Summary
Abstract
Tacrolimus (FK-506) is an immunosuppressant agent that acts by a variety of different mechanisms which include inhibition of calcineurin. It is used as a therapeutic alternative to cyclosporin, and therefore represents a cornerstone of immunosuppressive therapy in organ transplant recipients. Tacrolimus is now well established for primary immunosuppression in liver and kidney transplantation, and experience with its use in other types of solid organ transplantation, including heart, lung, pancreas and intestinal, as well as its use for the prevention of graft-versus-host disease in allogeneic bone marrow transplantation (BMT), is rapidly accumulating.
Large randomised nonblind multicentre studies conducted in the US and Europe in both liver and kidney transplantation showed similar patient and graft survival rates between treatment groups (although rates were numerically higher with tacrolimus-versus cyclosporin-based immunosuppression in adults with liver transplants), and a consistent statistically significant advantage for tacrolimus with respect to acute rejection rate. Chronic rejection rates were also significantly lower with tacrolimus in a large randomised liver transplantation trial, and a trend towards a lower rate of chronic rejection was noted with tacrolimus in a large multicentre renal transplantation study.
In general, a similar trend in overall efficacy has been demonstrated in a number of additional clinical trials comparing tacrolimus-with cyclosporin-based immunosuppression in various types of transplantation. One notable exception is in BMT, where a large randomised trial showed significantly better 2-year patient survival with cyclosporin over tacrolimus, which was primarily attributed to patients with advanced haematological malignancies at the time of (matched sibling donor) BMT. These survival results in BMT require further elucidation. Tacrolimus has also demonstrated efficacy in various types of transplantation as rescue therapy in patients who experience persistent acute rejection (or significant adverse effects) with cyclosporin-based therapy, whereas cyclosporin has not demonstrated a similar capacity to reverse refractory acute rejection. A corticosteroid-sparing effect has been demonstrated in several studies with tacrolimus, which may be a particularly useful consideration in children receiving transplants.
The differences in the tolerability profiles of tacrolimus and cyclosporin may well be an influential factor in selecting the optimal treatment for patients undergoing organ transplantation. Although both drugs have a similar degree of nephrotoxicity, cyclosporin has a higher incidence of significant hypertension, hypercholesterolaemia, hirsutism and gingival hyperplasia, while tacrolimus has a higher incidence of diabetes mellitus, some types of neurotoxicity (e.g. tremor, paraesthesia), diarrhoea and alopecia.
Conclusion: Tacrolimus is an important therapeutic option for the optimal individualisation of immunosuppressive therapy in transplant recipients.
Pharmacodynamic Properties
Tacrolimus (FK-506) is a macrolide immunosuppressant that acts by a variety of different mechanisms which include inhibition of calcineurin. The drug inhibits T lymphocyte activation and transcription of cytokine genes including that for interleukin-2. Tacrolimus inhibits cell-mediated and, to a lesser extent, humoral immune responses. Cytokines produced by T helper (Th)1 cells are preferentially suppressed over those produced by Th2 cells.
The mechanism of action of tacrolimus is largely similar to that of cyclosporin, but tacrolimus is 10 to 100 times more potent. The drugs both inhibit calcineurin but do so via formation of complexes with different immunophilins: tacrolimus binds to FK-506 binding protein 12, whereas cyclosporin binds to cyclophilin A. The drugs appear to differ in their effects on patterns of Th2 cell cytokine expression and possibly some aspects of humoral immunity. Furthermore, lymphocyte sensitivity to the drugs may differ between patients.
In animal models, tacrolimus had an organ-specific effect in stimulating hepatic regeneration after partial hepatectomy, and attenuated hepatic ischaemic or reperfusion injury. Tacrolimus does not appear to cause postoperative cholestasis in liver transplant recipients, and postoperative disturbances in biliary secretion and flow rates may recover more rapidly with tacrolimus than cyclosporin.
Like cyclosporin, tacrolimus has nephrotoxic effects that appear to be mechanistically related to its immunosuppressive activity, possibly involving inhibition of calcineurin. Tacrolimus suppresses insulin production at the trans-criptional level and appears to be more diabetogenic than cyclosporin in some patients. In patients with liver transplants, tacrolimus reduced β cell secretory reserve, and was associated with significant insulin resistance and impaired β cell-α cell axis.
