Alexander Korn

Randomized double-blind study of immunoprophylaxis with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with mycophenolate mofetil-containing triple therapy in renal transplantation.

BACKGROUND Acute rejection remains a major problem in renal transplantation. Immunoprophylaxis with basiliximab (Simulect) has achieved significant reductions in acute rejection episodes in renal allograft recipients receiving dual immunosuppression. This study explored the tolerability and cumulative benefit of combining basiliximab with triple-drug therapy-cyclosporine (USP Modified, Neoral), mycophenolate mofetil, and steroids. METHODS In a randomized, double-blind, placebo-controlled, multicenter study, 123 kidney transplant recipients received either basiliximab at 20 mg before transplantation (day 0) and 20 mg on day 4 (n=59), or placebo (n=64). All received triple-drug immunosuppression and were followed for 6 months. RESULTS Tolerability of basiliximab was equivalent to placebo, with no increase in serious adverse events, infection, malignancy, or posttransplant lymphoproliferative disorder. At 6 months, there were trends in favor of basiliximab over placebo in the incidences of first biopsy-confirmed acute rejection (15.3% vs. 26.6%, P=NS) and of acute rejection treated with antibody (5.1% vs. 15.6%, P=NS). Kaplan-Meier estimates at 4 weeks and 6 months were significantly in favor of basiliximab treatment for first acute rejection, biopsy-confirmed rejection, rejection episodes treated with antibody therapy, and treatment failure. Renal function improved more rapidly in the basiliximab group, with mean creatinine clearance at week 2 being 54.7 mL/min versus 43.2 mL/min for placebo (P=0.034). At 12 months, patient survival was 100% in both groups; graft survival was 94.9% with basiliximab and 92.2% with placebo. CONCLUSIONS Basiliximab immunoprophylaxis is safe, well tolerated, and shows a trend toward reduction in number of acute rejection episodes in renal transplant patients receiving cyclosporine, mycophenolate mofetil, and steroids.

Early prognosis of the development of renal chronic allograft rejection by gene expression profiling of human protocol biopsies.

Background. Chronic allograft rejection (CR) is the major cause of failure of long-term graft survival and is so far irreversible. Early prognosis of CR by molecular markers before overt histologic manifestation would be a valuable aid for the optimization of treatment regimens and the design of clinical CR trials. Oligonucleotide microarray-based approaches have proven to be useful for the diagnosis and prognosis of a variety of diseases and were chosen for the unbiased identification of prognostic biomarkers. Methods. Renal allograft biopsies were taken at month 6 posttransplantation (PT) from two groups who were, at that time, healthy recipients: one group developed CR at month-12 PT, the other group remained healthy. Gene expression profiles from the two groups at month-6 PT biopsies were analyzed to identify differentially expressed genes with prognostic value for CR development at month 12. Results. A set of 10 genes was identified that showed differential expression profiles between the two patient groups and had a complete separation of the 15% to 85% quantile range for each individual gene. This set of genes was sufficient to allow the correct prediction of the occurrence or nonoccurrence of CR in 15 of 17 (88%) patients using cross-validation (occurrence for a patient was predicted on the basis of the other patients’ data only). In addition, a correct prediction could be made that a recipient with a normal biopsy 12 months PT developed CR within the following 6 months. Conclusions. Identified expression patterns seem to be highly prognostic of the development of renal CR.

A rational dosing algorithm for basiliximab (Simulect) in pediatric renal transplantation based on pharmacokinetic-dynamic evaluations.

Background. The pharmacokinetics and immunodynamics of basiliximab were assessed in 39 pediatric de novo kidney allograft recipients to rationally chose a dose regimen for this age group. Methods. In study part 1, patients were given 12 mg/m2 of basiliximab by bolus intravenous injection before surgery and on day 4. An interim pharmacokinetic evaluation supported a fixed-dose approach for study part 2 in which infants and children received two 10-mg doses and adolescents received two 20-mg doses. Blood samples were collected over a 12-week period for analysis of basiliximab and soluble interleukin-2 receptor concentrations, flow cytometry, and screening for anti-idiotype antibodies. Results. Basiliximab clearance in infants and children (n=25) was reduced by approximately half compared with adults from a previous study and was independent of age (1–11 years), weight (9–37 kg), and body surface area (0.44–1.20 m2). Clearance in adolescents (12–16 years, n=14) approached or reached adult values. CD25-saturating basiliximab concentrations were maintained for 31±12 days in study part 1 with mg/m2 dosing and for 36±14 days in study part 2 based on the fixed-dose regimen (P =0.31). A single patient experienced a rejection episode during CD25 saturation. The duration of CD25 saturation in patients who experienced a rejection episode after desaturation did not differ from those who remained rejection-free for the full 6-month period: 34±6 days (n=6) vs. 35±14 days (n=33 patients);P =0.74. Anti-idiotype antibodies were detected in two patients; however, this did not influence the clearance of basiliximab or the duration of CD25 saturation. Conclusions. To achieve similar basiliximab exposure as is efficacious in adults, pediatric patients <35 kg should receive two 10-mg doses and those ≥35 kg should receive two 20-mg doses of basiliximab by intravenous infusion or bolus injection. The first dose is given before surgery and the second on day 4 after transplantation.

