Individualized dosage regimen of immunosuppressive drugs based on pharmacokinetic and pharmacodynamic analysis

The calcineurin inhibitors cyclosporine and tacrolimus are widely used to prevent allograft rejection after transplantation. Since these drugs have narrow therapeutic windows and show considerable pharmacokinetic variability, therapeutic drug monitoring (TDM) is essential to avoid adverse effects such as nephrotoxicity while maximizing immunosuppressive efficacy. On the other hand, some patients experience acute rejection episodes or postoperative complications despite achieving therapeutic blood drug levels. Therefore, pharmacokinetic and pharmacodynamic factors by which to establish individualized dosage adjustment for these drugs should be identified. Recently, it was recognized that pharmacogenomics has the potential to facilitate personalized medicine by translating knowledge of human genome variability into rational therapeutics. In this paper, we review the population pharmacokinetic and pharmacogenomic analysis of tacrolimus, focusing on an efflux transporter P-glycoprotein (multidrug resistance 1 [MDR1/ABCB1]) and drug-metabolizing enzymes cytochrome P450 (CYP) 3A4 and 3A5, and describe Bayesian forecasting to individualize the tacrolimus dose in de novo living-donor liver transplant recipients. Furthermore, the pharmacodynamic properties of tacrolimus and cyclosporine, which were evaluated by measuring calcineurin phosphatase activity in peripheral blood mononuclear cells, are reviewed in relation to an optimal monitoring strategy as well as a rational dosage regimen for these drugs.     

Immunosuppression for lung transplantation: evidence to date

With the introduction of ciclosporin (cyclosporine) into routine clinical practice 20 years ago, lung transplantation has become an established treatment for patients with advanced lung disease. Most lung transplant recipients routinely continue to receive a triple-drug maintenance immunosuppressive regimen consisting of a calcineurin inhibitor, an antimetabolite and corticosteroids. The use of antibody-based induction therapy remains common, although there has been a shift away from T cell-depleting agents, such as antithymocyte globulin, towards anti-interleukin-2 receptor monoclonal antibodies. Recent years have seen the introduction of sirolimus and everolimus, immunosuppressive drugs that act by blocking growth factor-driven cell proliferation. While the newer immunosuppressive drugs have been rigorously evaluated in large randomised trials in kidney, liver and cardiac transplantation, such studies are lacking in lung transplantation. Despite a shift towards more potent immunosuppressive regimens that incorporate tacrolimus and mycophenolate mofetil, the development of chronic allograft rejection, as manifested by the bronchiolitis obliterans syndrome continues to negatively impact on the long-term survival of lung transplant recipients. This article reviews the evidence for the immunosuppressive regimens used during induction and maintenance of patients undergoing lung transplantation, and discusses current strategies in the management of chronic rejection.     

Calcineurin inhibitors in pediatric renal transplant recipients

The calcineurin inhibitors, cyclosporine (ciclosporin) [microemulsion] and tacrolimus, are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. For pediatric patients, both drugs should be dosed per body surface area, and pharmacokinetic monitoring is mandatory. While monitoring of the trough levels may suffice for tacrolimus, cyclosporine therapy that utilizes the microemulsion formulation requires additional monitoring (e.g. determination of 2-hour post-dose levels).In a well designed randomized study in children, as in studies in adults, there was no difference in short-term patient and graft survival with cyclosporine microemulsion and tacrolimus. However, tacrolimus was significantly more effective than cyclosporine microemulsion in preventing acute rejection after renal transplantation when used in conjunction with azathioprine and corticosteroids. With regard to long-term outcome, the difference in acute rejection episodes resulted in a better glomerular filtration rate at 1 year after transplantation and eventually in better graft survival 4 years after renal transplantation. Whether this difference persists when calcineurin inhibitors are used in combination with mycophenolate mofetil has not been determined. The prevalence of hypomagnesemia was higher in the tacrolimus group whereas hypertrichosis and gingival hyperplasia occurred more frequently in the cyclosporine group. In contrast with adults, the incidence of post-transplantation diabetes mellitus was not significantly different between tacrolimus- and cyclosporine-treated patients. There was also no difference with regard to post-transplantation lymphoproliferative disorder. Medication costs were similar, but in view of the lower rejection episodes and better long-term graft survival as well as the more favorable cosmetic side effect profile, tacrolimus may be preferable. The recommendation drawn from the available data is that both cyclosporine and tacrolimus can be used safely and effectively in children. We recommend that cyclosporine should be chosen when patients experience tacrolimus-related adverse events.     

