Protopic
The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation.

MacPhee IA, Fredericks S, Tai T, Syrris P, Carter ND, Johnston A, Goldberg L, Holt DW.

Cellular & Molecular Medicine-Renal Medicine, St. George's Hospital Medical School, London, UK. imacphee sghms.ac.uk

Previously, we reported that, at 3 months after renal transplantation, individuals with CYP3AP1 genotype CYP3AP1*1 (linked to CYP3A5*1 and strongly associated with expression of CYP3A5) required twofold higher doses of tacrolimus to achieve target blood concentrations than individuals with the genotype CYP3AP1*3/*3 (CYP3A5 nonexpressors). This study assesses the relationship between concentration-controlled dosing during the early period after transplantation, the time to achieve target concentrations and genotype in 178 renal transplant recipients (CYP3AP1*1/*3 or *1/*1: n = 53, CYP3AP1*3/*3: n = 125). Patients with CYP3AP1*1/*3 or *1/*1 had lower mean tacrolimus concentrations during the first week (Median 13.5 vs. 18.5 microg/L, p < 0.0001) with significant delay in achieving target concentrations (15-20 microg/L during week 1, then 10-15 microg/L). More CYP3AP1*3/*3 patients had tacrolimus concentrations above target during the first week (73.6% vs. 35.8%, p = 0.003). There was no difference in the rate of biopsy-confirmed acute rejection, but rejection occurred earlier in the CYP3AP1*1/*3 or *1/*1 group (median 7 d vs. 13 d, p = 0.005). In conclusion, an initial dosing regimen for tacrolimus based on knowledge of the CYP3AP1 genotype and subsequently guided by concentration measurements has the potential to increase the proportion of patients achieving target blood concentrations early after transplantation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15147425&dopt=Abstract tacrolimus Protopic



Protopic
Significant enhancement by anti-ICOS antibody of suboptimal tacrolimus immunosuppression in rat liver transplantation.

Guo L, Li XK, Enosawa S, Funeshima N, Suzuki S, Kimura H, Sugawara Y, Tezuka K, Makuuchi M.

Department of Innovative Surgery, National Research Institute for Child Health and Development, Tokyo, Japan.

A member of the costimulatory molecule family, inducible costimulator (ICOS), is expressed on activated T cells and plays a critical role in their primary activation and cytokine production. ICOS is involved in different immune phenomena, such as Th1-mediated autoimmune disease and graft rejection. Although blockade of ICOS costimulation theoretically may protect grafts from rejection, a single dose of anti-ICOS antibody did not result in the prolongation of rat liver allograft survival. However, in this article, we report that anti-rat ICOS antibody markedly enhanced the immunosuppressive activity of a suboptimal dose of tacrolimus (FK506). After fully allogenic DA to LEW liver transplantation, recipients received a single injection of tacrolimus (1 mg/kg, intramuscularly) with or without anti-ICOS antibody (1 mg/kg, intravenously). Recipient survival was significantly prolonged in rats treated with both the antibody and suboptimal tacrolimus (median survival time 44 days vs. 28 days with tacrolimus alone, P <.01). The extent of cell infiltration into the graft was closely associated with prolongation of recipient survival. Our findings thus demonstrate that anti-ICOS antibody immunotherapy combined with suboptimal tacrolimus has a synergistic effect in preventing hepatic allograft rejection and that it may induce long-term graft acceptance intimately associated with a marked reduction of intragraft T lymphocyte infiltration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15162468&dopt=Abstract tacrolimus Protopic



Protopic
Therapeutic drug monitoring of immunosuppressant drugs in Marmara University Hospital.

Karaalp A, Demir D, Goren MZ, Akc A, ISkender E, Yananl HR, Ozyurt H, Ozkaynakc A, Berkman K, Oktay S, Onat F.

Department of Pharmacology and Clinical Pharmacology, Marmara. University School of Medicine, 81326 Haydarpasa, Istanbul, Turkey.