A multicenter, open-label, pharmacokinetic/pharmacodynamic safety, and tolerability study of basiliximab (simulect) in pediatric de novo renal transplant recipients

Background. Basiliximab (Simulect) has been shown to be safe and effective in adult renal transplant recipients, when used in combination with cyclosporine (Neoral) and corticosteroids. We report on the safety and preliminary efficacy of basiliximab in pediatric de novo renal transplant recipients. Methods. This was an open-label, 12-month study of basiliximab in 41 patients (2 cohorts: <9 and 9 to <16 years). In phase 1, two intravenous (IV) bolus injections of basiliximab (12 mg/m2) were administered (before and 4 days postsurgery). In phase 2, two injections (<40 kg, 10 mg and ≥40 kg, 20 mg) were administered at the same time points. Most patients (26/41 [63%]) received cadaveric kidneys. Almost half of the patients had three human leukocyte antigen mismatches with the organ donors. Concurrent immunosuppression included Neoral and corticosteroids. Azathioprine was allowed after 28 days. Results. All patients completed the 1-year study. The acute tolerability of basiliximab via IV bolus injection was good, without evidence of cytokine-release syndrome or acute local reactions. All patients experienced adverse events, but most (71%) were mild or asymptomatic. No deaths or malignancies occurred. The incidence and types of serious adverse events (59%) and serious infections (44%) were as expected in this patient population, and few were drug-related (7% and 5%, respectively). Thirty-eight patients (93%) had infections, mostly urinary tract infections, as expected for renal transplant patients. Six patients (15%) had drug-related adverse events. Biopsy-confirmed acute rejection episodes occurred in 6/41 (15%) of patients during the first 6 months posttransplantation and in 9/41 (22%) patients during the first 12 months. Five patients (12%) experienced graft loss, none of which were preceded by acute rejection episodes. Conclusions. Basiliximab is safe and well tolerated when administered by IV bolus injection in de novo pediatric renal transplant recipients. These preliminary data suggest that basiliximab, given in combination with cyclosporine and corticosteroids, is an effective immunosuppressive regimen for the prevention of acute rejection in pediatric renal transplantation.

Basiliximab in pediatric liver transplantation: A pharmacokinetic-derived dosing algorithm

Abstract: The pharmacokinetics and immunodynamics of basiliximab were assessed in 37 pediatric de novo liver allograft recipients to rationally design a dose regimen for this age‐group. In part one of the study, patients were given 12 mg/m2 basiliximab by bolus intravenous injection after organ perfusion and on day 4 after transplant. An interim pharmacokinetic evaluation supported a fixed‐dose approach for part two of the study in which infants and children received two 10‐mg doses of basiliximab and adolescents received two 20‐mg doses. Blood samples were collected over a 12‐week period for screening for anti‐idiotype antibodies and analysis of basiliximab and soluble interleukin‐2 receptor (IL‐2R) concentrations. Basiliximab clearance in infants and children < 9 yr of age (n = 30) was reduced by ≈ 50% compared with adults from a previous study and was independent of age to 9 yr, weight to 30 kg, and body surface area to 1.0 m2. Clearance in children and adolescents 9–14 yr of age (n = 7) approached or reached adult values. An average of 15% of the dose was eliminated via drained ascites fluid, and drug clearance via this route averaged 29% of total body clearance. Patients with > 5 L of ascites fluid drainage tended to have lower systemic exposure to basiliximab. CD25‐saturating basiliximab concentrations were maintained for 27 ± 9 days in part one of the study (mg/m2 dosing) with infants exhibiting the lowest durations. CD25 saturation lasted 37 ± 11 days in part two of the study, based on the fixed‐dose regimen (p = 0.004 vs. mg/mg2 dosing), but did not show the age‐related bias observed in part one of the study. Anti‐idiotype antibodies were detected in four patients, but this did not influence the clearance of basiliximab or duration of CD25 saturation. All 40 enrolled patients were included in the intent‐to‐treat clinical analysis. Episodes of acute rejection occurred in 22 patients (55%) during the first 12 months post‐transplant. Three patients experienced loss of their graft as a result of technical complications, and six patients died during the 12‐month study. Basiliximab was well tolerated by intravenous bolus injection, with no cytokine‐release syndrome or other infusion‐related adverse events. Hence, basiliximab was safe and well tolerated in pediatric patients undergoing orthotopic liver transplantation. To achieve similar basiliximab exposure as is efficacious in adults, pediatric patients < 35 kg in weight should receive two 10‐mg doses and those ≥ 35 kg should receive two 20‐mg doses of basiliximab by intravenous infusion or bolus injection. The first dose should be given within 6 h after organ perfusion and the second on day 4 after transplantation. A supplemental dose may be considered for patients with a large volume of drained ascites fluid relative to body size.

