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PubMed2004

Increased tacrolimus trough levels in association with severe diarrhea, a case report.

It is well known that during diarrhea episodes decreased cyclosporine and tacrolimus levels are often observed, usually requiring an increase in dose. An increase in tacrolimus trough levels is infrequently recognized as a potential cause of the adverse effect of severe diarrhea. Herein, we report the case of a renal transplant patient who displayed increased tacrolimus trough levels during an episode of gastroenteritis with severe diarrhea. The patient is 32-year-old male who received a renal transplant from his mother. Immunosuppression was initiated with tacrolimus in combination with mycophenolate mofetil and prednisone. The postoperative course was uneventful. The function of the transplanted kidney was normal. Eight months after transplantation he presented to our hospital with a history of high fever, abdominal pain, nausea and severe diarrhea. He was admitted with a diagnosis of enterocolitis of unknown etiology. The blood trough level of tacrolimus had increased from 6.7 ng/mL to 28.7 ng/mL after the onset of diarrhea. A therapeutic trough level of tacrolimus was reached 6 weeks after complete relief of diarrhea. Tacrolimus shows large variability in bioavailability after oral administration, both due to intestinal metabolism by cytochrome P450 (CYP3A4) and active secretion from enterocyte into intestinal lumen by P-glycoprotein. The epithelial cells of the intestine, may be destroyed abrogating P-glycoproteins during the course of enterocolitis, thereby increasing the levels of tacrolimus. It is recommended to monitor trough levels of tacrolimus during severe diarrhea of any nature to prevent tacrolimus-related complications.

Adult↗

PubMed2004

Primary immunosuppression with tacrolimus in kidney transplantation: three-year follow-up in a single center.

INTRODUCTION: The 1-year results of the phase III US Multicenter Trial comparing tacrolimus- and cyclosporine (Sandimmun)-based immunosuppressive therapy in kidney transplantation revealed a significant reduction in the incidence and severity of acute rejection episodes among patients maintained on tacrolimus. This retrospective, nonrandomized, single-center study represented 3-year data for patient and graft survival and safety in the tacrolimus-treated patients. METHODS: Among 97 consecutive kidney transplant recipients 41 who received tacrolimus and 56 cyclosporine-based immunosuppression were followed for 3 years for patient and graft survivals and for the incidence of acute rejection episodes as well as serious adverse events. RESULTS: The 3-year patient and graft survival rates for tacrolimus and cyclosporine were similar (91.0% vs 90.2%, 96.5% vs 95.0%). However, the incidence of acute rejection episodes was significantly lower in the tacrolimus (17.1%) compared with the cyclosporine group (35.7%, P = .043). There was a higher incidence of headache, posttransplant diabetes, and alopecia reported in the tacrolimus group, whereas hypertension, hypercholesterolemia, and hirsutism were more frequent in the cyclosporine group. The incidences of hand tremor, hyperkalemia, and viral infections were comparable in both groups. Two patients in the tacrolimus group were converted to cyclosporine due to nephrotoxicity and posttransplant diabetes, respectively, whereas 12 patients in the cyclosporine group were converted to tacrolimus as rescue therapy for acute rejection (41.7%), gingival hyperplasia (33.3%), nephrotoxicity (8.3%), neurotoxicity (8.3%), and hirsutism (8.3%), respectively. CONCLUSION: The 3-year results of tacrolimus treatment show excellent efficacy and safety in kidney transplantation. Due to different side-effect profiles, it is necessary to develop individualized immunosuppressive strategies in kidney transplant recipients.

Cyclosporine↗

PubMed2005

Conversion of stable liver transplant recipients from a twice-daily Prograf-based regimen to a once-daily modified release tacrolimus-based regimen.