Further clarification is required of the comparative effects of tacrolimus and cyclosporin on factors involved in cardiac transplant-associated coronary artery disease. Although tacrolimus has been associated with a lower incidence of positivity for anti-endothelial cell antibodies than cyclosporin, a higher incidence of pathological microvascular endothelial dysfunction has also been reported. Tacrolimus may have an in vitro antithrombotic effect. Findings have been conflicting regarding the comparative effect of tacrolimus and cyclosporin on endothelium-independent microcirculatory responses 1 year after cardiac transplantation. Tacrolimus and cyclosporin appear to have similar effects on most aspects of cardiac function in renal or liver transplant recipients.
Pharmacokinetic Propertie
Like cyclosporin, the pharmacokinetic properties of tacrolimus can vary widely between individuals and dosage regimens are titrated according to whole-blood trough drug concentrations. Oral bioavailability of tacrolimus is about 20 to 25%, and food appears to have a significant effect in reducing the rate and extent of absorption. The drug binds extensively to erythrocytes, and whole-blood concentrations of tacrolimus are approximately 15 to 35 times those measured in plasma. Tacrolimus is almost completely metabolised prior to elimination. Metabolism is via 3A4 isoenzymes of the cytochrome P450 (CYP) system, primarily in the liver but also in the intestinal mucosa, and a number of metabolites are formed. At least 1 metabolite appears to be active, although the immunosuppressive activity of tacrolimus is primarily due to the parent drug. Elimination half-life of tacrolimus has been reported to be approximately 12 hours in liver transplant recipients and 19 hours in renal transplant recipients. Less than 1% of an intravenous dose of tacrolimus is eliminated unchanged in the urine. The main route of elimination for tacrolimus and its metabolites is via the biliary tract. Like cyclosporin, tacrolimus is subject to a number of pharmacokinetic (and pharmacodynamic) drug interactions of potential clinical significance, including those involving other drugs metabolised by the CYP enzyme system.
Therapeutic Efficacy
In most clinical trials, tacrolimus-based primary immunosuppression initially included concomitant administration of corticosteroids, typically with azathioprine or mycophenolate mofetil, and sometimes with adjunctive antilymphocyte antibody induction therapy. In general, rescue therapy with tacrolimus usually involved simple conversion from cyclosporin to tacrolimus without modification of concomitant drug therapy. Clinical trials comparing tacrolimus-with cyclo-sporin-based immunosuppression were conducted in a nonblind fashion, presumably because of the need to monitor whole-blood trough drug concentrations to optimise the clinical management of patients. In the following sections, cyclosporin refers to the standard formulation of the drug (the microemulsion formulation is specified when applicable).
Hepatic Transplantation
As primary immunosuppression in adults with hepatic transplantation, tacrolimus-based regimens achieved similar patient and graft survival rates to cyclosporin-based regimens, with a trend towards higher rates with tacrolimus, and significantly lower rates of acute rejection. This was demonstrated in 2 large multicentre randomised trials, one of which also showed significantly lower rates of chronic rejection at 1 and 3 years post-transplantation among patients receiving tacrolimus-based immunosuppression.
In general, similar overall efficacy trends were noted in more recent smaller randomised studies comparing tacrolimus with the cyclosporin microemulsion formulation. Results of these studies showed patient and graft survival rates of approximately 75 to 100% and 70 to 95%, respectively, after 6 to 30 months of tacrolimus-based therapy; acute rejection rates varied widely between studies. Long term survival data from a large cohort of 1000 patients treated with tacrolimus-based immunosuppression after liver transplantation indicate 6-year patient and graft survival rates of 68 and 63%, respectively. Several studies demonstrated that corticosteroid therapy could be successfully withdrawn in approximately 70 to 90% of liver transplant recipients treated with tacrolimus-based immunosuppressive therapy.
Tacrolimus is also effective as rescue therapy in adult patients with persistent acute or chronic rejection or drug-related toxicity with cyclosporin-based primary immunosuppression after hepatic transplantation. This has been demonstrated in a number of noncomparative studies, the largest involving a group of 475 patients with 2-year patient and graft survival rates of 80 and 73%, respectively, after conversion from cyclosporin to tacrolimus because of acute or chronic rejection.