Der Einfluß von Diltiazem auf die Konzentration von Cyclosporin-Metaboliten bei mit Sandimmun® und Neoral® behandelten nierentransplantierten Patienten

BACKGROUND Diltiazem reduces the cyclosporine dose required for blood levels in the therapeutic target range by 30 to 40%. The effect of diltiazem on the pharmacokinetic disposition of cyclosporine after oral Neoral application is unknown and it is unclear whether or not the diltiazem-cyclosporine interaction is affected by the galenic cyclosporine formulation. PATIENTS AND METHODS Fifty-one stable renal allograft patients (19 females, 32 males) were enrolled in this prospective, randomized and double-blind study. The patients were assigned to 3 treatment groups: with diltiazem (I, n = 17), with nifedipine (II, n = 17) and without calcium channel blockers (III, n = 17). Nine patients in each group received Sandimmun and 8 patients Neoral. Blood concentrations of cyclosporine and its metabolites AM1 and AM9 were measured using HPLC for 12 weeks. The 3 treatment groups were not different in respect to age, gender distribution and serum creatinine concentration. Cyclosporine doses were adjusted on basis of the blood levels. RESULTS The cyclosporine doses required to achieve target blood levels were significantly lower in group I compared with group II (-43%) and group III (-33%; p < 0.0001). Although the cyclosporine blood concentrations in all groups were in the therapeutic range, the blood levels in group I showed a much lower variability. The blood concentrations of the metabolite AM1 in group I were significantly higher than those in groups II and III after dose correction (p < 0.0001), those of AM9 were significantly lower in group I than in groups II and III (p < 0.0001). The average dose, and the blood concentration of cyclosporine was not different when patients receiving Neoral were compared with those receiving Sandimmun within the groups. In the patients in group I, the blood concentration of metabolite AM1 was significantly higher after Sandimmun application than after Neoral. No other differences in the metabolite concentrations were detected within the groups comparing patients taking Sandimmun or Neoral. The incidences of acute rejection were lower in group I (17.6%) than in the other groups (II: 52.9%; III: 41%). CONCLUSION Diltiazem significantly reduced the necessary dose of cyclosporine. Compared with groups II and III, the blood concentrations were more stable in patients in group I. Diltiazem increased the blood concentration of AM1 in patients treated with Sandimmun to a larger extent than in patients taking Neoral. No additional pharmacokinetic differences of the 2 cyclosporine applications different with Sandimmun or Neoral were found.Zusammenfassung□ HintergrundDiltiazem reduziert die für therapeutische Blutspiegel erforderliche Cyclosporin-Dosis um 30 bis 40%. Der Effekt von Diltiazem auf die Pharmakokinetik von Cyclosporin nach Gabe von Sandimmun® ist bekannt, nicht dagegen, ob die Diltiazem-Cyclosporin-Interaktion durch die galenische Cyclosporin-Formulierung Neoral® beeinträchtigt wird.□ Patienten und Methoden51 stabile nierentransplantierte Patienten (19 Frauen, 32 Männer) wurden in eine prospektive, randomisierte, doppelblinde Studie einbezogen. Die Patienten wurden drei Behandlungsgruppen zugewiesen: mit Diltiazem (I, n=17), mit Nifedipin (II, n=17) und ohne Calciumblocker (III, n=17). Neun Patienten jeder Gruppe erhielten Sandimmun® und acht Patienten Neoral®. Die Blutspiegel von Cyclosporin und die Metaboliten AM1 und AM9 wurden über zwölf Wochen mittels HPLC gemessen. Die drei Behandlungsgruppen zeigten keinen Unterschied in bezug auf Alter, Geschlecht und Serumkreatinin. Die Cyclosporin-Dosierung wurde entsprechend dem Blutspiegel angepaßt.