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PubMed1998

Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation.

Tacrolimus (FK506) is a macrolide lactone with potent immunosuppressive activity 100 times that of cyclosporine by weight. The molecular mechanism of action is mediated via an inhibition of the phosphorylase activity of calcineurin by drug-immunophilin complex, resulting in the inhibition of IL-2 gene expression. There are emerging studies now showing significant efficacy of tacrolimus in GVHD prevention in both related and unrelated donor transplantation. Three multicenter randomized studies comparing tacrolimus to cyclosporine have been completed, one each in related and unrelated donor transplantation; the remaining study involved both related and unrelated donor transplantation. All three studies showed a significantly lower incidence of grade II-IV acute GVHD in patients who received tacrolimus. One study in sibling donor transplantation showed that patients with advanced disease who received tacrolimus had a poorer survival than patients who received cyclosporine, but the survival was similar in patients with non-advanced disease. The remaining two studies, one in unrelated donors and the other combining both related and unrelated donors did not show any survival difference between the tacrolimus and cyclosporine groups. In addition, this review also highlights some of the critical questions regarding the role of this agent in allogeneic stem cell transplantation: (1) the contribution of methotrexate in combination with tacrolimus; (2) the starting i.v. dose of tacrolimus; (3) the suggested whole blood level of tacrolimus and its effect on nephrotoxicity; and (4) whether tacrolimus should be used in patients with advanced malignancy. Future studies using tacrolimus in combination with other immunosuppressants, and its use in patients with advanced malignancy will be warranted.

Acute Disease↗

PubMed1996

Rescue therapy with tacrolimus after combined kidney/pancreas and isolated pancreas transplantation in patients with severe cyclosporine nephrotoxicity.

This study details 11 pancreas transplant recipients (10 combined kidney and pancreas and 1 pancreas after kidney) who were converted to tacrolimus (FK506) due to acute severe cyclosporine nephrotoxicity in 8 cases and persistent rejection with cyclosporine toxicity in three cases. Arteriolopathy was documented by renal histology in all cases. Cyclosporine was discontinued for 24 hr immediately prior to initiation of tacrolimus. Tacrolimus was started orally at 0.1 mg/kg twice daily with dose adjustments to maintain whole blood trough levels of 8-15 ng/mL by IMx. Tacrolimus was initiated a mean of 14.5 months (range 1-81) after pancreas transplantation. The mean serum creatinine level had increased to 2.9 mg/dl from 1.0 mg/dl at the diagnosis of cyclosporine arteriolopathy (P=0.003). The mean serum creatinine and blood glucose levels at the time of initiation of tacrolimus were 2.1 mg/dl and 104 mg/dl, respectively. Serum creatinine was 1.7 mg/dl, 1.9 mg/dl, 1.8 mg/dl, and 1.7 mg/dl after 1, 2, 3, and 6 months of tacrolimus therapy, respectively; ANOVA (P = 0.02). The corresponding blood glucose levels were 117 mg/dl, 112 mg/dl, 109 mg/dl, and 116 mg/dl, respectively (P=NS). Normal C-peptide levels were present before (5.9 ng/ml) and after (6.2 ng/ml), the initiation of tacrolimus therapy (P=NS), and mean HbA1C was 6.1% before and 6.3% after tacrolimus therapy, (P=NS). There were 4 episodes of acute rejection, 3 responded to intravenous methylprednisolone, and 1 required OKT3 during tacrolimus therapy. Reversible tacrolimus nephrotoxicity was noted in three patients without any evidence of progressive vasculopathy. All 11 patients are alive, and 10/11 kidney and pancreas grafts are functioning with a mean follow-up of 7.7 months (range 5-10). In this study, conversion from cyclosporine to tacrolimus in kidney and pancreas recipients resulted in improvement and stabilization of renal function while maintaining stable blood glucose, C peptide, and HbA1C levels.

Administration, Oral↗

PubMed1996

Oral tacrolimus (FK506) induction therapy in pediatric orthotopic liver transplantation.

