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PubMed2003

Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients.

The immunosuppressive drug tacrolimus, whose pharmacokinetic characteristics display large interindividual variations, is a substrate for P-glycoprotein (P-gp), the product of the multidrug resistance-1 (MDR1) gene. Some of the single nucleotide polymorphisms (SNP) of MDR1 reported correlated with the in vivo activity of P-gp. Because P-gp is known to control tacrolimus intestinal absorption, it was postulated that these polymorphisms are associated with tacrolimus pharmacokinetic variations in renal transplant recipients. The objective of this study was to evaluate in a retrospective study of 81 renal transplant recipients the effect on tacrolimus dosages and concentration/dose ratio of four frequent MDR1 SNP possibly associated with P-gp function (T-129C in exon 1b, 1236C>T in exon 12, 2677G>T,A in exon 21, and 3435C>T in exon 26). As in the general population, the SNP in exons 12, 21, and 26 were frequent (16, 17.3, and 22.2% for the variant homozygous genotype, respectively) and exhibited incomplete linkage disequilibrium. One month after tacrolimus introduction, exon 21 SNP correlated significantly with the daily tacrolimus dose (P < or = 0.05) and the concentration/dose ratio (P < or = 0.02). Tacrolimus dose requirements were 40% higher in homozygous than wild-type patients for this SNP. The concentration/dose ratio was 36% lower in the wild-type patients, suggesting that, for a given dose, their tacrolimus blood concentration is lower. Haplotype analysis substantiated these results and suggested that exons 26 and 21 SNP may be associated with tacrolimus dose requirements. Genotype monitoring of the MDR1 gene reliably predicts the optimal dose of tacrolimus in renal transplant recipients and may predict the initial daily dose needed by individual patients to obtain adequate immunosuppression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months.

BACKGROUND: This is the first report of a randomized, multicenter, clinical trial comparing the combination of sirolimus or mycophenolate mofetil (MMF) with tacrolimus-based immunosuppression in kidney transplantation. Results at 6 months of follow-up are presented. METHODS: Before transplantation, patients were randomized to receive tacrolimus plus corticosteroids with sirolimus (n=185) or MMF (n=176). The primary endpoint of the study was the incidence of biopsy-confirmed acute rejection. Patient and graft survival, renal function, and composite endpoints also were evaluated. Safety was assessed by monitoring laboratory parameters and adverse events. RESULTS: By 6 months of follow-up, the incidence of biopsy-confirmed acute rejection was similar in both treatment groups (13.0% tacrolimus+sirolimus vs. 11.4% tacrolimus+MMF; P=0.64 log-rank). Patient survival (97.3% tacrolimus+sirolimus vs. 97.7% tacrolimus+MMF) and graft survival (93.0% tacrolimus+sirolimus vs. 95.5% tacrolimus+MMF) were equivalent (P=0.53, overall survival log-rank). There was a significantly higher incidence of study drug discontinuation in patients receiving sirolimus (21.1% vs. 10.8%; P=0.008). Renal function was significantly better in the MMF-treatment group (serum creatinine 1.44+/-0.45 mg/dL vs. 1.77+/-1.42 mg/dL; P=0.018). Hyperlipidemia was significantly more prevalent in the sirolimus-treatment group. Diastolic blood pressure was significantly higher in sirolimus-treated patients. There were significantly more leukopenia and gastrointestinal adverse events in the MMF-treatment group. The incidence of posttransplant diabetes mellitus was 7.6% in the sirolimus group and 7.7% in the MMF group. CONCLUSION: Tacrolimus is equally effective in renal transplantation when combined with sirolimus or MMF. The tacrolimus-MMF combination may be superior in terms of improved renal function and improved cardiovascular risk factors including hyperlipidemia and hypertension.

Acute Disease↗
PubMed2004

Results of lis2t, a multicenter, randomized study comparing cyclosporine microemulsion with C2 monitoring and tacrolimus with C0 monitoring in de novo liver transplantation.

