Supported by Roche Laboratories Inc., Nutley, NJ.
Pharmacokinetic and Pharmacodynamic Studies of One or Two Doses of Daclizumab in Renal Transplantation
Version of Record online: 19 DEC 2002
American Journal of Transplantation
Volume 3, Issue 1, pages 50–52, January 2003
How to Cite
Vincenti, F., Pace, D., Birnbaum, J. and Lantz, M. (2003), Pharmacokinetic and Pharmacodynamic Studies of One or Two Doses of Daclizumab in Renal Transplantation. American Journal of Transplantation, 3: 50–52. doi: 10.1034/j.1600-6143.2003.30109.x
- Issue online: 19 DEC 2002
- Version of Record online: 19 DEC 2002
- Received 13 February 2002,revised andaccepted for publication 2 August 2002
- kidney transplantation
In phase III trials daclizumab was used in a five-dose regimen of 1 mg/kg at 2-weekly intervals, resulting in saturation of IL-2Rα on circulating lymphocytes for up to 120 days after renal transplantation. The purpose of this study was to evaluate daclizumab blood concentrations and the saturation of the IL-2Rα on the circulating lymphocytes with a limited dosing regimen of daclizumab.
Twelve patients undergoing primary cadaver or living donor transplantation were randomized to either receive one dose (2 mg/kg) or two doses (2nd dose, 1 mg/kg) of daclizumab in addition to maintenance immunosuppression therapy consisting of either tacrolimus or cyclosporine, mycophenolate mofetil and prednisone. Patients were followed for 6 months after the transplantation. Pharmacokinetic and pharmacodynamic studies were performed up to 20 weeks after the transplantation.
In patients treated with a single dose of daclizumab, the blood concentrations of daclizumab declined to 1 µg/mL at 43 ± 7 days after the transplantation. In patients treated with two doses of daclizumab, the blood concentrations of daclizumab declined to 1 µg/mL at 45 ± 13 days after the second dose for a total of 59 ± 13 days after the transplantation. Daclizumab levels of 1 µg/mL or greater were associated with saturation of the IL-2Rα on the circulating lymphocytes.
In the new era of effective maintenance immunosuppression, a limited dosing regimen of daclizumab may be desired, practical and economical.
Daclizumab, a humanized antibody to the alpha chain (α) of the IL-2R was found to be an effective induction agent in two phase III trials, reducing the incidence of acute rejection in renal transplant recipients (1,2). In these trials, daclizumab was used in a dose of 1 mg/kg before transplantation and at 2-weekly intervals for a total of five doses. This regimen was found to result in saturation of IL-2Rα on the circulating lymphocytes for up to 120 days after renal transplantation (1). However, the maintenance immunosuppression regimens utilized in the phase III studies, cyclosporine, prednisone ± azathioprine, have been replaced by newer and more effective regimens that combine cyclosporine or tacrolimus, mycophenolate mofetil or sirolimus and prednisone (3,4). Several recent studies have reported excellent results with daclizumab in one- or two-dose regimens (5–8). The purpose of this study was to evaluate daclizumab blood concentrations and the saturation of the IL-2Rα on the circulating lymphocytes with a limited dosing regimen of daclizumab.
Materials and Methods
Twelve adult patients undergoing primary cadaver (n = 5) or living donor transplantation (n = 7) were randomized to receive one of two daclizumab regimens. Six patients were randomized to receive one dose of 2 mg/kg of daclizumab preoperatively and six patients were randomized to receive two doses of daclizumab, the first dose of 2 mg/kg preoperatively and the second dose of 1 mg/kg 14 days after the transplantation. All patients were treated with a calcineurin inhibitor (tacrolimus n = 11, cyclosporine n = 1), mycophenolate mofetil 2 g/day and corticosteroids (first dose 1000 mg, second dose 500 mg, third dose 250 mg and then tapered to 25 mg by month one). Calcineurin inhibitors were started within 48 h of the transplantation. All patients were followed for a minimum of 6 months. All patients signed an informed consent form before participating in the study.
Pharmacodynamic-IL-2Rα saturation and pharmacokinetics
Blood samples for flow cytometry and daclizumab levels were obtained before the transplantation and at 2-weekly intervals for up to 20 weeks after the transplantation. The percentage of circulating lymphocytes with a free IL-2Rα chain were analyzed by flow cytometry following staining with fluorescent-conjugated anti-CD25 (2A3 clone), an antibody that binds to the same epitope as daclizumab, as previously described (9). Blood daclizumab levels were measured with a sandwich ELISA solid-phase enzyme immunoassay.
IL-2Rα of the circulating lymphocytes were considered unsaturated if more than 2% of the lymphocytes had free or unbound α-chain receptors. Saturation of the IL-2Rα is reported as mean ± standard deviation (SD).
In the group of patients receiving a single dose of daclizumab, pharmacokinetic studies were monitored immediately before and following the single dose of 2 mg/kg of daclizumab. In the group that received two doses of daclizumab, these parameters were monitored following the first and second dose of daclizumab.
The approximate time for daclizumab blood concentrations to reach 1 µg/mL was determined based on a log-linear extrapolation for each patient.