We have adopted the use of an oral tacrolimus induction protocol in pediatric liver transplantation since the commercial release of tacrolimus in 1994. In this study we analyzed the efficacy of oral tacrolimus induction therapy in 17 consecutive transplants (15 patients) performed between 6/94 and 2/95 and 4 additional patients who were retransplanted between 11/93-5/94 and received compassionate oral tacrolimus induction. Sixteen transplants were treated with oral tacrolimus induction only; 5 transplants, oral tacrolimus + ATGAM/OKT3 induction. The protocol consisted of 0.2 mg/kg of tacrolimus orally on the first postoperative day with a corticosteroid taper. Oral tacrolimus was started at day 1-8 in the 5 patients receiving ATGAM/OKT3 induction. Dosages were adjusted over time to maintain a whole-blood trough level of 12-15 ng/ml at 0-1 month, 10-12 ng/ml at 1-3 months, and 5-10 ng/ml after 3 months. The incidence of acute rejection was 50% (8/16) in children on oral tacrolimus induction alone and 80% (4/5) in the tacrolimus + ATGAM/OKT3 group. Epstein-Barr virus infection occurred in 6 of 19 children (32%), with no child developing lymphoproliferative disorder. No adverse effect on renal function was noted. Serum fasting glucose was stable over time while a trend was noted in decreasing serum cholesterol levels at 6 months. Antihypertensive medication was required in 4 of 19 children (21%) posttransplantation. Corticosteroids were withdrawn in 11% (2/19) of patients. Actuarial 1-year patient and graft survivals were 95% and 86%, respectively. The use of oral tacrolimus induction therapy was associated with excellent survival and a low incidence of complications.

Administration, Oral↗

PubMed1998

Effects of tacrolimus on hyperlipidemia after successful renal transplantation: a Southeastern Organ Procurement Foundation multicenter clinical study.

BACKGROUND: Tacrolimus has been shown to have a less adverse effect on the lipid profiles of transplant patients when the drug is started as induction therapy. In order to determine the effect tacrolimus has on lipid profiles in stable cyclosporine-treated renal transplant patients with established hyperlipidemia, a randomized prospective study was undertaken by the Southeastern Organ Procurement Foundation. METHODS: Patients of the 13 transplant centers, with cholesterol of 240 mg/dl or greater, who were at least 1 year posttransplant with stable renal function, were randomly assigned to remain on cyclosporine (control) or converted to tacrolimus. Patients converted to tacrolimus were maintained at a level of 5-15 ng/ml, and control patients remained at their previous levels of cyclosporine. Concurrent immunosuppressants were not changed. Levels of total cholesterol, triglycerides, total high-density lipoprotein, low-density lipoprotein (LDL), very-low-density lipoprotein, and apoproteins A and B were monitored before conversion and at months 1, 3, and 6. Renal function and glucose control were evaluated at the beginning and end of the study (month 6). RESULTS: A total of 65 patients were enrolled; 12 patients failed to complete the study. None were removed as a result of acute rejection or graft failure. Fifty-three patients were available for analysis (27 in the tacrolimus group and 26 controls). Demographics were not different between groups. In patients converted to tacrolimus treatment, there was a -55 mg/dl (-16%) (P=0.0031) change in cholesterol, a -48 mg/dl (-25%) (P=0.0014) change in LDL cholesterol, and a -36 mg/dl (-23%) (P=0.034) change in apolipoprotein B. There was no change in renal function, glycemic control, or incidence of new onset diabetes mellitus in the tacrolimus group. CONCLUSION: Conversion from cyclosporine to tacrolimus can be safely done after successful transplantation. Introduction of tacrolimus to a stable renal patient does not effect renal function or glycemic control. Tacrolimus can lower cholesterol, LDL, and apolipoprotein B. Conversion to tacrolimus from cyclosporine should be considered in the treatment of posttransplant hyperlipidemia.

Adult↗

PubMed2005

Effect of hepatitis C infection on tacrolimus doses and blood levels in liver transplantation recipients.

BACKGROUND: In our cohort of patients with hepatitis-C virus, which is the most common indication for liver transplantation, we have noted higher relative blood levels of tacrolimus compared to patients without hepatitis-C virus. AIM: To verify this observation and determine its clinical significance, we performed a comparison of doses and blood levels of tacrolimus in hepatitis-C virus and non- hepatitis-C virus liver transplantation recipients. METHODS: Tacrolimus dose and trough level, as well as mean alanine aminotransferase, for all patients transplanted at our center with a deceased donor between 1/1995 and 12/1999 with hepatitis-C virus were recorded at monthly intervals during the first 24 months following transplantation and compared to patients without hepatitis-C virus. RESULTS: The tacrolimus levels for hepatitis-C virus and non-hepatitis-C virus patients were not significantly different at any of the monthly intervals, except month 9. In addition, the overall mean tacrolimus levels for hepatitis-C virus and non-hepatitis-C virus patients were not significantly different (P = ns). However, the mean tacrolimus dose (mg/kg) was significantly higher for hepatitis-C virus patients at 12, 15, 18, 21 and 24 months, P < 0.01. The total mean tacrolimus dose in hepatitis-C virus patients was lower during year one by 39% (P = 0.018) and by 73% (P = 0.001) during year two. The total difference in cost of tacrolimus (for year one and two) administered to hepatitis-C virus patients was $4920, P = 0.03. The serum alanine aminotransferase was significantly higher in hepatitis-C virus patients at each monthly interval except month 1, P < or = 0.01. CONCLUSIONS: Liver transplant recipients with hepatitis-C virus require significantly lower oral doses of tacrolimus to achieve the same blood levels compared to non-hepatitis-C virus patients. This difference may result in a significant reduction in the cost of tacrolimus in hepatitis-C virus patients. The most likely explanation for these findings is decreased hepatic clearance of tacrolimus caused by mild hepatic injury from recurrent hepatitis-C virus.