This is the first multicenter, randomized, open-label study to compare the efficacy and safety of cyclosporine A microemulsion (CsA-ME) (Neoral, Novartis, Basel, Switzerland ) with C2 monitoring versus tacrolimus in de novo liver transplant recipients. Patients were stratified according to hepatitis C virus status and randomized to receive CsA-ME (n= 250) or tacrolimus (n= 245) with steroids, with or without azathioprine. The primary endpoint was the incidence of biopsy-proven acute rejection (BPAR) at 3 months. Secondary endpoints included death or graft loss and safety evaluations at 6 months. The incidence of BPAR at 3 months was 26% in the CsA-ME group and 24% in the tacrolimus group (not significant). At 6 months, 89% of patients receiving CsA-ME and 88% of patients receiving tacrolimus were alive with a functioning graft. Among the hepatitis C virus-positive patients, there was no difference in BPAR, but death or graft loss was more frequent in those receiving tacrolimus (15% vs. 6%, P <0.05). Diabetes mellitus (14% vs. 7%, P <0.02) and diarrhea (29% vs. 14%, P <0.001) were significantly more often reported in patients receiving tacrolimus. The incidence of hypertension was similar in both groups. At 6 months, the median total cholesterol was 4.7 mmol/L (2.9-7.4 mmol/L) in the CsA-ME arm versus 4.3 mmol/L (2.5-6.4 mmol/L) in the tacrolimus arm; the median serum creatinine was 106 micromol/L (52-238 micromol/L) in the CsA-ME arm versus 103 micromol/L (44-477 micromol/L) in the tacrolimus arm. Efficacy is equivalent with CsA-ME using C2 monitoring or tacrolimus in liver transplant recipients. The incidence of adverse events is comparable except for a significantly higher incidence of diabetes mellitus and diarrhea in the tacrolimus group. Both agents are effective primary immunosuppressants in liver transplant recipients.

Adult↗
PubMed2004

Effects of tacrolimus (FK506) on encephalomyocarditic virus-induced diabetes in mice.

The effects of tacrolimus on insulin-dependent diabetes mellitus (IDDM) induced by the D-variant of encephalomyocarditis virus (D-EMCV) have been investigated. Male BALB/c mice were treated with tacrolimus before viral inoculation, and then were inoculated with 10 plaque forming units (PFU) of DEMCV. The mice continued to be treated with tacrolimus until the animals were sacrificed. D-EMCV-infected mice, which were treated with saline as controls, showed abnormal glucose tolerance test (GTT) values, whereas all infected mice with tacrolimus pretreatment were normal on 7 days-post inoculation (DPI). Histological observations revealed that non-treated tacrolimus D-EMCV-infected mice and which developed diabetes showed severe insulitis in their islets of Langerhans. On the other hand, D-EMCV-infected mice treated with tacrolimus were normal. In D-EMCV-infected mice, viruses in the pancreata were detected at the same level regardless of treatment with tacrolimus or saline. Expressions of TNF-alpha and IFN-gamma mRNA in spleens of tacrolimus-treated D-EMCV-infected mice were lower than that of non-treated tacrolimus DEMCV-infected mice on 7 DPI. The results suggest that tacrolimus suppresses expressions of TNF-alpha and IFN-gamma mRNAs to prevent the onset of D-EMCV-induced IDDM.

Animals↗
PubMedDate not supplied

A nomogram for predicting the optimal oral dosage of tacrolimus in liver transplant recipients with small-for-size grafts.

