Protopic
The cost effectiveness of tacrolimus versus microemulsified cyclosporin: a 10-year model of renal transplantation outcomes.

Orme ME, Jurewicz WA, Kumar N, McKechnie TL.

The Lewin Group, Bracknell, UK. Michelle.Orme quintiles.com

INTRODUCTION AND OBJECTIVE: In 1983, the launch of cyclosporin was a significant clinical advance for organ transplant recipients. Subsequent drug research led to further advances with the introduction of cyclosporin microemulsion (cyclosporin ME) and tacrolimus. This paper presents the results from a long-term model comparing the clinical and economic outcomes associated with cyclosporin ME and tacrolimus immunosuppression for the prevention of graft rejection following renal transplantation. STUDY DESIGN: A model was developed to project the costs and outcomes over a 10-year period following transplantation. The model was based on the results of a prospective, randomised study of 179 renal transplantation recipients receiving either cyclosporin ME or tacrolimus, which was conducted by the Welsh Transplantation Research Group (median follow-up: 2.7 years). METHODS: The short-term costs and outcomes were the averages from the actual head-to-head trial data. From this, the long-term costs and outcomes were extrapolated based on the rate of change in patient and graft survival at 3, 5 and 10 years post transplant, as reported in the 1995 United Kingdom Transplant Support Service Authority Renal Transplant Audit. PERSPECTIVE AND YEAR OF COST DATA: The analysis was conducted from the perspective of a UK transplant unit. Costs were at 1999 prices (pounds sterling 1 = dollars US 1.42 = Euro 1.5) and costs and outcomes were discounted at 6% and 1.5%, respectively. RESULTS: The model estimated that 10 years after transplantation, the proportion of patients surviving was 56% of the cyclosporin ME cohort and 64% of the tacrolimus cohort. The cumulative cost of maintenance therapy at 10 years was pounds sterling 23204 per patient maintained on cyclosporin ME versus pounds sterling 23803 per patient on tacrolimus. The cost per survivor at 10 years was pounds sterling 37000 (tacrolimus) versus pounds sterling 41000 (cyclosporin ME) and the cost per patient with a functioning graft was pounds sterling 39000 versus pounds sterling 45000. A Monte Carlo simulation of the model (10000 simulations) gave an average cost at 10 years of pounds sterling 23279 (SD pounds sterling 3457) for cyclosporin ME and pounds sterling 22841 (SD pounds sterling 3590) for tacrolimus. A (second order) probabilistic sensitivity analysis was also performed. The average cost at 10 years from a simulated cohort of 1000 was pounds sterling 23473 (SD pounds sterling 2154) for cyclosporin ME and pounds sterling 24087 (SD pounds sterling 2025) for tacrolimus. CONCLUSION: Renal transplant recipients maintained on tacrolimus have better short- and long-term outcomes than patients maintained on cyclosporin ME. The long-term use of tacrolimus is a more cost-effective solution in terms of the number of survivors, patients with a functioning graft and rejection-free patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14986738&dopt=Abstract tacrolimus Protopic



Protopic
Factors affecting variability in distribution of tacrolimus in liver transplant recipients.

Zahir H, McCaughan G, Gleeson M, Nand RA, McLachlan AJ.

Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.

AIMS: Therapeutic drug monitoring (TDM) of tacrolimus is complicated by conflicting data on the correlation between tacrolimus trough blood concentrations and the incidence of rejection. The aim of this cross-sectional study was to investigate the blood distribution and protein binding of tacrolimus in liver transplant recipients to explore better predictors of clinical outcome. METHODS: Blood and plasma distribution of 3H-dihydro-tacrolimus was investigated in 40 liver transplant recipients using Ficoll Paque and density gradient ultracentrifugation, respectively, and equilibrium dialysis to investigate plasma protein binding. RESULTS: In blood tacrolimus was mainly associated with the erythrocyte fraction (83.2%, range 74.6-94.9%), followed by diluted plasma (16.1%, range 4.5-24.9%), and lymphocyte fraction (0.61%, range: 0.11-1.53%). In plasma, lipoprotein deficient serum fraction (54.2%, range 38.5-68.2%) was the main reservoir of tacrolimus. The unbound fraction of tacrolimus was found to be 0.47 +/- 0.18% (range 0.07-0.89%). The percentage of tacrolimus associated with the lymphocytes (0.8 +/- 0.4 vs 0.3 +/- 0.1%, P = 0.012) and estimated unbound concentration (0.42 +/- 0.21 ng l-1vs 0.24 +/- 0.08 ng l-1, P < 0.001) of tacrolimus were significantly different in stable transplant recipients and those experiencing rejection. Haematocrit and red blood cell count significantly influenced the percentage of tacrolimus associated with erythrocytes. The fraction unbound of tacrolimus was correlated with alpha1-acid glycoprotein and high density lipoprotein cholesterol concentrations. CONCLUSIONS: Tacrolimus unbound concentration was observed to be lower in liver transplant recipients experiencing rejection and further study is required to evaluate its utility in the TDM of tacrolimus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14998426&dopt=Abstract tacrolimus Protopic



Protopic
Pharmacokinetic and immunosuppressive effects of tacrolimus-loaded biodegradable microspheres.