In general, results of studies with tacrolimus-based primary immunosuppressive and rescue therapy for paediatric liver transplantation have been very similar to those of studies in adult patients. Results of the only prospective randomised comparison between tacrolimus (n = 30; mean age 3.5 years) and cyclosporin (n = 21; mean age 3.2 years) as primary immunosuppression showed similar 1-year patient (80 vs 81%) and graft (70 vs 71%) survival rates, and a trend favouring tacrolimus for acute rejection rate (52 vs 79%). Importantly, some studies demonstrated that corticosteroid therapy can be successfully discontinued in approximately 70 to 85% of children receiving tacrolimus as primary immunosuppressive or rescue therapy.
Renal Transplantation
Tacrolimus-based regimens achieved similar patient and graft survival rates and lower rates of acute rejection compared with cyclosporin-based regimens when used as primary immunosuppression in adults with renal transplantation. This was demonstrated in 2 large multicentre randomised trials; 1-year patient survival rates were ≈95% and corresponding graft survival rates were ≈85 to 90% for both treatment groups. A statistically significant advantage favouring tacrolimus for acute rejections rates was noted in both studies (26 vs 46% and 31 vs 46%; both p < 0.001). One of the multicentre studies (European data) showed a nonsignificant trend towards a lower rate of chronic rejection among tacrolimus recipients than cyclosporin recipients at 4 years post-transplantation (5.5 vs 11.3%). Long term (3-year) survival data from one of the trials (US data) showed similar rates of patient (≈90%) and graft (≈80%) survival for both treatment groups. In this study, approximately 25% of patients were African-American, and results in this high-risk subgroup mirrored those for all patients in each treatment group. Numerous noncomparative, retrospective or meta-analytical trials, as well as a few small-to moderate-sized randomised comparisons with cyclosporin microemulsion, have also been conducted with tacrolimus-based regimens for primary immunosuppression in adult renal transplant recipients, and results generally support those of the large multicentre studies.
Rescue therapy with tacrolimus, primarily in patients who developed acute rejection while receiving cyclosporin-based primary immunosuppression (n = 40 to 169), was associated with patient survival rates >90% and corresponding graft survival rates >70% after 1 to 3 years of follow-up after conversion. In general, results of studies with tacrolimus-based primary immunosuppressive and rescue therapy for paediatric renal transplantation have been very similar to those of studies in adult patients. In the largest study, 81 children (82 transplants) received tacrolimus-based therapy as primary immunosuppression. One-year patient and graft survival rates approached 100%, and 4-year rates were 94 and 84%, respectively. About two-thirds of patients were successfully withdrawn from corticosteroid therapy.
Heart Transplantation
In prospective studies comparing tacrolimus-with cyclosporin-based primary immunosuppressive regimens in heart transplant recipients, patient survival rates were similar between treatment groups and there was a consistent trend towards more favourable acute rejection rates with tacrolimus. One-and ≈2-year patient survival rates were ≈80 to 90% for both treatment groups, and a large non-randomised comparison also showed similar 5-year patient survival rates between tacrolimus and cyclosporin treatment groups (76 vs 71%). In a moderate-sized randomised study of 73 patients, the mean number of acute rejection episodes per patient was significantly lower among tacrolimus than cyclosporin recipients (1.33 vs 1.87; p < 0.01). A number of small studies (n < 20) of tacrolimus as rescue therapy in adults showed that at least 70% of patients had either no rejection episodes or only mild rejection after conversion from cyclosporin to tacrolimus (follow-up periods were usually at least 6 months).
Tacrolimus has had limited use in paediatric heart transplantation. Tacrolimus-based primary immunosuppression was associated with good patient survival rates in a group of 26 children (≈80% at 1 and 3 years post-transplantation). In addition, rates of moderate to severe acute rejection were lower and corticosteroid withdrawal rates were much higher than those in historical controls treated with cyclosporin-based therapy. The results of a nonrandomised study of 40 paediatric heart transplant recipients showed that the presence of 2 HLA-DR loci donor/ recipient mismatches increased the risk of high-grade rejection in children receiving cyclosporin-based therapy, whereas the risk of rejection was not increased in those receiving tacrolimus-based therapy. Tacrolimus-treated children with 2 HLA-DR mismatches had a significantly lower risk of severe rejection than cyclosporin-treated children with only 1 HLA-DR mismatch. In small studies (n < 25) of tacrolimus as rescue therapy, graft loss was not reported (follow-up periods up to 40 months) and corticosteroid dosages were reduced or discontinued in most children.