Dose-Response Relationship, Drug↗

PubMedDate not supplied

Relative risk of new-onset diabetes during the first year after renal transplantation in patients receiving tacrolimus or cyclosporine immunosuppression.

Clinical trials have consistently shown a higher incidence of new-onset diabetes mellitus with tacrolimus than cyclosporine. However, in protocol-driven studies steroid doses are comparable in both treatment arms, while in clinical practice steroid dose used in conjunction with tacrolimus or cyclosporine may differ. This retrospective study analysed renal transplant recipients without pre-existing diabetes receiving tacrolimus (n = 100) or cyclosporine (n = 100) for whom one-year follow-up data were available. Diabetes was defined as use of insulin or oral hypoglycemic agents; fasting glucose >6.9 mmol/L; or non-fasting glucose >11 mmol/L on three consecutive occasions. Tacrolimus-treated patients were significantly older than cyclosporine-treated patients (49 +/- 14 vs. 44 +/- 13 yr, p < 0.05) and received a significantly lower cumulative dose of corticosteroids over the first three months post-transplant (1284 +/- 379 vs. 1714 +/- 486 mg, p < 0.0001). At 3, 6, 9 and 12 months significantly more tacrolimus-treated patients had new-onset diabetes than cyclosporine- treated patients. At 12 months, 18 patients receiving tacrolimus and two receiving cyclosporine had diabetes (p < 0.0001). There was a clear relationship between age and incidence of new-onset diabetes at three months in the tacrolimus cohort. After stratifying patients by age group, the frequency of diabetes was significantly higher with tacrolimus than with cyclosporine in patients aged 40-60 yr [8/46 (17.4%) vs. 2/48 (4.2%), p < 0.05] and >60 yr [9/28 (32.1%) vs. 0/14 (0%), p < 0.05]. The mean tacrolimus trough level during the first three months was similar in patients with diabetes (13.1 +/- 2.3 ng/mL) or without diabetes (13.0 +/- 2.8 ng/mL, n.s.). These results indicate that new-onset diabetes is strongly and significantly associated with tacrolimus vs. cyclosporine in renal transplant recipients, even when steroid dosing is lower with tacrolimus.

Adrenal Cortex Hormones↗

PubMed2006

Combined therapy of low-dose tacrolimus and prednisone in nephrotic syndrome with slight mesangial proliferation.

AIM: Tacrolimus is a calcineurin inhibitor that has been increasingly used in transplant medicine. However, the efficacy and safety of combined therapy of low-dose tacrolimus and prednisone in the treatment of nephrotic syndrome (NS) with slight mesangial proliferation has not been reported. PATIENTS AND METHODS: Sixty patients with NS with slight mesangial proliferation were randomly divided into a prednisone therapy group (control), a combined low-dose tacrolimus (2 mg/day) and a prednisone therapy group (tacrolimus group). The efficacy and safety of tacrolimus was analysed. The initial dose of prednisone was 1 mg/kg per day and 30 mg/day in the control group and tacrolimus group, respectively. The duration of treatment was 6 months. RESULTS: After a 6-month trial of combined low-dose tacrolimus and prednisone, complete remission was achieved in 29 patients (96.66%) and partial remission in one patient (3.33%). In the control group, complete remission was achieved in 27 patients (90%) and partial remission in three patients (10%). A significant improvement in proteinuria levels was observed in the tacrolimus group compared with the control group, starting at the second week and remaining throughout the study period. Furthermore, a significant improvement in serum albumin levels was observed in the tacrolimus group compared with the control group, starting at the first month and remaining until the third month. The main side-effect was obesity (100%) and acne (46.66%) in the control group. However, these adverse events were not observed in the tacrolimus group. CONCLUSION: The results demonstrated that combined therapy of low-dose tacrolimus and prednisone is an effective and safe therapeutic method for NS with slight mesangial proliferation.