No optimal tacrolimus dosage regimen suitable for clinical use in liver transplant recipients has yet been established. The purpose of this study was to determine the factors affecting the optimal dosage and pharmacokinetics of tacrolimus in living donor liver transplantation, and a nomogram for optimal tacrolimus dosage in the immediate postoperative period for recipients with small-for-size grafts was constructed. Twenty-four liver transplant patients (nine males and 15 females) and 24 donors (10 males and 14 females) were enrolled in this study. Two studies were performed. In study 1, the effect of the actual ratio of graft volume to standard liver volume (GV/SV ratio) on the elimination half-life (T1/2) of tacrolimus in the immediate postoperative period was analysed, and a nomogram for estimating the optimal oral dose of tacrolimus required to reach a target concentration was established. In study 2, the effect of donor age on the recovery of hepatic function with ability of the graft to eliminate tacrolimus was analysed. In the immediate postoperative period, T1/2 of tacrolimus showed great variability between patients, with values ranging from 16.3 to 110.9 h. Graft size (GV/SV ratio) is important and could influence intraindividual variations in the optimal dosage and T1/2 of tacrolimus. The recovered T1/2 ratio (T1/2 ratio=T1/2 1-10 d/T1/2 30-40 d), this ratio being related to the recovery of hepatic function with ability of the graft to eliminate tacrolimus, showed great variability between patients, with values ranging from 1.08 to 4.21 (mean+/-SD, 1.95+/-0.81). Age of the donor is a major factor affecting the recovered ratio of the graft to metabolize tacrolimus. The nomogram that we have constructed, based on graft size (GV/SV ratio), will easily provide optimal dose for each patient with small-for-size graft in the early postoperative period.

Adolescent↗
PubMed2006

Tacrolimus immunosuppression - an association with asymptomatic eosinophilia and elevated total and specific IgE levels.

De novo development of food allergy is an infrequent but potentially serious complication of transplantation. An increased prevalence of food allergy noted specifically in children receiving tacrolimus immunosuppression supports the hypothesis that selective suppression of Th1 lymphocytes by the IL-2 inhibitor immunosuppressants CsA, and the more potent drug, tacrolimus , promotes Th2 lymphocytes and an allergic immune response. This study was undertaken to characterize the IgE-mediated immune response, in CsA and tacrolimus-treated, post-OLT children. Thirty children and adolescents aged 1.9-21 yr, mean: 10.6 yr, (6.4 yr post-tx.) were studied. Immunosuppression-CsA: 10 patients, tacrolimus; 20 patients. Blood eosinophils, total IgE levels and specific IgE antibodies (Immulite 2000 Allergy; Diagnostic Products Corp., Los Angeles, CA, USA) to a panel of food and inhaled allergens were measured and correlated with clinical symptoms of allergy. Eosinophilia (>500/mm(3)) range: 599-3125, mean: 1294, was present in 10/20 of patients treated with tacrolimus and 1/10 treated with CsA. IgE levels were elevated in eight of these 10 tacrolimus-treated patients and in two CsA patients ; five were <3 yr of age and IgE levels ranged from 54 to 111 IU/mL (mean: 83), normal for age <45 IU/mL and five were > or =9 yr and IgE levels ranged from 134 to 1606 IU/mL (mean: 557), normal for age <87 IU/mL. Specific IgE levels to a wide panel of food allergens were positive in five tacrolimus-treated patients and to both food and inhaled allergens in three patients (two tacrolimus-treated, one CsA). Four children (tacrolimus-treated) had symptoms of food allergy . None had a family history of allergy. Eosinophilia is present in up to 50% of children and adolescents receiving tacrolimus immunosuppression. The majority of these patients also have elevated levels of total and specific (mainly to food allergens) IgE antibodies. Most patients are asymptomatic and do not manifest food allergy or asthma.

Adolescent↗
PubMed1996

Metabolism of the macrolide immunosuppressant, tacrolimus, by the pig gut mucosa in the Ussing chamber.