Lung Transplantation
Tacrolimus-and cyclosporin-based primary immunosuppressive regimens were associated with similar 1-(83 vs 71%) and 2-year (76 vs 66%) patient survival rates, as well as similar proportions of patients free from acute rejection (14 vs 11.5%), in a prospective randomised study of 133 lung transplant recipients. Results for all of these end-points tended to favour tacrolimus, and the trial showed a significantly lower incidence of obliterative bronchiolitis among tacrolimus than cyclosporin recipients (21.7 vs 38%; p < 0.05).
In general, the use of tacrolimus as rescue therapy in small numbers of patients with lung transplantation (n ≤15) was associated with a reduced incidence of acute rejection after conversion from cyclosporin, and at least two-thirds of patients remained alive during mean follow-up periods of approximately 6 to 18 months.
Pancreas or Kidney and Pancreas Transplantation
Numerous studies have been conducted demonstrating the efficacy of tacrolimus as primary immunosuppression after solitary pancreas transplantation or simultaneous pancreas and kidney transplantation (SPK); however, no large randomised trial has prospectively compared tacrolimus-with cyclosporin-based regimens in this clinical setting. Nevertheless, data from 2 large (n > 200) retrospective analyses indicate significantly better pancreas graft survival with tacrolimus-based therapy in patients with solitary pancreas or SPK transplantation, and patient and renal graft survival was better with tacrolimus than cyclosporin in SPK recipients. For example, a multicentre matched-pair analysis comparing tacrolimus-with cyclosporin-based therapy in SPK recipients at 18 months post-transplant showed pancreas graft survival rates of 88 versus 71%, renal graft survival rates of 94 versus 77% and patient survival rates of 97 versus 83% (p ≤0.002 for all comparisons). Results of 2 moderate-sized studies of tacrolimus as rescue therapy in SPK recipients showed patient survival rates approaching 100% and pancreas and renal graft survival rates of about 90% (follow-up period ≤1 year after conversion from cyclosporin to tacrolimus).
Intestinal Transplantation
Several reports involving small numbers of patients indicate that tacrolimus is effective in this clinical setting. Data from the International Transplant Registry (n = 170) indicate that, depending on the subgroup of intestinal transplant recipients, tacrolimus-based primary immunosuppression is associated with 1-and 3-year patient survival rates of 59 to 83% and 40 to 47%, respectively, and 1-and 3-year graft survival rates of 51 to 65% and 29 to 38%, respectively. In general, patient and graft survival rates were as good as or better than those achieved with cyclosporin-based regimens. Among cyclosporin recipients, 1-and 3-year patient survival rates were 41 to 57% and 28 to 50%, respectively, and 1-and 3-year graft survival rates were 17 to 44% and 11 to 41%, respectively.
Bone Marrow Transplantation
Three randomised comparative trials have consistently demonstrated a lower incidence of grade II to IV acute graft-versus-host disease (GVHD) with tacrolimus-than cyclosporin-based therapy after allogeneic bone marrow transplantation (BMT). However, the largest of the trials (n = 329) also showed that 2-year overall survival (57 vs 47%; p < 0.05) and disease-free survival (50 vs 41%; p = 0.01) were significantly better among cyclosporin-than tacrolimus-treated patients with haematological malignancy who received BMT from matched sibling donors. These differences were attributed primarily to patients with advanced haematological malignancy at the time of BMT. These survival data in BMT require confirmation. Tacrolimus has also been used with some success in the treatment of patients who developed acute or chronic GVHD or significant toxicity while receiving cyclosporin-based immunosuppressive therapy after BMT, but data are preliminary.
Tolerability
The principal adverse effects associated with tacrolimus treatment include nephrotoxicity, neurotoxicity, disturbances in glucose metabolism, gastrointestinal (GI) disturbance and hypertension. Susceptibility to infection and malignancy is also increased. All of these adverse effects also occur with cyclosporin, although the incidence of some adverse effects differs between the drugs (see later in this section). Tacrolimus is rarely associated with the cyclosporin-specific adverse effects hirsutism, gingivitis and gum hyperplasia, but it may cause alopecia and pruritus in some patients.