Adult↗

PubMedDate not supplied

Effect of topical 0.02% tacrolimus aqueous suspension on tear production in dogs with keratoconjunctivitis sicca.

OBJECTIVE: To investigate the effect of 0.02% tacrolimus in aqueous suspension on tear production in dogs with keratoconjunctivitis sicca (KCS). Animals studied One hundred five dogs diagnosed with KCS [Schirmer tear test (STT) < or = 10 mm/min and clinical signs of dry eye]. Eyes with marginally decreased STT (11 < or = 15 mm/min) and clinical signs of dry eye were also evaluated. PROCEDURE: The investigation was conducted in two parts: an initial efficacy study and a subsequent double blinded controlled study. In the efficacy study, the effect of topical tacrolimus (formerly FK-506) on tear production in dogs with primary KCS was evaluated. Dogs were divided into four categories: 1) 59 eyes (38 dogs) naïve to tear stimulation therapy with initial STT < or = 10 mm/min; 2) 28 eyes (21 dogs) naïve to tear stimulation therapy with initial STT 11 < or = 15 mm/min; 3) 30 eyes (15 dogs) maintained successfully on CsA therapy; 4) 47 eyes (24 dogs) unresponsive to CsA therapy. STT and clinical signs were evaluated prior to and after 6 to 8 weeks of twice daily tacrolimus administration. Tacrolimus was substituted for CsA therapy in categories 3 and 4. The controlled study compared the effect of topical tacrolimus in aqueous suspension to administration of the aqueous carrier alone on tear production in 20 dogs with primary KCS. RESULTS: In the efficacy study, STT increased by 5 mm/min in 84.7%, 25.0%, 26.7% and 51.1% of eyes in categories 1, 2, 3 and 4 respectively after tacrolimus administration. Eighty-three percent of eyes with extremely low initial STT (< or = 2 mm/min), increased 5 mm/min after tacrolimus. In the controlled study, STT increased by 5 mm/min in 7/10 dogs (14/20 eyes) that received tacrolimus and in none of the 10 dogs that received aqueous carrier alone. Dogs receiving just the aqueous carrier were subsequently treated with tacrolimus, and STT increased 5 mm/min in 9 dogs (18/20 eyes) after administration. CONCLUSIONS: Twice daily administration of 0.02% tacrolimus in aqueous suspension effectively increased tear production in dogs with KCS. Topical tacrolimus is a promising alternative to topical CsA for treatment of KCS and may be beneficial in patients with less than optimal response to topical CsA.

Animals↗

PubMed2006

Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro.

Previous investigations of solid organ transplant patients treated with tacrolimus showed that individuals carrying a CYP3A5*1 allele have lower dose-adjusted trough blood concentrations compared with homozygous CYP3A5*3 individuals. The objective of this investigation was to quantify the contribution of CYP3A5 to the hepatic and renal metabolic clearance of tacrolimus. Four primary tacrolimus metabolites, 13-O-desmethyl tacrolimus (13-DMT) (major), 15-O-desmethyl tacrolimus, 31-O-desmethyl tacrolimus (31-DMT), and 12-hydroxy tacrolimus (12-HT), were generated by human liver microsomes and heterologously expressed CYP3A4 and CYP3A5. The unbound tacrolimus concentration was low (4-15%) under all incubation conditions. For CYP3A4 and CYP3A5, V(max) was 8.0 and 17.0 nmol/min/nmol enzyme and K(m,u) was 0.21 and 0.21 muM, respectively. The intrinsic clearance of CYP3A5 was twice that of CYP3A4. The formation rates of 13-DMT, 31-DMT, and 12-HT were >or=1.7-fold higher, on average, in human liver microsomes with a CYP3A5*1/*3 genotype compared with those with a homozygous CYP3A5*3/*3 genotype. Tacrolimus disappearance clearances were 15.9 +/- 9.8 ml/min/mg protein and 6.1 +/- 3.6 ml/min/mg protein, respectively, for the two genotypes. In vitro to in vivo scaling using both liver microsomes and recombinant enzymes yielded higher predicted in vivo tacrolimus clearances for patients with a CYP3A5*1/*3 genotype compared with those with a CYP3A5*3/*3 genotype. In addition, formation of 13-DMT was 13.5-fold higher in human kidney microsomes with a CYP3A5*1/*3 genotype compared with those with a CYP3A5*3/*3 genotype. These data suggest that CYP3A5 contributes significantly to the metabolic clearance of tacrolimus in the liver and kidney.

