Drug Criteria & Outcomes-Daclizumab (Zenapax) for renal transplant patients
Drug Criteria & Outcomes-Daclizumab (Zenapax) for renal transplant patients
By Monica L. Burleson, PharmD
Drug Information Pharmacy Practice Resident
Medical University of South Carolina
Charleston, SC
Indications:
Daclizumab, manufactured by Hoffmann-La Roche Pharmaceuticals, is indicated for prophylaxis of acute organ rejection in renal transplant patients. It should be used in combination with cyclosporine and corticosteroids as part of an immunosuppressive regimen.1-2
Pharmacology:
Daclizumab is a humanized IgG1 monoclonal antibody that binds to the alpha subunit (Tac subunit) of the human high-affinity interleukin-2 (IL-2) receptor.1,3 It is composed of 90% human and 10% murine antibody sequences.1
The Tac subunit is only expressed on the surface of activated lymphocytes and is important for clonal expansion of activated T cells.1,4 Daclizumab is a receptor antagonist that binds to the Tac subunit and inhibits the ability of IL-2 to bind to the subunit, thus blocking a critical pathway of immune response in allograft rejection.1,4
Pharmacokinetics:
In clinical trials, patients receiving daclizumab 1 mg/kg intravenously (IV) every 14 days for five doses experienced increased peak serum concentrations between the first and fifth doses (21 ± 14 mcg/mL and 32 ± 22 mcg/mL, respectively). The average trough concentration prior to the fifth dose was 7.6 ± 4.0 mcg/mL. Previous data suggest that serum levels between 5 and 10 mcg/mL are needed to saturate the Tac subunit of the IL-2 receptors and block the response of activated lymphocytes.1-2
The volume of distribution is 2.5 liters for the central compartment and 3.4 liters peripherally. The elimination half-life is approximately 20 days (range 11 to 38 days), which is comparable to the 18 to 23 day elimination half-life of human IgG. Systemic clearance is variable and is influenced by body weight, thus supporting the milligram per kilogram dosing regimen.1-2
No dosage adjustment is needed based on age, race, gender, or degree of proteinuria.1-2
Selected clinical trials:
The efficacy and safety of daclizumab were assessed in two randomized, double-blind, multicenter, controlled trials that studied 535 patients.5-6 In both trials, the primary endpoint was the incidence of biopsy-confirmed acute rejection within six months after transplantation. Secondary endpoints included the number of acute rejections per patient in the first six months post-transplant, time to first acute rejection episode, incidence of delayed graft function, graft function at six months measured by serum creatinine and glomerular filtration rate, number of patients with graft loss, documented infection, patient survival, cumulative dose of prednisone in the first six months, and use of OKT3 or antilymphocyte globulins.5-6
Patients were eligible to participate if they were receiving their first renal allograft from a cadaveric donor and were at least 18 years old. Patients were excluded if they were receiving multiple organs or had a positive crossmatch for T-cell lymphocytes.5-6 Nashan and colleagues conducted a study of 275 patients receiving a first cadaveric renal allograft.5 Patients were randomly assigned to receive daclizumab 1 mg/kg IV or placebo for five doses, along with a baseline immunosuppressive regimen consisting of cyclosporine and corticosteroids. The first dose was given immediately before transplantation, and the remaining four were given at two-week intervals following transplantation.5
Vincenti and colleagues performed a similar trial in 260 patients receiving their first cadaveric renal allograft.6 In this trial, patients were randomized to daclizumab 1 mg/kg IV or placebo for five doses, along with a baseline immunosuppressive regimen consisting of cyclosporine, azathioprine, and prednisone. Again, the first dose was given immediately prior to transplantation, and the remaining four were given at two-week intervals post-transplant.6 Table 1, above, displays the results of these two trials.
The incidence of acute rejection at six months was clinically and statistically significantly lower in the daclizumab-treated groups than in the placebo group in both studies.5-6 In the study by Nashan and colleagues, the cumulative dose of corticosteroids was reduced in the daclizumab group vs. the placebo group (3750 mg vs. 4438 mg, P = 0.01).5 However, there was no difference in corticosteroid use between the two groups in the study by Vincenti and colleagues.6 The incidence of delayed graft function was similar between the two treatment groups in both studies. Additionally, there was no difference in graft function at one year post-transplant between the treatment groups in either study.5-6
No significant acute adverse effects or allergic reactions were reported in either study. Neither study showed a statistically significant increase in infections or malignancies in the daclizumab-treated group.5-6
The data from these two studies show that addition of daclizumab to a baseline immunosuppressive regimen of cyclosporine and corticosteroids, plus or minus azathioprine, reduces the frequency of biopsy-confirmed acute rejection episodes in the first six months after renal transplant. This benefit is obtained without an increase in infections or malignancies.5-6
Adverse reactions:
In clinical trials, daclizumab did not seem to alter any of the known toxicities of concomitant immunosuppressive therapy.1 Adverse events were reported in 95% of patients receiving placebo and 96% of those receiving daclizumab. Therapy was discontinued due to adverse effects in 8.5% of patients in the placebo group and 8.6% of patients in the daclizumab group. The incidence of malignancies at one year post-transplant was 2.7% in the placebo group and 1.5% in the daclizumab group. Daclizumab therapy did not increase the frequency of post-transplant lymphoma. The only infections that were higher in the daclizumab-treated group were cellulitis and wound infections. This occurred in 4.1% of patients receiving placebo and 8.4% of those receiving daclizumab. The frequency and type of side effects reported were similar between the daclizumab and placebo groups, with the most frequently reported side effect being gastrointestinal disorders. The most commonly reported events are shown in Table 2, p. 4.1
Pregnancy/lactation:
Daclizumab is designated as a Pregnancy Category C drug.1 No studies, animal or human, have been conducted with daclizumab to determine whether or not it causes fetal harm. IgG molecules do cross the placental barrier, so daclizumab should not be used in pregnant women unless the maternal benefit outweighs the fetal risk.1 In general, effective contraception should be used prior to, during, and for four months after completion of daclizumab therapy.1 The presence of daclizumab in human milk has not been determined, but as many drugs are passed into maternal milk, caution should be used in administering this drug to nursing mothers.1
Contraindications:
Zenapax is contraindicated in patients with a known hypersensitivity to daclizumab or any of its components.1-2
Warnings/precautions:
Daclizumab should only be administered by qualified practitioners. Patients should be informed about the potential benefits and risks of immunosuppressive therapy. Even though there was no increased incidence of infections or malignancies in clinical trials, patients receiving immunosuppressive therapy are at increased risk of developing these complications and should be monitored appropriately. Because daclizumab is a protein, anaphylactoid reactions are possible, and medications used to treat severe hypersensitivity reactions should be readily available.