1. The macrolide tacrolimus (FK506), used as an immunosuppressant, is a cytochrome P450 (CYP) 3A substrate in the liver. The metabolism of tacrolimus and the transport of its metabolites in the pig gut was studied in the Ussing chamber. Tacrolimus and its metabolites were quantified by h.p.l.c./mass spectrometry. 2. In the Ussing chamber, demethyl, didemethyl, hydroxy and hydroxy-demethyl tacrolimus were generated. Their formation was concentration- and time-dependent. The metabolite pattern was not different from that after incubation of tacrolimus with human small intestinal microsomes. 3. The metabolite formation was highest in the duodenum and declined in the order duodenum > jejunum > ileum > colon > stomach. 4. Since tacrolimus metabolism was inhibited by the specific CYP3A inhibitors, troleandomycin and ketoconazole, we concluded that these enzymes are involved in intestinal metabolism of tacrolimus. 5. Tacrolimus metabolites re-entered the mucosa chamber (> 90%) and passed through the small intestinal preparation into the serosa chamber. 6. It is concluded that tacrolimus is metabolized in the intestine, that the metabolites are able to re-enter the gut lumen and also enter into the portal vein and that small intestinal metabolism and transport is at least in part responsible for the low oral bioavailability of tacrolimus.

Animals↗
PubMed2001

Clinical utility of monitoring tacrolimus blood concentrations in liver transplant patients.

The relationship between the dose of tacrolimus, trough tacrolimus blood concentration, and selected clinical endpoints (acute rejection, nephrotoxicity, and other toxicities) were examined in a prospective, multicenter clinical trial to validate the use of an enzyme-linked immunosorbent assay (ELISA) for monitoring whole-blood concentrations of tacrolimus in liver transplant patients. A total of 111 subjects from six transplant centers were evaluated over 12 weeks posttransplantation. In addition to trough tacrolimus blood concentrations, hematocrit, ALT, AST, GGTP, alkaline phosphatase, total bilirubin, serum creatinine, BUN, serum potassium, serum magnesium, blood glucose, and serum albumin were also measured. The relationship between trough tacrolimus blood concentrations and clinical endpoints was analyzed using both a logistic regression model and a Cox proportional hazard model. By logistic regression analysis, a statistically significant (p = 0.0465) relationship between increasing trough tacrolimus blood concentrations and decreasing risk of acute rejection was demonstrated over a 7-day time window. Nephrotoxicity and other toxicities also demonstrated statistically significant relationships with trough tacrolimus blood concentrations. The results of the Cox analysis were consistent with the logistic regression analysis. Using receiver operator characteristic curves, trough tacrolimus concentrations as measured by the ELISA method were able to differentiate the occurrence of nephrotoxicity and toxicity from nonevents. To minimize nephrotoxicity of tacrolimus, it is necessary to maintain trough blood concentrations below 15 ng/ml. This study demonstrates that the ELISA method used to measure tacrolimus blood concentrations in this study provides information of predictive value for managing the risk of nephrotoxicity, other toxicity, and rejection in liver transplant patients.

Administration, Oral↗
PubMed2004

Increased bioavailability of tacrolimus after rectal administration in rats.

The oral bioavailability of tacrolimus is low and varies considerably in humans due to first-pass metabolism by cytochrome P450 (CYP) 3A4 and the active efflux mediated by P-glycoprotein. This study was undertaken to elucidate the usefulness of rectal administration of tacrolimus as an alternative route to improve its bioavailability. Tacrolimus powder was suspended in a suppository base (witepsol H-15) and the tacrolimus suppository was inserted into the anus of the rats. For comparison, tacrolimus was suspended in 0.5% sodium methylcellulose solution and administered orally to rats. The dose of tacrolimus was fixed to 2 mg/kg. Blood samples were collected periodically up to 24 h after dosing, and tacrolimus concentrations were assayed by microparticle enzyme immunoassay. The whole blood concentrations of tacrolimus after rectal administration were much greater than those after oral administration. The C(max) and AUC(0-24 h) values after rectal administration were 3.9- and 6.9-fold greater than those after oral administration, respectively. These results clearly suggest a possibility that rectal administration of tacrolimus is capable of improving its bioavailability and cutting the costs of tacrolimus treatment.

Administration, Oral↗
PubMed2004

[Successful treatment by tacrolimus in two patients with Osserman's grade III intractable myasthenia gravis and elderly IIb].