Algorithms↗

PubMed2005

Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomised controlled trials.

OBJECTIVE: To determine the efficacy and tolerability of topical pimecrolimus and tacrolimus compared with other treatments for atopic dermatitis. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Electronic searches of the Cochrane Library, Medline, and Embase. STUDY SELECTION: Randomised controlled trials of topical pimecrolimus or tacrolimus reporting efficacy outcomes or tolerability. DATA EXTRACTION EFFICACY: investigators' global assessment of response; patients' global assessment of response; proportions of patients with flares of atopic dermatitis; and improvements in quality of life. Tolerability: overall rates of withdrawal; withdrawal due to adverse events; and proportions of patients with burning of the skin and skin infections. DATA SYNTHESIS: 4186 of 6897 participants in 25 randomised controlled trials received pimecrolimus or tacrolimus. Both drugs were significantly more effective than a vehicle control. Tacrolimus 0.1% was as effective as potent topical corticosteroids at three weeks and more effective than combined treatment with hydrocortisone butyrate 0.1% (potent used on trunk) plus hydrocortisone acetate 1% (weak used on face) at 12 weeks (number needed to treat (NNT) = 6). Tacrolimus 0.1% was also more effective than hydrocortisone acetate 1% (NNT = 4). In comparison, tacrolimus 0.03% was more effective than hydrocortisone acetate 1% (NNT = 5) but less effective than hydrocortisone butyrate 0.1% (NNT = -8). Direct comparisons of tacrolimus 0.03% and tacrolimus 0.1% consistently favoured the higher strength formulation, but efficacy differed significantly between the two strengths only after 12 weeks' treatment (rate ratio 0.80, 95% confidence interval 0.65 to 0.99). Pimecrolimus was far less effective than betamethasone valerate 0.1% (NNT = -3 at three weeks). Pimecrolimus and tacrolimus caused significantly more skin burning than topical corticosteroids. Rates of skin infections in any of the comparisons did not differ. CONCLUSIONS: Both topical pimecrolimus and topical tacrolimus are more effective than placebo treatments for atopic dermatitis, but in the absence of studies that show long term safety gains, any advantage over topical corticosteroids is unclear. Topical tacrolimus is similar to potent topical corticosteroids and may have a place for long term use in patients with resistant atopic dermatitis on sites where side effects from topical corticosteroids might develop quickly. In the absence of key comparisons with mild corticosteroids, the clinical need for topical pimecrolimus is unclear. The usefulness of either treatment in patients who have failed to respond adequately to topical corticosteroids is also unclear.

Administration, Topical↗

PubMed1994

Tacrolimus, a new immunosuppressant--a review of the literature.

OBJECTIVE: To review the clinical pharmacology, pharmacokinetics, adverse effects, therapeutic uses, and current status of tacrolimus. DATA SOURCES: Data from scientific literature were identified by a MEDLINE search. The data were extracted, evaluated, and summarized for presentation. Experiences from studies evaluating tacrolimus in the form of articles, abstracts, letters to the editor, or proceedings were considered for inclusion. STUDY SELECTION: Open and controlled clinical and animal trials were reviewed in evaluating the pharmacology, pharmacokinetics, and adverse effects of tacrolimus. DATA EXTRACTION: Data from animal and human studies published in the English literature were evaluated. DATA SYNTHESIS: Tacrolimus is an 822-kDa macrolide antibiotic that has potent immunosuppressive properties. The mechanism of action is similar to that of cyclosporine in that it ultimately blocks the production of interleukin 2, thereby inhibiting further T-lymphocyte proliferation. Tacrolimus is metabolized solely in the liver and the metabolites are primarily excreted in the bile. The elimination half-life of tacrolimus is approximately 8.5 h, and is prolonged in hepatic dysfunction. Tacrolimus has shown efficacy in the prophylaxis of allograft rejection in both animals and human clinical trials, and has been used effectively to rescue patients who have exhibited refractory rejection failing cyclosporine prophylaxis. Adverse effects requiring tacrolimus dosage adjustment include nephrotoxicity, neurotoxicity, alterations in glucose metabolism, and infection or susceptibility to malignancy. CONCLUSIONS: To date, trials comparing tacrolimus with cyclosporine are not available in the literature; however, tacrolimus appears to be useful in rescuing grafts, particularly liver grafts that fail cyclosporine-based immunosuppression. Direct comparisons with cyclosporine are needed to define the role of tacrolimus as primary transplant therapy.

