Eva M. Vasquez

The pharmacokinetics of a microemulsion formulation of cyclosporine in primary renal allograft recipients

This study was a randomized, double-blind, 12-week comparison of the pharmacokinetics, safety, and tolerability of two cyclosporine (CsA) formulations, cyclosporine emulsion capsules and oral solution for microemulsion and cyclosporine, in the postoperative management of renal transplant patients. Of the 101 patients, aged 18 to 65, who entered the study, 89 were evaluable for pharmacokinetics. Initial dosage was 10 mg/kg per day, administered twice daily in two equal doses. Dosages were adjusted to achieve target CsA concentrations. The pharmacokinetic (PK) parameters (dose-normalized) of greatest interest were maximum blood concentration (C(max)/dose), time to reach maximum concentration (t(max), area under the blood concentration-vs.-time curve (AUC/dose), and trough blood concentrations (Co h/dose). The relative CsA bioavailabilty was found to be significantly enhanced with cyclosporine emulsion compared with cyclosporine with a 16% to 31% increase in AUC and a 32% to 42% increase in C(max). Intrapatient variability of PK parameters was significantly lower with cyclosporine emulsion than with cyclosporine for AUC, C(oh), t(max), and C(max) in many instances. This indicates a more consistent, rapid, and more complete total absorption of CsA. Despite higher CsA C(max) levels and AUCs with cyclosporine emulsion, safety and tolerability (detailed in a parallel report) were comparable to those of cyclosporine. The PK advantages of cyclosporine emulsion over cyclosporine are either independent of food conditions or possibly reflective of more consistent absorption of CsA with cyclosporine emulsion. The findings suggest that de novo use of cyclosporine emulsion may simplify and improve management of organ transplant recipients and that the PK advantages of cyclosporine emulsion may translate into clinical benefits.

The safety and tolerability of cyclosporine emulsion versus cyclosporine in a randomized, double-blind comparison in primary renal allograft recipients

A 12-week, randomized, double-blind, multicenter pharmacokinetic study was conducted to compare the clinical safety and tolerability of cyclosporine capsules and oral solution for microemulsion and cyclosporine in 101 primary renal transplant recipients. Cyclosporine emulsion has more complete absorption and improved bioavailability compared with cyclosporine, and dosing of both cyclosporine formulations was adjusted to achieve comparable whole-blood trough levels. Mean serum creatinine values were higher in the cyclosporine emulsion group at baseline, 8, and 12 weeks (P<0.05). The incidence of acute rejection was similar in both treatment groups although fewer patients required monoclonal antibody therapy in the cyclosporine emulsion group than in the cyclosporine group (31% vs. 82%, respectively). Despite the increased bioavailability of cyclosporine emulsion, no significant differences in the incidence of adverse events were observed ; the safety, tolerability, and efficacy of cyclosporine emulsion and cyclosporine were comparable.

Clotrimazole increases tacrolimus blood levels: a drug interaction in kidney transplant patients

In order to substantiate a previous case report of a drug interaction between tacrolimus and clotrimazole, we randomly assigned tacrolimus‐treated renal allograft recipients to therapy with either clotrimazole or nystatin for oral thrush prophylaxis immediately following transplantation. Patients receiving other agents known to interact with cytochrome P450 were excluded from the study. The clotrimazole group consisted of 17 patients and the nystatin group, which served as the control group, consisted of 18 patients. An oral loading dose (∼0.3 mg/kg) of tacrolimus was given pre‐operatively. Post‐transplant, tacrolimus (∼0.15 mg/kg) was orally administered twice daily. Clotrimazole therapy consisted of a 10‐mg troche administered three times daily. Nystatin therapy consisted of the oral suspension (5 mL) administered as a ‘swish and swallow’ four times daily. We evaluated tacrolimus trough blood levels and tacrolimus doses on days 1, 3, 5, and 7 following transplantation. On post‐transplant day 1, mean tacrolimus trough levels did not differ between clotrimazole‐ and nystatin‐treated patients. Mean tacrolimus blood trough levels were significantly higher in clotrimazole‐treated patients on days 3, 5, and 7 post‐transplant, 42±14, 53±7, and 33±17 ng/mL, respectively, compared to 15±8, 15±7, and 14±6 ng/mL in nystatin‐treated patients (p<0.05). The mean tacrolimus dose was significantly lower in the clotrimazole group by day 7 post‐transplant (p<0.05). We conclude that clotrimazole therapy may cause a significant rise in tacrolimus trough blood levels. Recognition of this potential drug interaction is essential to minimize tacrolimus‐associated toxicities in the early post‐transplant period.

Safety and tolerability of cyclosporine microemulsion versus cyclosporine: two-year data in primary renal allograft recipients: a report of the Neoral Study Group.