INTRODUCTION: Modified release (MR) tacrolimus is an extended release formulation administered once daily. The purpose of this pharmacokinetic (PK) study was to evaluate tacrolimus exposure in stable liver transplant recipients converted from Prograf twice a day to MR tacrolimus once daily. METHODS: This was an open-label, multicenter study with a single sequence, four-period crossover design. Eligible patients were 18 to 65 years of age, >6 months posttransplant with stable renal and hepatic function and receiving stable doses of Prograf twice a day for >2 weeks prior to enrollment. Patients received Prograf twice a day on days 1 to 14 and 29 to 42. Patients were converted to the same milligram-for-milligram daily dose of MR once daily on days 15 to 28 and 43 to 56. Twenty-four-hour PK profiles were obtained on days 14, 28, 42, and 56. Laboratory and safety parameters were also evaluated. RESULTS: Of 70 patients, 62 completed all four PK profiles. The AUC0-24 of tacrolimus was comparable for Prograf twice a day (days 14 and 42) and MR tacrolimus once daily (days 28 and 56). The 90% confidence intervals for MR tacrolimus versus Prograf at steady state (days 28 and 56 vs days 14 and 42) was 0.85 to 0.92 for AUC0-24. MR tacrolimus was well tolerated with a safety profile comparable to that of Prograf. AUC0-24 was highly correlated to Cmin for Prograf (day 14, r = .93; Day 42, r = .89) and for MR tacrolimus (day 28, r = .93; day 56, r = .92). Renal and liver function remained stable. One patient experienced acute rejection. CONCLUSION: The steady-state tacrolimus exposure of MR tacrolimus once daily is equivalent to Prograf twice a day after a milligram-for-milligram conversion in stable liver transplant recipients.

Area Under Curve↗

PubMed2005

Steroid withdrawal or steroid avoidance in renal transplant recipients: focus on tacrolimus-based immunosuppressive regimens.

Steroid-induced adverse effects after transplantation include cosmetic, metabolic, and cardiovascular complications. Steroid withdrawal or avoidance with cyclosporine-based regimens have been hampered by an unacceptably high rate of acute rejections and increased rates of graft loss. Recently the results of several large, randomized trials of steroid withdrawal/avoidance with tacrolimus-based immunosuppression in renal transplant recipients became available. A review of these trials appeared to be of clinical interest. Data from the THOMAS trial clearly indicate that steroid withdrawal from a regimen of tacrolimus, mycophenolate mofetil (MMF), steroids after 3 months after transplantation is safe with regard to acute rejection rate and graft survival. If an induction therapy with daclizumab is used in combination with tacrolimus and MMF (CARMEN trial), even steroid avoidance is safe with regard to acute rejection rate and graft survival. Finally, in the ATLAS trial, steroid avoidance with basiliximab in combination with tacrolimus (resulting in tacrolimus monotherapy) or alternatively with tacrolimus and MMF both resulted in similar graft survival, but higher rates of acute rejection. In conclusion, steroid withdrawal is safe from a triple-drug regimen of tacrolimus, MMF, and steroids after 3 months after transplantation, and steroid use may completely be avoided with tacrolimus, and MMF combined with daclizumab induction. Tacrolimus monotherapy may be achieved using basiliximab induction at the price of higher rates of acute rejection, but with unaffected graft survival. Thus tacrolimus-based immunosuppression with or without interleukin-2 receptor antagonist induction has made steroid withdrawal or avoidance a realistic option in renal transplantation.

Drug Therapy, Combination↗

PubMed2006

Differential pharmacokinetic interaction of tacrolimus and cyclosporine on everolimus.

OBJECTIVE: We characterized the pharmacokinetics of tacrolimus and everolimus in a combined immunosuppressive regimen. METHODS: This was an open-label exploratory trial in eight maintenance renal transplant patients with calcineurin inhibitor intolerance initially receiving mycophenolate mofetil (MMF) and tacrolimus. At enrollment, MMF was discontinued and replaced with everolimus 1.5 mg twice a day in study period 1 (days 1 to 10). In period 2 (day 11 to month 3), tacrolimus dose was reduced by half. RESULTS: At study entry tacrolimus trough level (C0) was 7.9 +/- 3.9 ng/mL and area under the curve over a dosing interval (AUC) was 132 +/- 56 ng x h/mL. The addition of everolimus in period 1 did not change tacrolimus exposure: C0 8.4 +/- 4.0 ng/mL, AUC 134 +/- 70 ng x h/mL. Everolimus pharmacokinetics in the presence of tacrolimus in period 1 were: C0 3.3 +/- 1.2 ng/mL, Cmax 10.4 +/- 5.1 ng/mL, AUC 58 +/- 20 ng x h/mL. When compared to pharmacokinetic data from a previous study in 47 renal transplant patients receiving everolimus at the same fixed dose (1.5 mg twice a day) with cyclosporine, everolimus exposure was 2.5-fold higher with cyclosporine relative to the data in this study with tacrolimus. After tacrolimus dose reduction in period 2, there was no clinically relevant change in everolimus exposure: C0 3.0 +/- 1.1 ng/mL, Cmax 8.2 +/- 1.3 ng/mL, AUC 49 +/- 10 ng x h/mL. CONCLUSIONS: Tacrolimus appears to have a minimal effect on everolimus blood levels compared with the influence of cyclosporine. The dose of everolimus when combined with tacrolimus needs to be higher than when combined with cyclosporine in order to reach a given everolimus blood level.