Tacrolimus, a potent immunosuppressive agent, has recently become available for the treatment of myasthenia gravis (MG). However, few reports have evaluated the usefulness of tacrolimus in the elderly and in intractable MG classified as Osserman's grade IIb or higher. In this study, we examined the effects of tacrolimus in two patients with postthymectomy Osserman's grade III and IIb MG. The effects of tacrolimus were evaluated using the modified quantitative MG score (QMG score) and anti-acetylcholine receptor antibody (AChRAb) titer. Patient 1 was a 39-year-old woman with Osserman grade III MG. Her MG score improved after tacrolimus administration (3 mg/day), allowing gradual decreases in the doses of prednisolone and pyridostigmine because of improvement in MG symptoms. The AChRAb titer also decreased from 100.0 to 25.7 nmol/l during tacrolimus treatment. The concentrations of tacrolimus in whole blood ranged from 5.5 to 8.2 ng/ml during treatment. Patient 2 was a 68-year-old man diagnosed with Osserman grade IIb MG. After the initiation of tacrolimus treatment, dysphagia improved dramatically, and he was able to swallow food without a nasal feeding tube. The AChRAb titer decreased from 42.4 to 23.4 nmol/l during the treatment period. The concentration of tacrolimus in whole blood was 7.0 ng/ml 6 days after the initiation of treatment. These findings suggest that tacrolimus is effective in intractable and elderly MG patients.

Adult↗
PubMed2003

Milk transfer and neonatal safety of tacrolimus.

OBJECTIVE: To report the first case of tacrolimus measurement in human milk following maternal dosing in a woman who breast-fed while taking the medication. CASE REPORT: A 32-year-old white woman who had taken tacrolimus 0.1 mg/kg/d throughout pregnancy contacted the Motherisk Program at 35 weeks' gestation inquiring about the safety of breast-feeding during maternal tacrolimus therapy. After benefit-risk assessment, the mother decided to breast-feed the baby. METHODS: Manually expressed milk samples were collected over 12 hours following the first tacrolimus dose of the day; pre-dosing and 1-hour post-dosing blood concentrations were also determined. The samples were analyzed for tacrolimus by tandem-mass spectrometry. Breast milk and blood samples were collected at steady-state. RESULTS: The highest and mean concentrations of tacrolimus in milk were 0.57 and 0.429 ng/mL, respectively. From these measurements, the exclusively breast-fed infant would ingest, on average, 0.06 micro g/kg/d, which corresponds to 0.06% of the mother's weight-adjusted dose. Given the low oral bioavailability of tacrolimus, the maximum amount the baby would receive is 0.02% of the mother's weight-adjusted dose. The milk-to-blood ratios of tacrolimus at pre-dosing and 1-hour post-dosing concentrations were calculated to be 0.08 and 0.09, respectively. At 2.5 months of age, the infant was developing well both physically and neurologically. COMMENT: This report is the first to measure tacrolimus concentrations in established human milk using tandem-mass spectrometry to detect drug while the infant was exclusively breast-fed by the mother, and in which the infant's growth and development were reported. CONCLUSIONS: Our results suggest that maternal therapy with tacrolimus for liver transplant may be compatible with breast-feeding.

Adult↗
PubMed2004

Sensitivity of whole-blood T lymphocytes in individual patients to tacrolimus (FK 506): impact of interleukin-2 mRNA expression as surrogate measure of immunosuppressive effect.