BACKGROUND The new microemulsion formulation of cyclosporine (CsA-ME) is more bioavailable than cyclosporine (CsA) in de novo renal transplant patients. Therefore, it was of interest to compare the safety profile of each formulation in such patients. METHODS In a multicenter, double-blind, parallel-group study, 101 renal transplant recipients were randomized after transplantation to receive either CsA (n=50) or CsA-ME (n=51) capsules twice daily for 2 years. Of these patients, 54 (CsA, n=26; CsA-ME, n=28) completed 1 year of the study and entered the second-year, double-blind extension. Initial dose at the time of transplantation was 5 mg/kg b.i.d.; doses were titrated to target trough levels. METHODS The mean (+/- SD) doses at the end of 2 years were 4.6 +/- 1.8 and 3.8 +/- 1.1 mg/kg per day for CsA- and CsA-ME-treated patients, respectively. The mean (+/- SD) CsA trough levels at end point were 187 +/- 63 and 210 +/- 95 ng/ml for CsA- and CsA-ME-treated patients, respectively. At least one adverse event was reported by 25/26 (96%) of CsA- and 27/28 (96%) of CsA-ME-treated patients. No patient discontinued the study because of adverse events. No deaths occurred during the study. Renal function, as measured by serum creatinine levels, and blood pressure were comparable over time in both treatment groups. CONCLUSIONS There was no significant difference in safety and tolerability between CsA- and CsA-ME-treated kidney recipients for 2 years after transplantation.

A Prospective Randomized Clinical Trial of Perioperative Treatment with Octreotide in Pancreas Transplantation

BACKGROUND Technical failures continue to plague clinical pancreas transplantation. The somastatin analogue octreotide has been shown able to decrease morbidity after pancreatic resection. We studied the effect of perioperative treatment with octreotide on technical complications after pancreas transplant. PATIENTS AND METHODS Seventeen recipients of bladder-drained transplant were randomized to receive either octreotide, 100 microg TID SQ for 5 days after transplant (n = 10) or no additional treatment (n = 7). We compared the two groups in terms of patient and graft survival and incidence of graft pancreatitis, intra-abdominal infections, and anastomotic leaks. RESULTS In the untreated group, 1 patient developed a bladder leak and 2 had intra-abdominal infections, while no complications occurred in the octreotide-treated patients (P = 0.05). Six-month patient and pancreas survival was 100% and 90%, respectively, in octreotide-treated patients versus 86% and 86% in the control group (P = NS). CONCLUSION Perioperative treatment with octreotide seems able to reduce the incidence of technical complications after pancreas transplantation.

Concomitant clotrimazole therapy more than doubles the relative oral bioavailability of tacrolimus

The purpose of this pharmacokinetic study was to determine whether the relative oral bioavailability of tacrolimus is increased with concomitant administration of clotrimazole. Pharmacokinetic studies were conducted in 6 adult kidney transplant patients receiving tacrolimus therapy. Pharmacokinetic profiling was performed by blood sampling over 12 hours before and after the administration of a 5-day course of clotrimazole. Tacrolimus whole-blood concentrations were determined by microparticle enzyme immunoassay. Noncompartmental pharmacokinetic analysis was conducted using WinNonLin, Standard Edition, Version 1.1. Concomitant administration of clotrimazole more than doubled the relative oral bioavailability of tacrolimus. The mean AUC0-12 of tacrolimus was increased 250% with clotrimazole (467.0 ± 170.0 ng·h/mL versus 188.7 ± 50.2 ng·h/mL; P = 0.002). Tacrolimus blood trough concentrations also more than doubled with coadministration of clotrimazole (27.7 ± 10.4 ng/mL versus 11.6 ± 4.0 ng/mL; P = 0.003). Mean Cmax was significantly increased with clotrimazole (70.7 ± 34.7 ng/mL versus 27.4 ± 11.1 ng/mL, P = 0.01). Tmax decreased from 3.2 ± 1.6 hours to 1.9 ± 1.0 hours (P = NS). In addition, the apparent oral clearance decreased 60% with coadministration of clotrimazole (median oral clearance 0.16 L/h/kg versus 0.40 L/h/kg; P = 0.03). Thus, clotrimazole causes a significant increase in the relative oral bioavailability, Tmax, and trough concentration of tacrolimus. Tacrolimus levels should be monitored following initiation or discontinuation of clotrimazole to minimize toxicity or precipitation of an acute rejection episode due to subtherapeutic levels.