Absorption↗

PubMed2004

Tacrolimus impairment of insulin secretion in isolated rat islets occurs at multiple distal sites in stimulus-secretion coupling.

Tacrolimus causes posttransplant diabetes mellitus, although the pathogenetic mechanisms remain controversial. We studied the mechanism of tacrolimus-induced impairment of insulin secretion using isolated rat pancreatic islets. Tacrolimus caused reductions in DNA and insulin contents per islet during 7-d culture. Tacrolimus time-dependently suppressed glucose-stimulated insulin secretion, and at a therapeutic concentration of 0.01 micromol/liter, it suppressed glucose-stimulated insulin secretion to 32 +/- 5% of the control value after 7-d incubation. Tacrolimus did not change islet glucose utilization and oxidation, ATP production, insulin mRNA expression, or the capacity for high glucose to increase intracellular Ca(2+), but altered the rapid frequency oscillations of Ca(2+) concentration. Tacrolimus suppressed insulin secretion stimulated by mitochondrial fuel (combination of l-leucine and l-glutamine, and alpha-ketoisocaproate) and glibenclamide, but not by l-arginine. Tacrolimus suppressed insulin secretion induced by carbachol and by a protein kinase C agonist in the presence or absence of extracellular Ca(2+). Under stringent Ca(2+)-free conditions, tacrolimus did not affect mastoparan-induced insulin secretion, but suppressed its glucose augmentation. Our results suggest that tacrolimus impairs glucose-stimulated insulin secretion downstream of the rise in intracellular Ca(2+) at insulin exocytosis, and that protein kinase C-mediated (Ca(2+)-dependent and independent) and Ca(2+)-independent GTP signaling pathways may be involved. However, tacrolimus-induced impaired insulin secretion was reversed 3 d after removal of the drug. Our study demonstrated that tacrolimus impairs insulin secretion at multiple steps in stimulus-secretion coupling.

Adenosine Triphosphate↗

PubMed2005

Potential elevation of tacrolimus trough concentrations with concomitant metronidazole therapy.

OBJECTIVE: To report the occurrence of a potential tacrolimus elevation in a renal transplant recipient after adding metronidazole to the medication regimen. CASE SUMMARY: A 24-year-old white man status post living-related renal transplant who had been stabilized on tacrolimus 4 mg twice daily (trough concentrations 7-10 ng/mL) for 2 months and prednisone 20 mg daily presented to the clinic with severe diarrhea. Stool cultures were positive for Clostridium difficile, and therapy with metronidazole 500 mg 4 times daily was initiated. Between days 4 and 14 of metronidazole therapy, the patient's tacrolimus trough concentration and serum creatinine level increased to maximum levels of 26.3 ng/mL and 3.3 mg/dL (baseline 1.6-1.8 mg/dL), respectively. Tacrolimus was withheld for one dose and then decreased to 1 mg twice daily. Two days after metronidazole discontinuation, tacrolimus trough concentrations dropped to 9.4 ng/mL and serum creatinine to 2.3 mg/dL, warranting a tacrolimus dose increase to 3 mg daily. DISCUSSION: As of April 15, 2005, one other case has been reported documenting an elevation in tacrolimus concentrations with the addition of metronidazole. The possible mechanism may be related to metronidazole's weak inhibition of CYP3A4 and, possibly, P-glycoprotein. According to the Naranjo probability scale, metronidazole was the probable cause of this adverse reaction. CONCLUSIONS: Coadministration of tacrolimus with metronidazole may result in elevated tacrolimus concentrations, possibly leading to tacrolimus toxicity. Practitioners should be aware of this potential interaction and closely monitor tacrolimus concentrations and renal function.

Adult↗

PubMed2002

Mechanisms of clinically relevant drug interactions associated with tacrolimus.