BACKGROUND: To optimize immunosuppressive treatment in individual transplant patients, functional measurements of the effects of tacrolimus (FK 506) are of clinical importance. Previous investigations have demonstrated the occurrence of tacrolimus-resistant production of interleukin-2 (IL-2) in vitro, which may explain in part why rejection episodes are still a frequent problem despite attainment of therapeutic blood concentrations and HLA matching. However, an adequate surrogate marker to define the tacrolimus response in individual patients has not been established. METHODS: We investigated the immunosuppressive effects of tacrolimus on anti-CD3/anti-CD28 T-cell costimulation in a human whole-blood assay, analyzing T-cell proliferation, activation marker expression (CD25, CD69), IL-2 protein expression, and cytokine mRNA expression in vitro (n = 11 healthy individuals). We also quantified IL-2 mRNA expression in patients undergoing tacrolimus (n = 4) or cyclosporin A (CsA; n = 4) monotherapy before ex vivo living-donor kidney transplantation. RESULTS: T-cell proliferation; CD25, CD69, and IL-2 concentrations; and IL-4 mRNA were significantly decreased in vitro. In contrast, cytokine mRNA profiles revealed variable tacrolimus sensitivity. Whole-blood samples from 3 of 11 healthy individuals demonstrated marked suppression of IL-2 mRNA expression (>50%) when tacrolimus was administered in vitro. When CsA was added to whole-blood cultures, the influence on IL-2 mRNA expression was comparable to that of tacrolimus in 9 of 11 individuals. Two individuals responded conversely, indicating that differences in the in vitro response to tacrolimus and CsA among individuals may be attributable to potential heterogeneity in the involvement of the CD28 pathway. Kinetic profiles of IL-2 mRNA expression also revealed individually distinct degrees of calcineurin inhibitor sensitivity in patients undergoing tacrolimus or CsA monotherapy before living-donor kidney transplantation. CONCLUSIONS: Our results suggest an individual degree of calcineurin inhibitor sensitivity of activated whole-blood lymphocytes based on IL-2 mRNA expression. Our approach is potentially valuable for identifying transplant patients in whom IL-2 mRNA expression is unaffected or even enhanced after initiation of immunosuppressive therapy. Such individuals may be less sensitive to the immunosuppressive agent and therefore at increased risk of transplant rejection. Prospective studies are necessary to determine the correlation of IL-2 mRNA expression with the clinical risk of transplant rejection.

Adult↗
PubMed2001

Influence of tacrolimus on glucose metabolism before and after renal transplantation: a prospective study.

Most studies concerning the influence of tacrolimus on glucose metabolism have been performed either in animals or after organ transplantation. These clinical studies have largely been transversal with patients who were using steroids. Therefore, this prospective, longitudinal study investigated the influence of tacrolimus on glucose metabolism before and after transplantation. Eighteen Caucasian dialysis patients underwent an intravenous glucose tolerance test before and 5 d after the start of tacrolimus. Insulin sensitivity index (k(G)), insulin resistance (insulin/glucose ratio and homeostasis model assessment), and C-peptide and insulin secretion were calculated. Trough levels of tacrolimus were measured. After transplantation, the occurrence of posttransplantation diabetes mellitus (PTDM) was prospectively monitored. Statistical analysis was performed using the Wilcoxon signed ranks test and Spearman's rho for correlation. Before tacrolimus, k(G) was indeterminate in three patients. During tacrolimus, k(G) decreased in 16 of 18 patients, from a median of 1.74 mmol/L per min to 1.08 mmol/L per min (P<0.0001). The correlation between C-peptide and insulin data was excellent. Insulin secretion decreased from 851.0 mU x min/L to 558.0 mU x min/L (P = 0.014), whereas insulin resistance did not change. Insulin sensitivity correlated negatively with tacrolimus trough level. After transplantation, three patients developed PTDM; before tacrolimus, two had an indeterminate and one a low normal k(G). During tacrolimus administration, k(G) decreased in almost all patients as a result of a diminished insulin secretion response to a glucose load, whereas insulin resistance did not change. Patients with an abnormal or indeterminate k(G) seem to be at risk of developing PTDM while on tacrolimus.

Adult↗
PubMed2003

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

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.

Adult↗
PubMed2006

Comparison of the efficacy and safety of 0.1% tacrolimus ointment with topical corticosteroids in adult patients with atopic dermatitis: review of randomised, double-blind clinical studies conducted in Japan.