Immunosuppressive therapy is the most crucial treatment of organ-transplanted patients. Both cyclosporin and tacrolimus have become a part of the standard immunosuppressive therapy for prevention of rejection. However, lower levels of these drugs are associated with insufficient therapy and eventually result in rejection of the organ, and, on the contrary, higher levels are associated with toxicity to certain organs such as liver and kidneys. Therefore, the levels of these drugs in body fluids should be monitored for the prevention of unwanted situations. In this retrospective study, the authors evaluated the 18-month profile of blood drug concentrations of cyclosporin and tacrolimus in patients admitted to the TDM Unit of the Marmara University Hospital (Istanbul, Turkey) between June 2000 and November 2001. A total of 578 blood samples (347 cyclosporin and 231 tacrolimus) from 134 patients (88 for cyclosporin, 46 for tacrolimus) were evaluated in this period. The therapeutic trough ranges were accepted as 100-350 ng/mL for cyclosporin and 5-20 ng/mL for tacrolimus, and levels below or above the identified levels were accepted to be subtherapeutic or toxic. Most of the results were found within the range of therapeutic levels (67.48% for cyclosporin and 82.71% for tacrolimus). Subtherapeutic levels were found in 19.92% of all cyclosporin and 10.53% of all tacrolimus assays, whereas toxic levels were seen in 12.60% and 6.77% of cyclosporin and tacrolimus results, respectively. In conclusion, this study gives information about the TDM practice in institutional clinical laboratory and also indicates the importance of critical information such as sampling time for individual decision making in dosage regiment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15167625&dopt=Abstract tacrolimus Protopic



Protopic
The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients.

Haufroid V, Mourad M, Van Kerckhove V, Wawrzyniak J, De Meyer M, Eddour DC, Malaise J, Lison D, Squifflet JP, Wallemacq P.

Industrial and Environmental Toxicology Unit, Kidney and Pancreas Transplantation Unit, Clinical Chemistry Department, Universite catholique de Louvain, St Luc Hospital, Brussels, Belgium. haufroid toxi.ucl.ac.be

Cyclosporine and tacrolimus are immunosuppressive drugs largely used in renal transplantation. They are characterized by a wide inter-individual variability in their pharmacokinetics with a potential impact on their therapeutic efficacy or induced toxicity. CYP3A5 and P-glycoprotein appear as important determinants of the metabolism of these drugs. The objective of this study was to investigate the effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood concentrations in stable transplant patients. Stable renal transplant recipients receiving cyclosporine (n = 50) or tacrolimus (n = 50) were genotyped for CYP3A5*3 and *6, and MDR1 C1236T, G2677T/A and C3435T. Dose-adjusted trough blood levels (ng/ml per mg/kg body weight) as well as doses (mg/kg body weight) required to achieve target blood concentrations were compared among patients according to allelic status for CYP3A5 and MDR1. Dose-adjusted trough concentrations were three-fold and 1.6-fold higher in CYP3A5*3/*3 patients than in CYP3A5*1/*3 patients for tacrolimus and cyclosporine, respectively. In the case of tacrolimus, the difference was even more striking when considering CYP3A5*1/*1 patients showing dose-adjusted trough concentrations 5.8-fold lower than CYP3A5*3/*3 patients. For both drugs, no association was found between trough blood concentrations or dose requirement and MDR1 genotype. Multiple regression analyses showed that CYP3A5*1/*3 polymorphism explained up to 45% of the variability in dose requirement in relation to tacrolimus use. Given the importance of rapidly achieving target blood concentrations after transplantation, further prospective studies should consider the immediate post-graft period and assess the influence of this specific polymorphism. Beside non-genetic factors (e.g. steroids dosing, drugs interactions), CYP3A5 pharmacogenetic testing performed just before transplantation could contribute to a better individualization of immunosuppressive therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15167702&dopt=Abstract tacrolimus Protopic



Protopic
Treatment of erosive oral lichen planus with topical tacrolimus.

Thomson MA, Hamburger J, Stewart DG, Lewis HM.

Department of Dermatology, Selly Oak Hospital, Birmingham, UK.