Many of the adverse effects of tacrolimus are dose-related; nephrotoxicity, neurotoxicity, glucose metabolism disturbances, GI disturbances and infections may occur more frequently or be more severe at higher whole-blood tacrolimus concentrations. Importantly, these adverse events can often be managed by dosage reductions. Concomitant drugs such as corticosteroids may also contribute to some adverse effects.
In the major trials in patients undergoing liver or kidney transplants, withdrawal rates because of adverse events tended to be higher with tacrolimus than cyclosporin. Nephrotoxicity occurred in as many as half of patients treated with either tacrolimus or cyclosporin. Neurotoxicity associated with tacrolimus most frequently manifests as tremor, headache, insomnia and paraesthesia, and some neurological effects (including tremor and paraesthesia) may be more problematic with tacrolimus than with cyclosporin.
Diabetes mellitus and/or hyperglycaemia also tended to occur more frequently with tacrolimus than with cyclosporin in the major trials in kidney or liver transplant recipients. In 2 large multicentre randomised kidney transplantation trials, the incidence of new-onset type 1 diabetes mellitus was 20 vs 4% in the US trial and 8 vs 2% in the European study. However, about one-quarter to one-third of affected tacrolimus recipients were able to discontinue insulin therapy within 1 year. Furthermore, tacrolimus has generally not been more diabetogenic than cyclosporin in cardiac transplant trials. Also, at least 1 recent study in renal transplant recipients showed a lower incidence of post-transplantation diabetes mellitus with tacrolimus than in previous reports, suggesting that, with more experience, it may be possible to reduce the risk of developing this complication. Other metabolic disturbances that can occur with tacrolimus include hyper-kalaemia and hypomagnesaemia.
A number of studies have shown that tacrolimus has less adverse effect than cyclosporin on lipid profiles and/or the general cardiovascular risk profile. In particular, significantly lower serum levels of total cholesterol, triglycerides and/or low density lipoprotein-cholesterol have been reported with tacrolimus. Hypertension occurred in up to half of patients treated with tacrolimus in major trials, but it was normally mild to moderate in severity, whereas hypertension can be more severe with cyclosporin. In cardiac transplant recipients, hypertension requiring treatment occurred more frequently with cyclosporin-than tacrolimus-based regimens.
GI disturbance, including diarrhoea, nausea and constipation, occurs commonly in patients treated with tacrolimus; diarrhoea is more frequent with tacrolimus than with cyclosporin.
Infection rates were similar in tacrolimus-and cyclosporin-treated groups in the major clinical trials in kidney or liver transplant recipients.
The tolerability profile of tacrolimus in children is generally similar to that in adults. However, children are at increased risk of potentially fatal Epstein-Barr virus-related post-transplant lymphoproliferative disorders (PTLD). The inci-dence of PTLD in paediatric liver transplant recipients may be higher with tacrolimus-than cyclosporin-based immunosuppression. From the reported ex-periences (in >10 patients) of using tacrolimus in primary liver transplantation in children, the incidence of PTLD usually ranged from 3 to 11%, although higher values have been reported. The incidence of PTLD in paediatric patients converted to tacrolimus therapy appears to be higher than that in primary therapy, but this may be associated with high cumulative dosages of immunosuppressive agents required to treat intractable rejection.
The risks of tacrolimus treatment during pregnancy appear to be no greater than those with cyclosporin, and it has been suggested that tacrolimus may be associated with a lower incidence of maternal hypertension or pre-eclampsia.
Dosage and Administration
The dosage recommendations outlined in this section focus on the use of tacrolimus in the US and UK in patients who have undergone liver or kidney transplantation. Although treatment regimens can vary between countries and individual transplantation centres, it is likely that tacrolimus is used in a similar manner for immunosuppression following other types of transplantation.