At 6 months, patient and graft survival was 100% in the groups receiving either one or two doses of daclizumab. In the first 6 months after the transplantation, none of the patients had an episode of acute rejection. Table 1 shows the percentage of lymphocytes with free IL-2Rα in patients treated with one or two doses of daclizumab. Patients treated with one dose of daclizumab had saturation of the IL-2Rα on the circulating lymphocytes for up to 42 days post transplant, while patients who received two doses of daclizumab had saturation lasting up to 70 days post transplant. At day 56, there was a statistically significant difference in the percentage of cells with free IL-2Rα in patients who received the one-dose vs. two-dose daclizumab regimen. In patients treated with a single dose of daclizumab, the blood concentration of daclizumab was equal to or greater than 1 µg/mL for 43 ± 7 days (range 35–55).
|Pre Transplant||Post Transplant (days)|
|One dose||30.6 ± 9.2%||0.4 ± 0.5%||0.3 ± 0.3%||1.5 ± 1.4%||5.7 ± 3.5%*||5.6 ± 6.4%||8.4 ± 5.4%|
|Two dose||27.1 ± 6.4%||0.1 ± 0.2%||0.0 ± 0.0%||0.6 ± 0.7%||0.9 ± 1.0%*||1.6 ± 1.4%||8.6 ± 5.7%|
In patients treated with the two-dose regimen, daclizumab concentrations declined to 1 µg/mL at 45 ± 13 days (range 29–61) after the second dose. Thus, patients who received a second dose had a daclizumab concentration equal to or greater than 1 µg/mL for approximately 60 days after the transplantation.Figure 1 shows the relationship between the daclizumab concentrations and the percentage of lymphocytes with free IL-2Rα in the patients receiving one and two doses of daclizumab. Daclizumab levels greater than 1 µg/mL were associated with saturation of the IL-2Rα on the circulating lymphocytes.
The phase III trials with daclizumab utilized a regimen of daclizumab 1 mg/kg administered at pretransplant and at 2-weekly intervals following the transplantation for a total of five doses (1,2). This regimen resulted in saturation of the IL-2Rα on the circulating lymphocytes for up to 120 days after the transplantation (1). While this regimen was associated with a significant reduction in acute rejection rate, the maintenance immunosuppression utilized in the phase III trials consisted of cyclosporine, prednisone and ± azathioprine. However, after the phase III trials were completed, newer and more powerful immunosuppressive agents were introduced, including mycophenolate mofetil, sirolimus and tacrolimus (3,4). The addition of daclizumab induction to these potent maintenance immunosuppressive regimens has resulted in further reductions in the incidence of acute rejection (10–12). Because of the increased effectiveness of the newer maintenance immunosuppressive regimens, a shorter duration of saturation of the IL-2Rα on the circulating lymphocytes may be adequate, and therefore more limited dosing of daclizumab is being utilized (5–8). In this prospective study, we analyzed the pharmacokinetics and pharmacodynamics of one or two doses of daclizumab in patients receiving primary renal transplants and immunosuppressed with triple therapy consisting of a calcineurin inhibitor, mycophenolate mofetil and prednisone. The first dose of daclizumab was changed from the 1 mg/kg used in the phase III trials to 2 mg/kg in order to increase the first dose area under the curve and provide more effective drug concentrations of daclizumab. Patients treated with one dose of daclizumab were found to have saturated IL-2Rα for up to 42 days after the transplantation while patients treated with the two-dose regimen had saturated IL-2Rα for up to 70 days.
In addition, this is the first report demonstrating in renal transplant recipients that in vivo saturation of IL-2Rα on circulating lymphocytes requires a blood concentration of daclizumab of 1 µg/mL. We have previously shown that saturation of IL-2Rα on lymphocytes in vitro is achieved with a lower concentration of daclizumab (0.1 µg/mL), however, to inhibit the biologic responses of T cells higher daclizumab concentrations are required (1 µg/mL) (13). Thus, dosing patients to achieve higher daclizumab blood concentrations than required for saturation may result in more effective immunosuppression. In a recently reported trial in kidney-pancreas transplant recipients, induction with a two-dose regimen of 2 mg/kg of daclizumab was found to be more effective than a five-dose regimen of 1 mg/kg (7). Thus it can be speculated that induction daclizumab therapy of short duration with a higher dosage (2 mg/kg) may be preferable to longer duration with a lower dosage (1 mg/kg). In brief, this pharmacokinetic and pharmacodynamic study provides evidence that limited dosing of daclizumab results in effective drug concentrations and prolonged saturation of IL-2Rα on circulating lymphocytes. The limited dosing of daclizumab is simple, practical and economical (5–9).
- 1et al, for the Daclizumab Triple Therapy Study Group. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. New Engl J Med 1998: 338: 161–165., ,
- 6Two doses of daclizumab provides effective induction for simultaneous pancreas and kidney transplantation [Abstract]. Am J Transplant 2001; 1: 430., , .
- 8Limited dose monoclonal IL-2R antibody induction in kidney transplantation – a prospective, randomized, controlled clinical trial (Abstract #1313). Am J Transplant 2002; 2: 469., , .
- 13Importance of daclizumab concentrations in immunosuppression effectiveness: in vitro and in vivo analysis. Transplantation 2002; [abstract 3295]74: 4., , , .