The clinical management of tacrolimus, a macrolide used as immunosuppressant after transplantation, is complicated by its narrow therapeutic index in combination with inter- and intraindividually variable pharmacokinetics. As a substrate of cytochrome P450 (CYP) 3A enzymes and P-glycoprotein, tacrolimus interacts with several other drugs used in transplantation medicine, which also are known CYP3A and/or P-glycoprotein inhibitors and/or inducers. In clinical studies, CYP3A/P-glycoprotein inhibitors and inducers primarily affect oral bioavailability of tacrolimus rather than its clearance, indicating a key role of intestinal P-glycoprotein and CYP3A. There is an almost complete overlap between the reported clinical drug interactions of tacrolimus and those of cyclosporin. However, in comparison with cyclosporin, only few controlled drug interaction studies have been carried out, but tacrolimus drug interactions have been extensively studied in vitro. These results are inconsistent and are of poor predictive value for clinical drug interactions because of false negative results. P-glycoprotein regulates distribution of tacrolimus through the blood-brain barrier into the brain as well as distribution into lymphocytes. Interaction of other drugs with P-glycoprotein may change tacrolimus tissue distribution and modify its toxicity and immunosuppressive activity. There is evidence that ethnic and gender differences exist for tacrolimus drug interactions. Therapeutic drug monitoring to guide dosage adjustments of tacrolimus is an efficient tool to manage drug interactions. In the near future, progress can be expected from studies evaluating potential pharmacokinetic interactions caused by herbal preparations and food components, the exact biochemical mechanism underlying tacrolimus toxicity, and the potential of inhibition of CYP3A and P-glycoprotein to improve oral bioavailability and to decrease intraindividual variability of tacrolimus pharmacokinetics.

Adrenal Cortex Hormones↗

PubMed2002

Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study.

BACKGROUND: In previous comparative studies tacrolimus was superior to the standard formulation of ciclosporin in preventing acute rejection after renal transplantation. We have compared the microemulsion formulation of ciclosporin with tacrolimus in a multicentre randomised trial. METHODS: The 6-month open study involved 560 patients in 50 European centres. 287 patients were randomly assigned tacrolimus and 273 ciclosporin microemulsion plus azathioprine and corticosteroids. The initial oral daily doses were 0.30 mg/kg for tacrolimus and 8-10 mg/kg for ciclosporin. The primary endpoint was the proportion of patients with biopsy-proven acute rejection and the time to this event. FINDINGS: The two study groups were similar in terms of baseline characteristics. Three patients did not receive study treatment or did not undergo transplantation (one tacrolimus, two ciclosporin). The rate of biopsy-confirmed acute rejection was significantly lower with tacrolimus than with ciclosporin microemulsion (56 patients [19.6%] vs 101 [37.3%]; 17.7% difference [95% CI 10.3-25.1]; p<0.0001). Biopsy-confirmed corticosteroid-resistant rejection was also significantly lower with tacrolimus (27 [9.4%] vs 57 [21.0%]; 11.6% difference [5.7-17.5]; p<0.0001). Cross-over between therapies because of biopsy-proven rejection was judged necessary in one of 286 (0.3%) tacrolimus-group patients and 27 of 271 (10.0%) ciclosporin-group patients (p<0.0001). There were no significant differences in survival of patients or grafts or in renal function. The overall frequency of adverse events was similar in the two groups, though hypertension and hypercholesterolaemia were more common in the ciclosporin group and tremor and hypomagnesaemia were more frequent in the tacrolimus group. INTERPRETATION: Tacrolimus was significantly more effective than ciclosporin microemulsion in preventing acute rejection after renal transplantation and had a superior cardiovascular-risk profile.

Adolescent↗

PubMed2005

Topical tacrolimus ointment combined with 6% salicylic acid gel for plaque psoriasis treatment.

BACKGROUND: While oral tacrolimus is effective for the treatment of psoriasis, tacrolimus ointment has shown only spotty efficacy in the treatment of plaque psoriasis. The efficacy of tacrolimus ointment for the treatment of facial and intertriginous psoriasis suggests that if tacrolimus penetration can be increased, the ointment could be used for effective treatment of plaque psoriasis. OBJECTIVE: To assess whether tacrolimus ointment is an effective psoriasis treatment when used in a combination regimen with the penetration-enhancer salicylic acid. METHODS: A total of 30 adult subjects with generally symmetrical plaque-type psoriasis were randomized to treatment with 6% salicylic acid gel plus vehicle or 6% salicylic acid gel plus 0.1% tacrolimus ointment in a 12-week left-right comparison study. The primary outcome was the difference between tacrolimus- and vehicle-treated target lesions in the change in the sum of erythema, scale, and thickness scores from baseline to end of treatment. RESULTS: A total of 24 subjects completed the trial. Combination treatment with tacrolimus ointment or vehicle plus salicylic acid gel was well tolerated. There was greater improvement of the sum score in the tacrolimus plus salicylic acid-treated target plaques than in the vehicle plus salicylic acid-treated plaques at weeks 1, 2, and 8 (P<.05). The efficacy of this regimen was confirmed by investigator and subject global assessments of plaque severity. CONCLUSIONS: The combination of 0.1% tacrolimus ointment and 6% salicylic acid gel is an effective treatment for psoriasis. Although the results reported herein are from a small exploratory study, the magnitude of the effect was sufficiently large as to be detectable with statistical significance (P<.05).