BACKGROUND: Erosive oral lichen planus (LP) is a painful chronic inflammatory condition that is frequently resistant to immunosuppressive agents. Topical tacrolimus has been reported as a safe and effective treatment. OBJECTIVE: To evaluate the efficacy and safety of topical tacrolimus in the treatment of symptomatic erosive oral LP. METHODS: A retrospective review of consecutive patients with oral LP treated with topical tacrolimus between June 1999 and November 2003 was performed. Clinical improvement and adverse events were recorded by the physician. Patients were asked retrospectively to rate their symptoms immediately prior to and after tacrolimus therapy using a visual analogue scale. RESULTS: Physician-observed clinical improvement was found in 21 of 23 patients (91.3%) within 6 weeks. Six patients (26.1%) remained asymptomatic after stopping treatment and 15 patients (65.2%) required maintenance therapy to prevent subsequent flares. Patients' self-reported symptom scores were significantly better (p<0.001) with tacrolimus treatment, which supported physician-observed clinical improvement. There was no evidence of systemic absorption and only minor local side effects were noted. CONCLUSIONS: Topical tacrolimus is an effective treatment for erosive oral LP. The majority of patients require long-term therapy to maintain remission.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15370399&dopt=Abstract tacrolimus Protopic



Protopic
Effects of tacrolimus ointment on facial eruption, itch, and scratching in patients with atopic dermatitis.

Katoh N, Hirano S, Yasuno H, Kishimoto S.

Department of Dermatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.

The action of tacrolimus ointment on pruritus in atopic dermatitis is still unclear. In this open study we investigated both the relationship between the severity of eruptions and the degree of itch and scratching in patients with atopic dermatitis and the effects of topical tacrolimus on these symptoms. Seventy adults with moderate to severe atopic dermatitis with facial eruptions that were recalcitrant to topical steroids applied a 0.1% tacrolimus ointment twice per day after discontinuation of topical steroid. The eruption scores and an assessment of the itch and scratching were recorded for 12 weeks. Oral antihistamine was prescribed at least one month before the study and continued unchanged during the study in each patient. The percentage reduction in the score of itch and scratching after two weeks (n=59) was significantly higher than in the score of eruption. Although there was no significant relationship between the severity of the eruptions and the degree of itch and scratching during steroid application, a relationship became significant after four weeks (n=59) of tacrolimus use by a one-factor ANOVA analysis. This suggests that tacrolimus ointment is effective for the itch and scratching in cases where degrees might be discrepant from the severity of eruptions in patients with recalcitrant facial eruptions of AD.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15187339&dopt=Abstract tacrolimus Protopic



Protopic
Cyclosporine versus tacrolimus in kidney transplantation: are there differences in nephrotoxicity?

Martins L, Ventura A, Branco A, Carvalho MJ, Henriques AC, Dias L, Sarmento AM, Amil M.

Nephrology Department, Hospital de Santo Antonio, Porto, Portugal. lasalete clix.pt

Cyclosporine and tacrolimus, two calcineurin inhibitors, show different side effects and toxicities. The data concerning their nephrotoxicity are few and conflicting. A retrospective study was performed in 2 groups of renal transplant recipients treated with cyclosporine or tacrolimus to evaluate graft function and side effects. All patients had completed at least 6 months of follow-up before inclusion in the study. Group I included 10 patients who were converted from cyclosporine to tacrolimus, due to cosmetic problems or due to chronic graft dysfunction with creatinine values <3 mg/dL. After conversion, there was a significant reduction in creatinine values (from 2.43 +/- 1.21 to 1.86 +/- 0.72 mg/dL; P =.023) and an improvement in creatinine clearance (from 47.5 +/- 19.2 to 56.1 +/- 18.9 mL/min; P =.047). The lipid profile did not change, but there was a trend to better blood pressure control with less antihypertensive drugs. Group II compared 2 subgroups of patients receiving kidneys from the same donor, one treated with cyclosporine and the other with tacrolimus. Tacrolimus patients showed better renal function; namely, creatinine was 1.15 +/- 0.27 versus 1.44 +/- 0.33 mg/dL (P =.029) and creatinine clearance was 87.7 +/- 27.1 versus 60.3 +/- 25.9 mL/min (P =.043). Lipid and blood pressure values were not different between the 2 subgroups, but tacrolimus patients tended to need a lower number of antihypertensive medications. The incidence of de novo diabetes mellitus was approximately 20% among patients using tacrolimus. We concluded that tacrolimus may be less nephrotoxic than cyclosporine. Tacrolimus patients showed better graft function and easier blood pressure control, but a high incidence of posttransplantation diabetes mellitus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15194300&dopt=Abstract tacrolimus Protopic