Adrenal Cortex Hormones↗

PubMed2000

Minor immunophilin binding of tacrolimus and sirolimus metabolites.

OBJECTIVES: We have previously identified three minor immunophilins of molecular weights 37 kDa, 14 kDa, and 5-8 kDa capable of binding tacrolimus and sirolimus. DESIGN AND METHODS: When tested against pure preparations of five sirolimus metabolites, the 14 kDa protein had almost no cross-reactivity, the 37 kDa protein cross-reacted from a high of 23.2% to <10% and the 5-8 kDa protein cross-reacted from <10% to 46.4%. When the 5-8 kDa immunophilin was tested in whole blood samples to assess interference in clinical samples, the demethylated sirolimus metabolites showed about 25% less cross-reactivity while the hydroxylated metabolites reacted about the same. RESULTS: Since MLC data on sirolimus metabolites to date indicates that their pharmacologic potencies are < or =10% of the parent, the 14 kDa immunophilin appears to be the best candidate for a sirolimus radioreceptor assay. The 5-8 kDa immunophilin is newly identified and its cross-reactivity with tacrolimus metabolites had not been assessed. Binding of the 5-8 kDa immunophilin to pure preparations of three tacrolimus metabolites showed virtually no binding of the protein to 13-O-demethyl and 31-O-demethyl tacrolimus and binding to 15-O-demethyl tacrolimus at 121% relative to parent tacrolimus. Cross-reactivity of 15-O-demethyl tacrolimus with the 5-8 kDa protein was then assessed in whole blood samples, and it bound at a level of 163%. MLC data indicates that 31-O-demethyl tacrolimus is equipotent to parent tacrolimus in immunosuppressive activity, while the 13-O-demethyl and 15-O-demethyl have negligible immunosuppressive activity. CONCLUSIONS: Therefore, the 5-8 kDa immunophilin would have limitations in a radioreceptor assay for tacrolimus. In addition, we have evidence that the 5-8 kDa immunophilin is a subunit of a 52 kDa immunophilin previously identified by our group, and the cross-reactivity of the 5-8 kDa immunophilin with these metabolites is similar to that found previously with the 52 kDa, indicating that the two proteins could be related.

Animals↗

PubMed1997

Tacrolimus oral bioavailability doubles with coadministration of ketoconazole.

OBJECTIVE: To quantitate the effect of ketoconazole, an azole antifungal agent and potent inhibitor of CYP3A4 and P-glycoprotein, on the bioavailability of tacrolimus, a substrate of the CYP3A system and of P-glycoprotein. SUBJECTS AND METHODS: The pharmacokinetics of tacrolimus were studied in six healthy volunteers (two women and four men) in a four-dose study after each received single doses of tacrolimus alone (0.1 mg/kg orally and 0.025 mg/kg intravenously) and with coadministered ketoconazole (200 mg orally at bedtime for 12 days). The dose of tacrolimus was reduced during the ketoconazole phase (0.04 mg/kg orally; 0.01 mg/kg intravenously). Ketoconazole and tacrolimus doses were separated by approximately 10 hours. Whole blood tacrolimus concentrations were determined by enzyme-linked immunosorbent assay. Estimated pharmacokinetic parameters in whole blood (mean +/- SD) before and with ketoconazole were calculated with noncompartmental techniques. RESULTS: Coadministration of ketoconazole did not consistently affect tacrolimus clearance (55.6 +/- 16.7 ml/hr/kg versus 42.5 +/- 7.6 ml/hr/kg), and steady-state volume of distribution was unchanged (0.99 +/- 0.26 L/kg versus 0.93 +/- 0.25 L/kg). However, a significant increase in tacrolimus bioavailability (14% +/- 5% versus 30% +/- 8%; p < 0.01) was observed with coadministered ketoconazole. Hepatic bioavailability was unchanged by the presence of ketoconazole (96% +/- 1% versus 97% +/- 1%). CONCLUSIONS: Because ketoconazole did not alter hepatic bioavailability and because 10 hours separated administration times of the drugs, it appears that the marked increase in tacrolimus bioavailability can be explained by ketoconazole having a local inhibitory effect on tacrolimus gut metabolism or on intestinal P-glycoprotein activity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Coadministration of tacrolimus and ketoconazole in renal transplant recipients: cost analysis and review of metabolic effects.