Tacrolimus (FK506) ointment is widely used in the treatment of patients with atopic dermatitis. The drug exerts its action by down-regulating antigen-specific T-cell activities and associated proinflammatory cytokine production. A number of clinical studies have evaluated the efficacy and safety of 0.1% tacrolimus ointment compared with vehicle or topical corticosteroids in adult patients with atopic dermatitis. These studies have suggested that topical tacrolimus has a rapid onset of action and exerts sustained therapeutic effects, with an efficacy similar to that of moderate to potent topical corticosteroids, but without causing skin atrophy. Two phase III randomised, controlled clinical trials have been conducted in Japanese adult patients with atopic dermatitis to compare the efficacy and safety of topical 0.1% tacrolimus with topical corticosteroid ointments. In the first study, patients with moderate or severe atopic dermatitis on the trunk and extremities were randomised to 3 weeks of treatment with topical 0.1% tacrolimus or the mid-potency topical corticosteroid 0.12% betamethasone valerate. Over 90% of the patients in each study group experienced at least a moderate improvement at the end of the study. In the second study, patients with moderate or severe atopic dermatitis on the head or neck were randomised to 1 week of treatment with 0.1% tacrolimus or the mild-potency corticosteroid 0.1% alclometasone dipropionate. Significantly greater improvements in individual symptom scores were observed with topical tacrolimus compared with alclometasone dipropionate, with overall global improvement at 1 week being statistically superior with tacrolimus. Furthermore, in a long-term open-label study involving 568 patients, at least a moderate global improvement in symptoms was observed in 85% of patients at 6 weeks, increasing to 91% at both 26 weeks and 52 weeks; this rate was maintained throughout the 2-year duration of the study. 0.1% tacrolimus ointment was considered to be safe in the majority of patients. The most prevalent adverse reactions were local application site irritations, which generally resolved with continued therapy. In summary, these findings suggest that 0.1% tacrolimus ointment is an effective and safe nonsteroidal alternative therapy for adult patients with atopic dermatitis.

Adult↗
PubMed1999

Co-administration of co-trimoxazole does not augment tacrolimus-induced impairment in kidney function in rats.

Co-trimoxazole is an antibiotic that is frequently used in organ transplant patients. Our objective was to determine the effect of co-trimoxazole on tacrolimus-mediated functional impairment of the kidney in rats. Sprague Dawley rats were divided into three groups. Group 1 (dextrose) received 5% dextrose and Group 2 (tacrolimus) received tacrolimus (1 mg/kg/day) as a continuous intravenous infusion for seven days. Group 3 (combination) received tacrolimus as above and co-trimoxazole (30 mg/kg/day trimethoprim and 150 mg/kg/day sulfamethoxazole) intraperitoneally for six or seven days. Biochemical and functional parameters were measured pre- and post-drug infusion. On day 7, glomerular filtration rate (GFR) was evaluated using 3H-inulin while the effective renal plasma flow (ERPF)/cationic tubular secretion was assessed using 14C-tetraethylammoniumbromide(TEA). GFR (mL/min/kg) as measured by inulin clearance was higher (p < or = 0.05) in the dextrose (12.0 +/- 1.4) group as compared to tacrolimus group (6.0 +/- 1.3) and combination group (6.4 +/- 1.6), but there was no difference between the tacrolimus and combination group. ERPF/cationic tubular secretion (mL/min/kg) was also significantly higher in the dextrose group (62.6 +/- 10.3) as compared to the other two groups. ERPF/cationic tubular secretion was not different between the combination (33.3 +/- 5.9) and the tacrolimus (35.1 +/- 6.7) groups when there was no co-trimoxazole in the body. However, in the presence of co-trimoxazole ERPF/cationic tubular secretion was significantly reduced in the combination (23.1 +/- 3.5) group as compared to the tacrolimus group (35.1 +/- 6.7). These results indicate that co-trimoxazole does not further potentiate tacrolimus induced impairment in kidney function but is likely to further inhibit cationic tubular secretion in patients on tacrolimus therapy.