The long-term effect of daclizumab therapy on the immune system's ability to respond to antigens first encountered during daclizumab therapy is not known. During clinical trials, low titers of anti-idiotype antibodies to daclizumab were detected. These antibodies did not affect daclizumab's efficacy, safety, or serum levels. To date, no well-controlled studies have been published assessing the efficacy of daclizumab in prevention of acute rejection in the pediatric population.1,7
Dosage and administration:
The recommended dose of daclizumab is 1 mg/kg administered IV over 15 minutes. The calculated volume should be mixed with 50 mL of sterile 0.9% sodium chloride solution. The usual course of therapy is five doses. The first dose is given within 24 hours prior to transplantation, and the four remaining doses are given at 14-day intervals.1-2
Drug interactions:
No drug interactions have been observed between daclizumab and other agents commonly prescribed in renal transplant patients. Other drugs should not be added or infused through the same IV line as daclizumab.1-2
Dosage forms available:
Daclizumab is available in preservative-free, single-use 25 mg/5 mL glass vials for IV injection. Vials should be stored between 2 and 8 degrees Celsius (36 to 46 degrees Fahrenheit) and should be protected from light.1-2
Potential for medication errors:
There is potential for medication errors between daclizumab, basiliximab, infliximab, and abciximab, as well as between Zenapax and Zanaflex, due to their similar spelling and pronunciation.8
Discussion:
Daclizumab and basiliximab are FDA-approved chimeric monoclonal antibodies indicated to prevent rejection in renal allograft recipients. Both agents are to be used in conjunction with a baseline immunosuppressive regimen including cyclosporine and corticosteroids.1,9 Both are receptor antagonists that work by binding to the Tac subunit of the human high-affinity interleukin-2 receptor, thus inhibiting the ability of IL-2 to bind to the subunit. This blocks a critical pathway of immune response in allograft rejection.1,9
Clinical trials evaluating 525 patients were performed to assess the safety and efficacy of daclizumab. The data from these two studies support that addition of daclizumab to a baseline immunosuppressive regimen reduced the frequency of biopsy-confirmed acute rejection episodes in the first six months after renal transplant. This benefit was obtained without an increase in infections or malignancies.5-6
In clinical trials, adverse effects were similar to the placebo-treated group. The most commonly reported adverse events were gastrointestinal disorders. No dosage adjustment is required based on age, race, gender, or degree of proteinuria.1
Currently, there are no trials comparing the efficacy of daclizumab and basiliximab. These agents have similar adverse effect profiles, and neither has demonstrated any drug-drug interactions. Until one agent is proven clinically superior to the other, cost will remain a prominent concern. Based on the FDA-approved five-dose regimen, daclizumab is more expensive than basiliximab. In clinical practice, daclizumab is administered as a two-dose regimen with the first dose administered within 24 hours before transplantation and the second dose seven to 10 days after transplant. This regimen is less expensive than a course of basiliximab ($100 less per regimen for a 70 kg adult); however, there are no published studies supporting this regimen. Also, since daclizumab is administered over a longer dosing interval, the first dose can be given inpatient and subsequent doses can be given in the outpatient setting. Thus, reimbursement is acquired from Medicare for the inpatient dose and Medicare Part B or private insurance for the outpatient doses.
In children, less drug is wasted using daclizumab because it is dosed on a mg/kg basis rather than on a mg/m2 basis; fewer vials are used, resulting in cost savings ($400 less per regimen for a 25 kg child). Although pediatric renal transplants typically account for a small percentage of transplants at institutions (approximately 10% to 15% of transplants performed at MUSC), the use of daclizumab in this population still can result in significant cost savings.
References
1. Zenapax package insert. Nutley, NJ: Roche Laboratories Inc.; July 1999.
2. Burnham T, ed. Drug Facts and Comparisons. Loose-leaf edition. St. Louis: Wolters Kluwer; 2000.
3. DRUGDEX editorial staff: "Daclizumab." In: Rumack BH, Bird PE, Gelman CR, eds. Drugdex System. Englewood, CO: Micromedex Inc.
4. Waldmann TA, O'Shea J. The use of antibodies against the IL-2 receptor in transplantation. Curr Opinion in Immunol 1998; 10:507-512.
5. Nashan B, Light S, Hardie IR, et al. Reduction of acute renal allograft rejection by daclizumab. Transplantation 1999; 67:110-115.
6. Vincenti F, Kirkman R, Light S, et al. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. NEJM 1998; 338:161-165.
7. Data on file. Roche Laboratories Inc., Nutley, NJ.
8. Billups NF. American Drug Index 2000. 44th ed. St. Louis: Wolters Kluwer Co.; 2000.
9. Simulect package insert. East Hanover, NJ: Novartis Pharmaceuticals; May 1998.
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