ETHNIC DIFFERENCES IN CLINICAL RESPONSE TO CORTICOSTEROID TREATMENT OF ACUTE RENAL ALLOGRAFT REJECTION

Background. Limitedin vitro data suggest that African-Americans exhibit greater resistance to corticosteroids than do non-African-American transplant recipients. However, ethnic differences in clinical response to corticosteroids for treatment of acute rejection have not been investigated previously. The purpose of this study was to evaluate the clinical response to corticosteroid treatment for acute rejection in both African-American and non-African-American renal allograft recipients. Methods. We retrospectively reviewed the medical records of 497 consecutive renal allograft recipients to identify patients who had received corticosteroids as initial treatment of acute rejection. One hundred and twenty patients who received corticosteroids for treatment of acute rejection were evaluated in this analysis. The study population was divided into two groups: the African-American group (n=73) and non-African-American group (n=47). All acute rejection episodes were documented by biopsy and were classified as mild-moderate histologically. Corticosteroid therapy consisted of either methylprednisolone, 500 mg intravenously for 3 days, or oral prednisone, 2 mg/kg/day rapidly tapered over 3 weeks. Results. Twenty-six percent (26%) of African-Americans were considered corticosteroid treatment failures compared to an 8.0% failure rate among non-African-Americans (P <0.05). One-year graft survival was 78% in African-American versus 96% in non-African-American (P <0.05). Among African-American and non-African-American recipients, 1-year patient survival rates were 97% and 100%, respectively (P =NS). Conclusions. African-American patients exhibit higher failure rates with corticosteroid treatment of acute rejection. Alternative anti-rejection therapies may need to be considered for this “high-risk” patient population to improve long-term graft survival.

Impact of mycophenolate mofetil on recurrent rejection in kidney transplant patients

Purpose: Mycophenolate mofetil (MMF) has emerged as a valuable adjunctive agent in renal transplantation. However, due to intolerable adverse effects associated with MMF use in our transplant population, we have used MMF selectively in patients at high risk for recurrent graft rejection, since these patients are known to be at risk for poor long‐term graft outcomes. The purpose of this study was to assess the efficacy of MMF in preventing the recurrence of acute rejection following an initial rejection episode in kidney transplant patients in the first year following transplantation. 
Methods: Forty‐four kidney transplant recipients were given MMF prospectively following treatment of their initial rejection episode to prevent recurrent rejection. MMF 1–2 g/d was given. Doses were adjusted based on tolerance; MMF therapy was to be continued for at least 6 months. The control group consisted of 124 consecutive kidney transplant recipients who had received standard anti‐rejection therapy without the addition of MMF. Maintenance immunosuppression consisted predominantly of cyclosporine, prednisone±azathioprine. Anti‐rejection therapy for both groups consisted of either corticosteroids (methylprednisolone 500 mg i.v. for 3 d or oral prednisone 2 mg/kg/d with rapid taper over 3 wk), OKT3 5 mg/d for 10 d or ATG 15 mg/kg/d for 10 d. All rejection episodes were confirmed by biopsy. 
Results: The majority of rejection episodes were characterized histologically as mild or moderate. Most patients (76%) received corticosteroids for treatment of their first rejection episode. There was a 68% reduction in the incidence of recurrent rejection episodes within the first year of transplant in patients receiving MMF; only 14% of recipients receiving MMF developed recurrent rejection compared to 44% of patients in the control group (p<0.05). Approximately 50% of patients developed MMF‐associated adverse effects (leukopenia, GI toxicity). Only 52% of patients remained on MMF at 6 months. One‐yr graft survival was 86% in the MMF group and 89% in the control group (p>0.05). One‐year patient survival was 93 and 100%, respectively (p>0.05). 
Conclusions: The addition of MMF to maintenance therapy for patients experiencing acute renal allograft rejection may prevent recurrent rejection episodes in the subsequent follow‐up year.

Effect of pretransplant erythropoietin therapy on renal allograft outcome.

Erythropoietin (EPO) is widely used among patients with end-stage renal disease awaiting transplantation. Data suggest that EPO therapy may be immunomodulatory. The purpose of this study was to assess the effects of pretransplant EPO therapy on renal allograft outcome. We evaluated 120 consecutive renal transplant recipients to assess the effect of EPO on graft outcome following renal transplantation. Among the study population, 58 patients were receiving EPO before transplantation (EPO group) and 62 patients were not treated with EPO (non-EPO group). Twenty-four of 58 EPO-treated patients (41%) experienced delayed graft function after transplantation, compared with 11 of 62 (18%) non-EPO-treated patients (P<0.05). The incidence of acute rejection, time to first rejection, and 1-year graft survival rate did not differ between the two groups. In conclusion, pretransplant EPO therapy does not appear to adversely impact on the incidence of acute rejection or 1 year graft survival rate. However, EPO-treated patients may be predisposed to the development of delayed graft function.