Animals↗
PubMed2005

The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation.

OBJECTIVES: To consider the effectiveness and cost-effectiveness of pimecrolimus for mild to moderate atopic eczema and tacrolimus for moderate to severe atopic eczema compared with current standard treatment in adults and children. DATA SOURCES: Electronic databases. Experts and the manufacturers of these agents were also approached for information. REVIEW METHODS: The systematic review was carried out using standard methodological guidelines and a stringent quality assessment strategy. A state transition (Markov) model was developed to estimate cost--utility of tacrolimus and pimecrolimus separately, compared with current standard practice with topical corticosteroids, (a) as first-line treatment and (b) as second-line treatment. Pimecrolimus was also compared to emollients only. RESULTS: The pimecrolimus trial reports were of varying quality; however when compared with a placebo (emollient), pimecrolimus was found to be more effective and to provide quality of life improvements. There is very little evidence available about pimecrolimus compared with topical corticosteroids. Compared with a placebo (emollient), both 0.03% and 0.1% tacrolimus were found to be more effective. Compared with a mild corticosteroid, 0.03% tacrolimus is more effective in children as measured by a 90% or better improvement in the Physician's Global Evaluation (PGE). Compared with potent topical corticosteroids, no significant difference in effectiveness is seen with 0.1% tacrolimus as measured by a 75% or greater improvement in the PGE. Minor application site adverse effects are common with tacrolimus. However, this did not lead to increased rates of withdrawal from treatment in trial populations. The PenTag economic model demonstrates a large degree of uncertainty, which was explored in both deterministic and stochastic analyses. This is the case for the cost-effectiveness of pimecrolimus and tacrolimus in first- or second-line use compared with topical steroids. In all cases immunosuppressant regimes were estimated to be more costly than alternatives and differences in benefits to be small and subject to considerable uncertainty. CONCLUSIONS: There is limited evidence from a small number of randomised controlled trials (RCTs) that pimecrolimus is more effective than placebo treatment in controlling mild to moderate atopic eczema. Although greater than for pimecrolimus, the evidence base for tacrolimus in moderate to severe atopic eczema is also limited. At both 0.1% and 0.03% potencies, tacrolimus appears to be more effective than the placebo treatment and mild topical corticosteroids. However, these are not the most clinically relevant comparators. Compared with potent topical corticosteroids, no significant difference was shown. Short-term adverse effects with both immunosuppressants are relatively common, but appear to be mild. Experience of long-term use of the agents is lacking so the risk of rare but serious adverse effects remains unknown. No conclusions can be confidently drawn about the cost-effectiveness of pimecrolimus or tacrolimus compared with active topical corticosteroid comparators. Areas for further research should focus on the effectiveness and safety of the treatments through good-quality RCTs and further economic analysis.

Adrenal Cortex Hormones↗
PubMed2004

Modified release tacrolimus.

Modified Release (MR) tacrolimus is an extended release formulation of tacrolimus (Prograf) administered once daily in the morning. In healthy volunteers, the MR tacrolimus formulation given qd AM and Prograf administered twice daily (bid) have a similar exposure (AUC) and trough levels (Cmin), with a reduced peak level (Cmax). Subsequently, pharmacokinetic studies were performed in stable kidney and liver transplant recipients converted from Prograf bid to MR tacrolimus qd AM. The steady-state tacrolimus exposure and target trough level range of MR tacrolimus were equivalent to Prograf after a mg-for-mg daily dose conversion in these two groups of patients, and there is a high correlation of exposure to trough levels for both Prograf and MR tacrolimus, as well as significantly less intra-subject variability in exposure after conversion to MR tacrolimus. These results indicate that stable kidney and liver transplant recipients can be safely converted from standard Prograf twice daily dosing to the same mg-for-mg daily dose of MR tacrolimus once daily in the morning. Hopefully a once daily dosing regimen of tacrolimus can improve patient compliance while maintaining effective immunosuppression.

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