BACKGROUND: The high cost of tacrolimus is a major problem in Mexico. Ketoconazole increases tacrolimus bioavailability by inhibiting cytochrome P450 3A4 and glycoprotein-p. OBJECTIVE: To demonstrate that the coadministration of tacrolimus and ketoconazole allows a significant dose and cost reduction. PATIENTS AND METHODS: This prospective study administered tacrolimus and ketoconazole to renal transplant recipients with dose adjustment according to tacrolimus blood levels. At 0-1, 1-6, 6-12, and 12-24 months posttransplant demographic, transplant type, immunosuppression, and clinical data were reviewed. The cost of tacrolimus treatment was calculated based on the dose used as compared to the recommended dose (0.15-0.20 mg/kg/d). RESULTS: Eleven patients with an age of 40 years (range, 13-71) were studied from May 2000 to August 2002. Follow-up was 15 +/- 10 months. Graft source was living donor in six patients and cadaveric in five. All patients received tacrolimus + mycophenolate mofetil + prednisone. The mean ketoconazole dose was 87 mg/d. Since the dose of tacrolimus was 0.04 mg/kg/d versus the recommended dose of 0.15-0.20 mg/kg/d, there was a 78% cost reduction (P =.000). Tacrolimus blood levels remained in the therapeutic range. There were no drug-related side effects. CONCLUSIONS: The co-administration of tacrolimus and ketoconazole results in a substantial dose and cost reduction while maintaining therapeutic levels. No adverse metabolic consequences were seen with this combination.

Adolescent↗

PubMed1999

Practical considerations in the use of tacrolimus for allogeneic marrow transplantation.

Tacrolimus has been shown to be more effective than cyclosporine for prevention of acute graft-versus-host disease (GVHD). A number of transplant centers have therefore adopted tacrolimus as standard prophylaxis, but with additional experience, current management of tacrolimus differs from that in the clinical studies. Therefore, a consensus conference was convened to assess the current practices. For prevention of GVHD, conference participants recommended administering tacrolimus at 0.03 mg/kg/day (by lean body weight) i.v. by continuous infusion from day -1 or -2 pretransplant, with day -2 used especially for pediatric patients. Therapeutic drug monitoring was considered essential in the management of patients on tacrolimus. The consensus target range for the whole blood concentration was 10-20 ng/ml. Doses were modified for blood levels outside the target range or for nephrotoxicity, and tacrolimus was discontinued for intolerable tremor, hemolytic uremic syndrome, leukoencephalopathy or other serious toxicity. Tacrolimus was employed most frequently in combination with minimethotrexate (5 mg/m2 i.v. days 1, 3, 6 and 11). Tapering was individualized according to center practice. No patient category was excluded from use of tacrolimus based on age, extent of disease, patient-donor histocompatibility or stem cell source. Tacrolimus was also used successfully for treatment of chronic GVHD. The responsiveness of steroid-refractory acute GVHD was marginal, so it was deemed more prudent to use tacrolimus for prophylaxis instead.

Bone Marrow Transplantation↗

PubMed2000

Tacrolimus clearance is age-dependent within the pediatric population.