Whenever possible, tacrolimus should be initiated using the oral route of administration. For patients unable to take tacrolimus orally, therapy may be initiated by continuous intravenous infusion. In the US, the recommended intravenous starting dose is 0.03 to 0.05 mg/kg/day for adults receiving liver or kidney transplantation and for children receiving liver transplantation; no specific recommendation for paediatric kidney transplantation is provided in US prescribing information. In the UK, initial intravenous dose recommendations for adults are 0.01 to 0.05 mg/kg/day for liver and 0.05 to 0.10 mg/kg/day for kidney transplantation; corresponding recommendations for children are 0.05 mg/kg/day for liver and 0.1 mg/kg/day for kidney transplantation. Conversion from intravenous to oral therapy should occur as soon as is clinically feasible, usually within 2 to 3 days. Whether administered by the oral or intravenous route, the initial dose of tacrolimus should begin approximately 6 hours after the completion of liver transplant surgery and within 24 hours of kidney transplantation surgery.
Oral tacrolimus is administered in 2 divided daily doses at 12-hour intervals. In adults, the recommended starting oral dosage of tacrolimus as primary immunosuppression is 0.10 to 0.15 mg/kg/day (US) or 0.10 to 0.20 mg/kg/day (UK) for liver transplantation and 0.2 mg/kg/day (US) or 0.15 to 0.30 mg/kg/day (UK) for kidney transplantation. Initial recommended dosage in children receiving liver transplantation is 0.15 to 0.20 mg/kg/day (US) or 0.3 mg/kg/day (UK). In the UK, 0.3 mg/kg/day is the recommended initial dose of tacrolimus in paediatric renal transplant recipients; US prescribing information does not provide a corresponding recommendation for this patient population.
During maintenance therapy the dose of tacrolimus can often be reduced. In general, children require higher doses than adults to achieve similar blood concentrations of tacrolimus. Likewise, African-American patients typically require higher tacrolimus doses than Caucasian patients (at least in kidney transplantation) to achieve similar blood concentrations of the drug. Patients with hepatic or renal dysfunction should receive doses at the lowest value of the recommended intravenous and oral dosage ranges (and further dosage reductions may be required).
When tacrolimus is used as rescue therapy in patients not responding to (or not tolerating) cyclosporin-based therapy, treatment should begin with the same initial dosage as for primary therapy in that particular allograft (UK recommendation). Tacrolimus should not be started until approximately 24 hours after discontinuation of cyclosporin therapy.
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Various sections of the manuscript reviewed by: P.R. Atkison, Paediatric Transplant Program, Children’s Hospital of Western Ontario, London, Ontario, Canada; O. Goulet, Department of Pediatric Gastroenterology and Nutrition, Hôpital Necker-Enfants Malades, Paris, France; R.W.G. Gruessner, Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA; R. Hattori, Department of Urology, Okazaki City Hospital, Okazaki, Japan; M.L. Henry, Department of Surgery, Division of Transplantation, Ohio State University Medical Center, Columbus, Ohio, USA; A.B. Jain, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; S.C. Jensik, Rush University Transplant Program, Rush-Presbyterian-St Luke’s Medical Center, Chicago, Illinois, USA; H. Kreis, Assistance Publique Hôpitaux de Paris, Hôpital Necker, Paris, France; Ph. Lang, Service de Néphrologie et Transplantation, Hôpital Henri Mondor, Créteil, France; R. Shapiro, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; N. Yoshimura, Second Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Data Selection
Sources: Medical literature published in any language since 1997 on tacrolimus, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand) and Medline. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: AdisBase search terms were ‘Tacrolimus’ or ‘FK-506’ or ‘FR-900506’ or ‘L-679934’ and ‘Transplant’ or ‘Transplant-Rejection’. Medline search terms were ‘Tacrolimus’ or ‘FK 506’ and ‘Transplantation’ or ‘Graft-Rejection’. Searches were last updated 27 January 2000.
Selection: Studies in patients with solid organ transplantation or bone marrow transplantation who received tacrolimus. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic, pharmacokinetic and pharmacoeconomic data are also included.
Index terms: Tacrolimus, immunosuppressant, transplantation, pharmacodynamics, pharmacokinetics, drug interactions, therapeutic use, tolerability, pharmacoeconomics.
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Plosker, G.L., Foster, R.H. Tacrolimus. Drugs 59, 323–389 (2000). https://doi.org/10.2165/00003495-200059020-00021
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DOI: https://doi.org/10.2165/00003495-200059020-00021