Administration, Topical↗

PubMed2002

Sublingual tacrolimus for immunosuppression in lung transplantation: a potentially important therapeutic option in cystic fibrosis.

Lung transplantation has emerged as an option to prolong and increase the quality of life in patients with end-stage pulmonary lung disease. In lung transplant recipients, because of the high potential for acute and chronic allograft rejection, optimal selection, dosage and delivery of immunosuppressive medications is critical. Cystic fibrosis (CF), a multi-organ system disease that often includes pulmonary and gastrointestinal manifestations, represents the leading indication for bilateral lung transplantation. The gastrointestinal manifestations of CF, however, confound post-transplant management by causing significant variation in the rate and extent of absorption of orally administered immunosuppressive medications. Tacrolimus, a new calcineurin inhibitor, is increasingly employed as the primary immunosuppressive agent in lung transplant recipients. Unfortunately, tacrolimus itself exhibits variable bioavailability, particularly in CF transplant recipients. A novel approach to the absorption dilemma is administration of tacrolimus via the sublingual (SL) route. Little published information exists concerning the use of SL immunosuppression in transplant recipients. However, emerging evidence suggests that SL tacrolimus provides is an effective means of drug delivery particularly for CF lung transplant recipients. Preliminary results from a pilot study, demonstrate that SL delivery of tacrolimus achieves therapeutic serum levels, in lung transplant recipients with CF, over the first few postoperative months. In addition, the early postoperative use of SL tacrolimus has been associated with acceptable rates of transplant rejection and normal renal function in a cohort of 22 lung transplant recipients that included CF and non-CF transplant recipients. Potential pharmacokinetic advantages of the SL route of delivery include good permeability, rapid absorption, acceptable bioavailability and easy accessibility. From an economic standpoint, considerable cost savings could be achieved by using the SL rather than the intravenous route of drug delivery for tacrolimus. Comparative, prospective randomized trials are necessary to evaluate the long-term safety and efficacy of SL tacrolimus in lung transplant patients. Until such data are available, the use of SL tacrolimus should be considered in situations where alternative routes of delivery are unavailable or as part of ongoing research studies. Ultimately, SL tacrolimus may prove efficacious for short-term use in the early postoperative lung transplant recipients, particularly in patients with malabsorption problems such as CF transplant recipients.

Administration, Oral↗

PubMed2005

Tacrolimus: in vitro effects on myelopoiesis, apoptosis, and CD11b expression.

BACKGROUND: Tacrolimus is a common component of multi-drug immunosuppressive regimens that are used for the prevention of rejection in transplant recipients. Tacrolimus therapy has been associated with anemia after transplantation, and recent clinical evidence in children suggests its association with the development of neutropenia for which an alternative etiology is not apparent. Mechanisms of suspected tacrolimus-related neutropenia have not been previously elucidated. We hypothesized that this variety of neutropenia might be due to a negative effect of tacrolimus on neutrophil production and/or survival. METHODS: We designed in vitro studies to determine the dose-dependent effect of tacrolimus on myeloid cell production and/or apoptosis. CD34+ cells and neutrophils isolated from umbilical cord blood of term gestations were cultured with tacrolimus (0-1,000 ng/ml). To evaluate apoptosis, cells cultured for 24 hours were stained with annexin V-fluorescein isothiocyanate (V-FITC) and 7-amino-actinomycin D (7-AAD) and analyzed by flow cytometry. For clonal analysis, CD34+ cells cultured in cytokine-enhanced semi-solid media were scored for their myeloid/erythroid mix colony forming units (CFU-Mix) and myeloid (CFU-GM) progenitor cell contents. RESULTS: Tacrolimus induced a dose-dependent enhancement of clonogenesis and survival of CD34+ cells at clinically relevant doses. Conversely, tacrolimus had no effect on the survival of mature neutrophils or on the upregulation of CD11b in response to chemotactic stimulation. CONCLUSION: In contrast to our initial hypothesis, we observed that tacrolimus at clinically relevant concentrations enhanced clonogenesis of neutrophil progenitors and promoted their survival. Our in vitro studies suggest that tacrolimus alone is unlikely to be a significant factor in the neutropenia observed during immunosuppressive therapy.

Apoptosis↗