For prevention of graft-versus-host disease, the consensus initial intravenous dose of tacrolimus for adults is 0.03 mg/kg/day. Whether target whole blood concentrations of tacrolimus in children undergoing hematopoietic stem cell transplantation can be achieved reproducibly with this dose is not known. We reviewed the tacrolimus blood levels and calculated clearances for 55 children (aged 6 months to 18 years, median 9 years) using tacrolimus after allogeneic marrow, blood stem cell or cord blood transplantation. The tacrolimus dose regimen was 0.03 mg/kg/day by continuous infusion starting on day -1 or day -2. At the first sampling in the peritransplant period, 71% of the tacrolimus blood levels were within the target range of 5-15 ng/ml, 87% were in the safe range of 5-20 ng/ml, 9% were toxic, and 4% were subtherapeutic. Twenty-five children were converted to oral drug using the recommended oral/intravenous dose ratio of 4.0. At the first sampling after oral conversion, 80% were in the target range, and 20% were subtherapeutic. Clearance of tacrolimus was calculated from the blood levels for patients during intravenous dosing and normalized by ideal body weight. There was a decreased clearance over the first 2 weeks only for the children >12 years old (P = 0.014). The initial calculated clearances of tacrolimus did not differ between age groups, but at steady state the mean tacrolimus clearance (+/- s.d.) was higher for those <6 years old (0.159+/-0.082 l/h/kg) than for those 6-12 years old (0.109+/-0.053 l/h/kg) or >12 years old (0.104 +/-0.068 l/h/kg). Children <6 years old undergoing hematopoietic stem cell transplantation have a higher weight-normalized tacrolimus clearance than older children and adults, and careful therapeutic monitoring is needed in the first 2 weeks after transplantation to avoid prolonged subtherapeutic dosing for this age group.

Administration, Oral↗

PubMed2000

Clinical outcome after conversion to FK 506 (tacrolimus) therapy for acute graft-versus-host disease resistant to cyclosporine or for cyclosporine-associated toxicities.

This retrospective study describes the outcome in 53 patients who had immunosuppressive treatment changed from cyclosporine (CSP) to tacrolimus for resistant acute GVHD (n = 23), hemolytic uremic syndrome (HUS) (n = 13) or CSP-associated neurotoxicity (n = 17). Tacrolimus was administered at doses of 0.03 mg/kg/day intravenously or 0.12 mg/kg/day orally in divided doses, as tolerated. Median time of conversion to tacrolimus after transplant was day 47. Nineteen patients had treatment changed to tacrolimus for resistant acute GVHD grades III or IV, with the median day of conversion being day 49 after transplant. Two of 20 evaluable patients had a complete resolution of GVHD after changing treatment to tacrolimus, with 18 showing no improvement. Eleven evaluable patients had therapy changed to tacrolimus for CSP-associated neurotoxicity at a median of 36 days after transplant. Eight patients had resolution of neurotoxicity and three had partial improvement. Eleven evaluable patients had therapy changed to tacrolimus for HUS at a median of 46 days after transplant. One patient had complete resolution of HUS and 10 showed no response. Side-effects related to tacrolimus included renal toxicity (34%), neurotoxicity (15%) and HUS (9%). Nine (17%) patients remain alive, including six patients who had therapy changed to tacrolimus for CSP-associated neurotoxicity. While often successful for dealing with neurotoxicity, only a rare patient improved after therapy was changed from CSP to tacrolimus for HUS or resistant acute GVHD.

Acute Disease↗

PubMed2001

An open study of a lotion formulation to improve tolerance of tacrolimus in facial atopic dermatitis.

BACKGROUND: We identified 19 patients with facial atopic eczema who failed to respond to tacrolimus (FK506) ointment, although tacrolimus ointment has shown excellent benefit for the treatment of recalcitrant facial erythema in most patients with atopic dermatitis. OBJECTIVES: We attempted to determine the efficacy of an original lotion formulation of tacrolimus for facial atopic dermatitis resistant to tacrolimus ointment. PATIENTS/METHODS: Recalcitrant facial erythema of these 19 patients was treated with an original tacrolimus lotion preparation for 6 months. Patch testing with white petrolatum was performed in both the 19 patients and in 30 other atopic dermatitis patients who had experienced excellent results with tacrolimus ointment. RESULTS: Of the 19 resistant patients, those whose symptoms were greatly or moderately improved by the lotion were 95%, 89% and 89% after 2 weeks, 3 months and 6 months of treatment, respectively. Further, patch testing to petrolatum showed positive reactions in several (six of 19) patients, compared with none of 30 controls with atopic eczema that had responded to topical tacrolimus ointment. CONCLUSIONS: The tacrolimus lotion had a significant effect on the recalcitrant facial erythema in adult patients with atopic dermatitis who were resistant to tacrolimus ointment. We suggest that one reason for the unresponsiveness to tacrolimus ointment may be because of contact sensitivity to white petrolatum.

