of cardiac rejection and infection. RESULTS: Ketoconazole reduced the dose of cyclosporine needed to maintain target levels by 62 percent at one week and by 80 percent at one year. The cost savings per patient (in U.S. dollars, inclusive of the cost of ketoconazole) was about $5,200 in the first year and about $3,920 in each subsequent year. The mean (+/- SD) rate of rejection in the first month was lower in the ketoconazole group than in the controls (4.2 +/- 0.8 vs 5.7 +/- 1.0 episodes per 100 patient-days, P < 0.001), and the average number of days to the first rejection was higher (30 +/- 29 vs. 15 +/- 8, P = 0.03). In the first year, 22 percent of the ketoconazole group required cytolytic therapy, as compared with 35 percent of the controls, and 9 percent of the ketoconazole group required total lymphoid irradiation, as compared with 15 percent of the controls (P = 0.07). The incidence of infection was lower in ketoconazole-treated patients than in controls in the second month (1.4 +/- 0.5 vs. 2.8 +/- 0.7 episodes per 100 patient-days, P < 0.001) and in the third month (0.8 +/- 0.3 vs. 2.3 +/- 0.6 episodes per 100 patient days, P < 0.001). Transient, asymptomatic cholestasis was observed in the ketoconazole group. CONCLUSIONS: After cardiac transplantation, ketoconazole greatly reduced the need for cyclosporine, resulting in substantial cost savings. Ketoconazole also reduced the rates of rejection and infection, without persistent toxic effects. We now use ketoconazole routinely in cardiac-transplant recipients.

Cost-effectiveness analysis for onychomycosis therapy in Canada from a government perspective.

An economic analysis of the oral antifungal drugs griseofulvin (GRI), ketoconazole (KET), and terbinafine (TER), currently registered and used in treating onychomycosis of fingernails and toenails, was performed using a model that incorporates elements of both meta-analysis and pharmacoeconomics. The meta-analysis of published studies determined rates of success, relapse and side-effects. The perspective taken for the analysis was that of the government payer, with expected total cost and cost-effectiveness being calculated. A multiphase approach was used. The studies of onychomycosis of the fingernails showed that TER had a 95.0% success rate, KET 80.9%, and GRI 59.6%. GRI had the lowest acquisition costs. The success rates for onychomycosis of the toenails were: TER 78.3%, KET 40.8%, and GRI 17.5%. GRI had the lowest acquisition costs. However, expected cost comparison showed TER had the lowest cost because of shorter treatment duration. The expected cost of therapy with a 100% government payer perspective for fingernail onychomycosis was the lowest for TER ($439.83), followed by GRI ($480.80), then KET ($755.46). Toenail onychomycosis showed the same order for the comparators, with TER $1049.77, GRI $1388.54 and KET $1936.48. When compared with TER, fingernail cost-effectiveness ratios for GRI and KET were 1.51 and 2.00. Toenail cost-effectiveness ratios were 2.49 and 2.48, respectively. For both fingernail and toenail onychomycosis, TER had the greatest number of disease-free days (973 for fingernails; 1073 for toenails), followed by KET (837; 798), then GRI (702; 569).(ABSTRACT TRUNCATED AT 250 WORDS)

A multinational pharmacoeconomic analysis of oral therapies for onychomycosis. The Onychomycosis Study Group.

Due to increased interest in economic evaluation and the rapid international spread of new healthcare technologies across borders, there is a need to interpret economic evaluations on a worldwide basis. We conducted a multinational cost-effectiveness analysis, from a government payer perspective, comparing four primary oral treatment regimens for onychomycosis of the fingernails and toenails: griseofulvin, itraconazole, ketoconazole and terbinafine. We used a four-step pharmacoeconomic research model which includes all relevant factors affecting costs in 13 countries: Austria, Belgium, Canada, Finland, France, Germany, Greece, Italy, The Netherlands, Portugal, Spain, Switzerland and the U.K. A worldwide meta-analysis of published clinical data served as the statistical input for the pharmacoeconomic model, and demonstrated that terbinafine had the highest success rates (95.0% and 78.3%) of the clinical comparators for fingernails and toenails, respectively. We found that terbinafine was the most effective therapy in relation to cost (therefore giving it the lowest cost-effectiveness ratio) for both infections in all health-care systems analysed.