Miyamoto Y, Uno T, Yamamoto H, Xiao-Kang L, Sakamoto K, Hashimoto H, Takenaka H, Kawashima Y, Kawarasaki H.

Division of Hospital Pharmacy, Hamamatsu University School of Medicine, Shizuoka, Japan. ymiyamo hama-med.ac.jp

The objective of this study was to characterize the pharmacokinetics and immunosuppression of a tacrolimus-loaded biodegradable microsphere (TLBM) in rats. We prepared TLBM. DA/Slc rats were given TLBM at a dose of 1.6 mg/kg (n = 9), 2.4 mg/kg (n = 5), or 7.2 mg/kg (n = 7) tacrolimus contents by a single subcutaneous administration to achieve sustained release over a long period. DA/Slc rats were given TLBM by a single subcutaneous administration at a dose of 4.8 mg/kg (n = 6) tacrolimus contents to clarify the main site of TLBM uptake in the organs. In the rat liver transplantation model, the recipients were given TLBM at a dose of 0.16 mg/kg (n = 5), 2.4 mg/kg (n = 4), or 4.8 mg/kg (n = 5) tacrolimus contents by a single subcutaneous administration on the first day after operation. Overall survival days were compared. Continuous flat parallel concentration profiles were significant for 10 days from the first day after a single subcutaneous administration of TLBM (P <.01). The relationship between the dosages of TLBM administration and area under the concentration-time curve (AUC) up to 18 days demonstrated a linear regression line (P <.01). In addition, the relationship between the dose of TLBM and the survival days of the recipients in the liver transplantation model showed a positive correlation. The current pharmacokinetic study of TLBM revealed significantly increased tacrolimus levels in the regional lymph nodes compared with other organs except bone marrow (P <.01). In conclusion, TLBM allowed tacrolimus to release gradually in a very stable manner for 10 days, with dose-dependent immunosuppression after a single subcutaneous administration. The main site of TLBM uptake after subcutaneous administration was the regional lymph node of administration site.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15004766&dopt=Abstract tacrolimus Protopic



Protopic
The yield of surveillance endomyocardial biopsies as a screen for cellular rejection in pediatric heart transplant patients.

Levi DS, DeConde AS, Fishbein MC, Burch C, Alejos JC, Wetzel GT.

Division of Pediatric Cardiology, Department of Pediatrics, Mattel Children's Hospital at UCLA, B2-427 MDCC, Los Angeles, CA 90095-17, USA. dlevi ucla.edu

Endomyocardial biopsy is commonly used to screen for cellular rejection in pediatric heart transplant patients. The yield of EMBs when combined with newly developed immunohistochemical techniques and modern immunosuppression in pediatric heart transplant patients is unknown. After OHT, surveillance biopsies were performed on a routine basis on all pediatric patients. EMBs were also performed on symptomatic OHT patients suspected to have rejection. All positive results (greater than ISHLT grade 1B) were confirmed with immunohistochemical staining. A retrospective review of consecutive EMBs performed in this institution from January 1995 to January 2003 was performed. The echocardiographic results, clinical history and treatment changes at the time of every biopsy were also catalogued. Of the 1093 EMB results from 136 pediatric heart transplant grafts (127 patients, 64 male) reviewed, 825 biopsies were performed on patients managed with tacrolimus and 268 were performed on patients managed with cyclosporine. The patients managed with tacrolimus had an incidence of 0.85% (7/825) for significant rejection (greater than ISHLT grade 1B rejection) vs. an incidence of 4.1% (11/268) for the patients on cyclosporine (p < 0.0005). In the asymptomatic tacrolimus patients, only two screening biopsies (0.26%) manifest significant rejection, and both of these were performed within the first month after transplantation. Of the symptomatic tacrolimus patients, 9.1% (n = 5) had findings on biopsy consistent with significant cellular rejection. There were 25 patients with grade 1B rejection. Twenty-two of these patients were not treated, and all cases of grade 1B rejection resolved without clinical sequelae. For pediatric patients more than 30 days after OHT, EMB has failed to reveal significant episodes of cellular rejection in asymptomatic patients managed with tacrolimus. Copyright 2004 Blackwell Munksgaard

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15009837&dopt=Abstract tacrolimus Protopic



Protopic
Evaluation of the new EMIT tacrolimus assay in kidney and liver transplant recipients.

Akbas SH, Yavuz A, Tuncer M, Yurdakonar E, Akcit F, Gurkan A, Demirbas A, Gultekin M, Ersoy F, Akaydin M.

Department of Central Laboratory, Akdeniz University, Antalya, Turkey.