Adolescent↗

PubMed1999

Relationship of tacrolimus whole blood levels to efficacy and safety outcomes after unrelated donor marrow transplantation.

Tacrolimus has proved effective for preventing acute graft-vs.-host disease (GVHD) after unrelated donor marrow transplantation, but the therapeutic window is apparently narrow. Therapeutic drug monitoring could potentially be used to guide dose modifications, but the optimal target range of tacrolimus blood concentrations is unknown. We determined whether acute GVHD and renal dysfunction correlated with tacrolimus whole blood levels as measured by the IMx assay. Data were analyzed for 97 adults treated in a multicenter trial of tacrolimus and methotrexate or methylprednisolone as GVHD prophylaxis after unrelated donor marrow transplantation. The rate of grades II-IV GVHD was 49%; 81% of patients had a doubling of the serum creatinine; and 61% had a serum creatinine <2 mg/dL. The initial tacrolimus target range for the clinical trial was 10-60 ng/mL. Tacrolimus blood levels were averaged over a 14-day period, and Cox models were used with averaged blood levels as a time-dependent covariate. No significant change was observed in the risks of acute GVHD, doubling of creatinine, need for dialysis, or death over a tacrolimus blood level range of 5-40 ng/mL, but there was a direct correlation between risk of developing a creatinine <2 mg/dL and increasing tacrolimus blood levels (4.7% increased risk for each 1 ng/mL increase in blood concentration, p < 0.001). When the tacrolimus level exceeded 20 ng/mL, there was a 2.2-fold increase in the rate of renal toxicity (p < 0.001), a trend for an increase in mortality (relative risk 3.9, p=0.08), and no impact on the risk of GVHD. This analysis supports 10-20 ng/mL as the therapeutic range of tacrolimus whole blood steady state or trough levels for unrelated donor marrow transplantation.

Adolescent↗

PubMed2002

The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients.

Solid organ transplantations have been performed successfully in selected HIV-positive patients with highly active antiretrovirus therapy (HAART). However, some of the medications in the HAART regimen require metabolism via the cytochrome P4503A, the same enzyme complex responsible for clearance of the calcineurin inhibitors cyclosporine and tacrolimus. Several case reports have described significant interactions between the agents used in HAART and immunosuppressive drugs. The goal of this report is to examine the extent of potential drug interactions between antiretroviral agents and tacrolimus after liver and kidney transplantation. Seven liver transplant (LTx) patients (M = 6, F = 1) and four kidney transplant (KTx) patients (M = 4) infected with HIV underwent surgery between September 1997 and January 2001. Initial immunosuppression consisted of tacrolimus and steroids for LTx patients or tacrolimus, steroids, and mycophenolate mofetil for KTx recipients. Their current baseline immunosuppression and HAART regimen were examined retrospectively. Of the seven liver recipients, one (case 4) died 2 weeks after LTx and never received HAART therapy posttransplantation. The remaining six patients were placed on a regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTI) and one protease inhibitor (PI) (nelfinavir in 5, indinavir in 1) based on known viral sensitivities or history of a previous clinical response. Kidney recipients received NRTI and nonnucleoside reverse transcriptase inhibitors (NNRTI). The mean dose of tacrolimus in liver recipients was 0.6 mg/d, with mean trough concentration of 9.7 mg/mL. Compared with historic controls (liver transplant patients not on HAART), the average tacrolimus dose was 16-fold lower in patients on HAART. In contrast to liver recipients, HIV-positive kidney recipients not on PI therapy required a mean tacrolimus dose of 9.5 mg/d to maintain a mean trough concentration of 9.6 ng/mL. Of the two protease inhibitors used, nelfinavir seems to have a more profound effect than indinavir. When patients on nelfinavir alone (n = 5) were compared with a control group not on antiretroviral therapy, the need for a tacrolimus dose was 38 times lower (mean dose, 0.26 mg/d). Profound drug interactions between PI and tacrolimus have been observed requiring up to 50-fold reductions in dosage. This effect seems to be most pronounced with the use of nelfinavir as opposed to indinavir, although further experience is required to confirm this observation. In contrast, HAART using NRTI and NNRTI without the use of PI, as shown in kidney recipients, produces less significant effects on tacrolimus metabolism. Great caution and frequent drug level monitoring are necessary when HAART is introduced or withdrawn in HIV-positive recipients of organ transplants.