□ ErgebnisseDie erforderliche tägliche Cyclosporin-Dosis bis zum Erreichen des therapeutischen Blutspiegels war signifikant niedriger in Gruppe I (198,8±6,1 mg/Tag) im Vergleich zur Gruppe II (346,9 ± 10,2 mg/Tag; −43%; p < 0,0001) und Gruppe III (296,9 ± 6,7 mg/Tag; −33%, p < 0,0001). Die Cyclosporin-Konzentrationen im Blut lagen in allen Gruppen im therapeutischen Bereich, aber die Blutspiegel in Gruppe I zeigten eine viel geringere Variabilität. Die Konzentration des Metaboliten AM1 war nach Dosiskorrektur in Gruppe I signifikant höher, die von AM9 signifikant niedriger als in den Gruppen II und III (p < 0,0001). Zwischen den beiden Cyclosporin-Verabreichungsformen innerhalb der Gruppen gab es nach zwölf Wochen keinen Unterschied in der durchschnittlichen Dosierung und den Blutspiegeln von Cyclosporin. In Gruppe I war die Blutkonzentration von AM1 signifikant höher nach Sandimmun®-Gabe als nach Neoral®. Die Inzidenz von akuten Abstoßungen war in Gruppe I mit 17,6% niedriger als in den Gruppen II (52,9%) und III (41,2%).□ SchlußfolgerungDiltiazem reduziert signifikant die Cyclosporin-Dosis mit Konzentrationen im therapeutischen Bereich, führt zu stabileren Cyclosporin-Blutspiegeln und erhöht die Konzentration von AM1 besonders bei Patienten, die mit Sandimmun® behandelt werden. Darüber hinaus gab es keine signifikanten Unterschiede zwischen den beiden Darreichungsformen von Cyclosporin mit und ohne begleitend verabreichten Calciumantagonisten.Summary□ BackgroundDiltiazem reduces the cyclosporine dose required for blood levels in the therapeutic target range by 30 to 40%. The effect of diltiazem on the pharmacokinetic disposition of cyclosporine after oral Neoral® application is unknown and it is unclear whether or not the diltiazem-cyclosporine interaction is affected by the galenic cyclosporine formulation.□ Patients and MethodsFifty-one stable renal allograft patients (19 females, 32 males) were enrolled in this prospective, randomized and double-blind study. The patients were assigned to 3 treatment groups: with diltiazem (I, n=17), with nifedipine (II, n=17) and without calcium channel blockers (III, n=17). Nine patients in each group received Sandimmun® and 8 patients Neoral®. Blood concentrations of cyclosporine and its metabolites AM1 and AM9 were measured using HPLC for 12 weeks. The 3 treatment groups were not different in respect to age, gender distribution and serum creatinine concentration. Cyclosporine doses were adjusted on basis of the blood levels.□ ResultsThe cyclosporine doses required to achieve target blood levels were significantly lower in group I compared with group II (−43%) and group III (−33%; p < 0,0001). Although the cyclosporine blood concentrations in all groups were in the therapeutic range, the blood levels in group I showed a much lower variability. The blood concentrations of the metabolite AM1 in group I were significantly higher than those in groups II and III after dose correction (p < 0,0001), those of AM9 were significantly lower in group I than in groups II and III (p < 0,0001). The average dose, and the blood concentration of cyclosporine was not different when patients receiving Neoral® were compared with those receiving Sandimmun® within the groups. In the patients in group I, the blood concentration of metabolite AM1 was significantly higher after Sandimmun® application than after Neoral®. No other differences in the metabolite concentrations were detected within the groups comparing patients taking Sandimmun® or Neoral®. The incidences of acute rejection were lower in group I (17,6%) than in the other groups (II: 52,9%; III: 41,%).□ Conclusion:Diltiazem significantly reduced the neccessary dose of cyclosporine. Compared with groups II and III, the blood concentrations were more stable in patients in group I. Diltiazem increased the blood concentration of AM1 in patients treated with Sandimmun® to a larger extent than in patients takingNeoral®. No additional pharmacokinetic differences of the 2 cyclosporine applications different with Sandimmun® or Neoral® were found.