Tacrolimus (FK506) is a potent macrolide immunosuppressant used for prevention of organ transplant rejection following transplantation. Monitoring of blood tacrolimus concentrations is essential to assess organ rejection and toxicity, because of the agent's narrow therapeutic range, wide inter- and intraindividual pharmacokinetic variability as well as drug interactions mediated by alteration in cytochrome P450. Several methods have been developed to monitor tacrolimus; immunoassays, bioassays, and HPLC/MS. The purpose of this study was to compare two analytical methods: the well-established MEIA II tacrolimus immunoassay using the IMx analyzer and the new EMIT 2000 tacrolimus immunoassay on the Cobas Integra 400 system. Tacrolimus results obtained using the two methods have been compared on 180 whole blood samples from kidney and liver transplant patients. The analytical sensitivities of both methods were defined as 1.2 ng/mL for EMIT and 1.5 ng/mL for MEIA II. The within-run CVs (n = 15) obtained with four-level controls were 9.08%, 9.41%, 5.23% and 4.4% for EMIT 2000. The comparison showed the following relationship between two methods: MEIA = 1.08.EMIT + 0.20 (r =.893). In conclusion, the EMIT 2000 tacrolimus immunoassay is a reliable alternative for the MEIA II method to monitor tacrolimus in organ transplant recipients. It provides a valid quantitative measurement of tacrolimus with comparable % CVs in quality-control as well as patient blood samples. Additionally, the EMIT 2000 method provides a rapid analysis of a large number of samples in one run with a low turnaround time and possibilities to reanalyze critical samples.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15013308&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus conversion in kidney transplant recipients: analysis of 107 patients.

Yagmurdur MC, Sevmis S, Emiroglu R, Moray G, Bilgin N, Haberal M.

Baskent University Faculty of Medicine, Department of General Surgery Division of Transplantation, Ankara, Turkey.

Early results of an alteration in immunosuppressive protocol of tacrolimus conversion at a mean follow-up of 16 (range 1 to 36) months are presented with a mean time after transplantation of 34 +/- 1.4 months (range 1 to 158 months). Chronic allograft nephropathy in 16 (17%) patients, nephrotoxicity related to cyclosporine in 27(23%) patients and steroids resistant acute rejection in 64 (58%) represented the indications for tacrolimus conversion. Before starting tacrolimus there were 1 acute rejection episode in 37 patients, 2 in 17 patients, and 3 in 10 patients. After the drug conversion, 1 acute rejection occurred in 18 and 2 acute rejection in 4 patients. Graft loss was seen in 16 (16%) patients after drug conversion. Tacrolimus was withdrawn due to diabetes mellitus (n = 9), epilepsy (n = 4), and severe Nocardia sepsis, lymphoma and Kaposi sarcoma (each in one patient). Decreases in serum creatinine and increases in blood glucose levels were significantly associated with the tacrolimus doses (P = 0.0004 and P = 0.0400, respectively). The increase in creatinine clearance values were closely related to higher tacrolimus levels. The target range with maximum efficacy and minimum toxicity seemed to be 10 to 15 ng/mL. Tacrolimus conversion can be successful in cases of rejection and nephrotoxicity, but dose-dependent blood glucose elevations require close observation in these patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15013327&dopt=Abstract tacrolimus Protopic



Protopic
Plasma homocysteine levels in renal transplant patients on tacrolimus therapy.

Akbas SH, Tuncer M, Gurkan A, Yucetin L, Yavuz A, Demirbas A, Ersoy F, Gultekin M, Yakupoglu G, Akaydin M.

Akdeniz University, Faculty of Medicine, Central Laboratory, Clinical Biochemistry Unit, Antalya, Turkey. halideakbas akdeniz.edu.tr

Increased plasma total homocysteine levels afford an independent risk factor to assess cardiovascular morbidity in patients with normal and impaired renal function, including stable transplant recipients. The purpose of this study was to evaluate plasma homocysteine levels and factors known to influence homocysteine metabolism (folate and Vitamin B(12)) in renal transplanted patients treated with tacrolimus. Plasma homocysteine, serum folate and serum vitamin B(12) concentrations were measured in 18 cadaveric renal transplant patients with stable function both before and 3 months after the renal transplantation. While the mean plasma homocysteine level in the renal transplant group was significantly higher than in the control group, no significant change was observed following renal transplantation under tacrolimus therapy (16.84 +/- 6.43 micromol/L vs 16.02 +/- 6.54 micromol/L). The levels of folate before and after transplantation were considerably lower than the control group; a significant effect of tacrolimus has not been observed (7.32 +/- 4.68 ng/mL and 7.55 +/- 5.20 ng/mL). Serum vitamin B(12) levels in the transplant group were significantly lower than the control group; a significant decline was seen 3 months after the renal transplantation (448.94 +/- 230.03 pg/mL vs 334.38 +/- 240.61 pg/mL). Consequently, although plasma homocysteine levels of renal transplant recipients are higher, a lowering effect of tacrolimus therapy was not observed on plasma homocysteine levels. The lower levels of folate and Vitamin B(12) in the transplant group compared to a control group supports therapy with folate and Vitamin B(12) to decrease homocysteine concentrations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15013332&dopt=Abstract tacrolimus Protopic