Adult↗

PubMed2001

Nonclinical and early clinical development of tacrolimus ointment for the treatment of atopic dermatitis.

Tacrolimus ointment, formulated for the treatment of atopic dermatitis, is the first in a class of topical immunomodulators. Its mechanism of action is based on calcineurin inhibition, which results in suppression of antigen-specific T-cell activation and inhibition of inflammatory cytokine release. Animal and human studies have shown that topically applied tacrolimus is minimally absorbed into the systemic circulation, the fraction that is absorbed is extensively distributed, and tacrolimus does not accumulate in tissues following repeated topical application. In addition, tacrolimus ointment is not inherently irritating, sensitizing, phototoxic, or photoallergenic when applied to intact skin. Unlike some topical corticosteroids, tacrolimus ointment does not cause a decrease in collagen synthesis or skin thickness, nor does it produce skin abnormalities or depigmentation. In animal studies, repeated daily application of tacrolimus ointment up to 1 year is associated with dermal findings similar to those following vehicle application (mild to moderate dermal irritation and microscopic findings of acanthosis, hyperkeratosis, and superficial inflammation). In a 52-week study with Yucatan micropigs, no noteworthy macroscopic or microscopic changes (either dermal or systemic) related to the application of tacrolimus ointment (0.03% to 0.3% concentrations) were observed. Tacrolimus ointment was shown to be safe and effective in phase 2 and early phase 3 studies. Significant improvements in atopic dermatitis were observed in the majority of patients treated with tacrolimus ointment. The most common adverse events associated with its use were a transient burning sensation and pruritus at the site of application. Blood tacrolimus concentrations were below the limit of quantitation in most patients.

Animals↗

PubMed1998

Tacrolimus impairs wound healing: a possible role of decreased nitric oxide synthesis.

BACKGROUND: The effect of the immunosuppressant tacrolimus on wound healing is not known. Tacrolimus has been shown to decrease nitric oxide synthesis. The systemic inhibition of wound nitric oxide synthesis leads to impaired healing. METHODS: We studied the effect of systemic tacrolimus treatment on wound-breaking strength and collagen deposition 10 days after wounding in rats and to correlate the outcome of healing with wound nitric oxide synthesis. Beginning at the day of wounding, rats were treated once daily by intraperitoneal injections with 0.5, 1.0, or 2.0 mg tacrolimus/kg body weight. Nitrite and nitrate were measured in wound fluid as an index of wound nitric oxide synthesis. Expression of inducible nitric oxide synthase in the wound was investigated by immunohistochemistry. Splenic lymphocytes were tested for proliferative activity. Tacrolimus levels in blood and wound fluid were measured by enzyme-linked immunosorbent assay. RESULTS: Systemic tacrolimus treatment was well tolerated by all rats. Tacrolimus accumulated in wound fluid. Tacrolimus levels in wound fluid were found to be approximately 10-fold higher than blood levels (P < 0.001). Tacrolimus (2.0 mg/kg/day) reduced wound-breaking strength (P < 0.01) and collagen deposition (P < 0.05). This was paralleled by decreased wound nitrite + nitrate levels (P < 0.001) and wound-inducible nitric oxide synthase expression. Splenic lymphocyte proliferative activity was significantly decreased by 1.0 and 2.0 mg tacrolimus/kg body weight/day (P < 0.05), indicating that the tacrolimus doses used were immunosuppressive. CONCLUSION: Our data show for the first time that tacrolimus impairs wound healing, and this is reflected by diminished wound nitric oxide synthesis.

Animals↗

PubMed1999

A pilot study of immunosuppressive monotherapy in liver transplantation: tacrolimus versus microemulsified cyclosporin.

BACKGROUND: Many reports of successful early withdrawal of regular maintenance steroids in transplant recipients have appeared in recent years. The question now arises whether, in the current age of powerful nonsteroidal immunosuppressants such as Neoral and Tacrolimus, routine administration of steroids posttransplant is necessary at all. This single center pilot study reports on the feasibility, safety, and efficacy of single agent immunosuppression "ab initio" with either Neoral or Tacrolimus, and no routine or maintenance steroids. METHODS: A total of 64 adult patients receiving first liver grafts for a variety of indications were randomized to receive either Neoral 5 mg/kg BDS or Tacrolimus 0.05 mg/kg BDS orally. Liver biopsies were performed on postoperative days 5 and 10, and whenever else clinically indicated. Rejection episodes were treated with 1.0 g of Methylprednisolone daily for 3 consecutive days. A further episode of rejection after two courses of Methylprednisolone was considered to be monotherapy failure, and consequently other immunosuppressive agents, usually Prednisolone 1 mg/kg/day, was started on a regular basis, tapering slowly. RESULTS: Actuarial 1 year survival was 85% for Tacrolimus patients, and 78% for Neoral patients (P = NS), with 80% for Tacrolimus and 73.5% for Neoral at 30 months. Graft survival at 1 and 2.5 years was 73 and 62% for Tacrolimus and Neoral, respectively (P = NS). Two-thirds of patients in both groups showed biopsy evidence of acute cellular rejection. Rejection severity measured by a histological scoring system was similar for both patient groups. Additional longterm immunosuppressive therapy was necessary in 36% of patients receiving Neoral, compared with 13% of Tacrolimus patients (P = NS). No graft was lost on account of acute or chronic rejection. Short-term pulse steroid therapy to treat acute rejection was necessary for 60% of Tacrolimus patients and 40% of Neoral patients. CONCLUSION: Tacrolimus or Neoral monotherapy after liver transplantation provides adequate immunosuppression for 87% of Tacrolimus patients and 64% of Neoral patients. In this study, 33% of patients in both groups showed no evidence of acute rejection, either clinically, biochemically or histologically, and were not exposed to steroids at any time. Evaluation of the long-term morbidity related to the side effects of the immunosuppressants given as monotherapy, for example, renal impairment and posttransplant lymphoproliferative disorder, and the effect on recurrent viral hepatitis in the graft, would be suitable areas for further study.

Adult↗

PubMed2000

Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation.

BACKGROUND: Our clinical trial was designed to investigate the optimal combination of immunosuppressants for renal transplantation. METHODS: A randomized three-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare three immunosuppressive regimens: tacrolimus + azathioprine (AZA) versus cyclosporine (Neoral) + mycophenolate mofetil (MMF) versus tacrolimus + MMF. All patients were first cadaveric kidney transplants receiving the same maintenance corticosteroid regimen. Only patients with delayed graft function (32%) received antilymphocyte induction. A total of 223 patients were randomized, transplanted, and followed for 1 year. RESULTS: There were no significant differences in baseline demography between the three treatment groups. At 1 year the results are as follows: acute rejection 17% (95% confidence interval 9%, 26%) in tacrolimus + AZA; 20% (confidence interval 11%, 29%) in cyclosporine + MMF; and 15% (confidence interval 7%, 24%) in tacrolimus + MMF. The incidence of steroid resistant rejection requiring antilymphocyte therapy was 12% in the tacrolimus + AZA group, 11% in the cyclosporine + MMF group, and 4% in the tacrolimus + MMF group. There were no significant differences in overall patient or graft survival. Tacrolimus-treated patients had a lower incidence of hyperlipidemia through 6 months posttransplant. The incidence of posttransplant diabetes mellitus requiring insulin was 14% in the tacrolimus + AZA group, 7% in the cyclosporine + MMF and 7% in the tacrolimus + MMF groups. CONCLUSIONS: All regimens yielded similar acute rejection rates and graft survival, but the tacrolimus + MMF regimen was associated with the lowest rate of steroid resistant rejection requiring antilymphocyte therapy.

Adult↗