A case of acquired aplastic anemia with repeated cerebral infarctions at the beginning of immunosuppressive therapy

Acquired aplastic anemia is a rare hematopoietic stem-cell disorder that results in pancytopenia and hypocellular bone marrow. The pathophysiology is immune mediated in most cases, with activated type 1 cytotoxic T cells implicated. Acquired aplastic anemia can now be cured or ameliorated by stem-cell transplantation or immunosuppressive drug therapy such as antithymocyte globulin or cyclosporine. We present a rare case report of a 68-year old patient with acquired severe aplastic anemia with repeated cerebral infarctions at the beginning of immunosuppressive therapy. He started immunosuppressive drug therapy with antithymocyte globulin and cyclosporine. During follow-up, magnetic resonance imaging revealed high signals at right thalamus and right pons by diffusion-weighted image. He was diagnosed with repeated cerebral infarctions of right thalamus and right pons. We successfully managed cerebral infarctions by frequent transfusions, edaravone administration, keeping the trough of serum cyclosporine (CsA) concentration around lower limit. This is the first report of successful management of acquired aplastic anemia with repeated cerebral infarctions.     

Therapy for acute rejection in pediatric organ transplant recipients

Despite the availability of potent immunosuppressive drugs, rejection after organ transplantation in children remains a serious concern, and may lead to significant morbidity, graft loss, and death of the patient. Acute graft rejection in pediatric recipients is first treated with methylprednisolone pulses, followed by progressive taper of corticosteroid doses. After control of the rejection episode, baseline immunosuppression has to be adjusted and closely monitored since rejection (especially late episodes, occurring more than 6 months after transplantation) may be due to a lack of compliance or sub-therapeutic drug concentrations. The management of corticosteroid resistant rejection is not standardized, and depends on the transplanted organ and previous immunosuppressive regimen. In patients experiencing corticosteroid resistant acute rejection while on a cyclosporine-based immunosuppressive regimen, cyclosporine is generally changed to tacrolimus. In case of tacrolimus-based immunosuppression, tacrolimus blood levels may be increased, and/or mycophenolate mofetil (which nowadays tends to replace azathioprine) or sirolimus may be added, although pharmacodynamic data and clinical studies with these agents are still scarce in pediatric recipients. The use of antithymocyte globulins or monoclonal anti-CD3 antibodies, muromonab CD3 (OKT3) is hampered by numerous adverse effects, including a significant risk of over-immunosuppression. These therapies are nowadays indicated in very selected cases. Other treatments such as plasmapheresis and high dose immunoglobulins may be useful in difficult cases. In patients with refractory rejection despite therapeutic escalation, the risks of over-immunosuppression, including opportunistic infections and malignancies (especially the Epstein-Barr virus related post-transplant lymphoproliferative disease) have to be balanced with the consequences of graft loss due to rejection. Detransplantation or retransplantation may, in some instances, be preferable to severe infectious or tumoral complications.     

Hypogammaglobulinemia after heart transplantation: use of intravenous immunoglobulin replacement therapy in relapsing CMV disease

Secondary hypogammaglobulinemia after heart transplantation may follow immunosuppressive therapy with the resultant increased risk of infections, including cytomegalovirus (CMV) disease. There is limited information on the use of intravenous immunoglobulin replacement therapy (IVIG) in heart-transplanted patients with hypogammaglobulinemia and CMV disease. We present data on five consecutive heart-transplanted patients with relapsing CMV disease, four of whom developed gastrointestinal disease. The immunosuppressive regimen included prednisone, cyclosporine A, azathioprine, mycophenolate mofetil, tacrolimus and antithymocyte globulin (ATG). Evaluation revealed CMV antigenemia. All the patients had been treated with intravenous ganciclovir. In addition, hyperimmune CMV immunoglobulin was administered in three patients. Significantly reduced levels of immunoglobulin G (IgG) were observed in the patients as compared with 15 heart-transplanted individuals without CMV disease [mean IgG levels: 323+/-18 and 639+/-63 mg/dl, respectively (p=0.003)]. IVIG [FLEBOGAMMA], 200-400 mg/kg every 21 days with the goal of maintaining normal serum IgG levels, was added for the treatment of CMV disease. Selected batches with the highest anti-CMV titers were set apart for the treatment of the patients. IVIG treatment, in combination with antiviral therapy, proved able to control CMV disease. There was a favorable clinical response and the patients became free of gastrointestinal symptoms. Detection of CMV antigens was negative after treatment. During IVIG therapy no immediate or delayed adverse effects were observed. Even if our survey was limited to five cases, the results suggest that addition of IVIG to antiviral chemotherapy might improve outcome in heart-transplanted patients with hypogammaglobulinemia and CMV disease.     

环孢素A与他克莫司应用于肝移植受者的药物经济学评价

目的评价环孢素A胶囊与他克莫司胶囊治疗肝移植受体排斥的经济性。方法选择在我院接受肝移植,并于2010年1月-2011年12月在门诊继续治疗的患者共60例,比较用药半年后的临床疗效、不良反应及用药成本,运用药物经济学的最小成本分析法对两种药物的经济效果进行评价。结果环孢素A胶囊组总有效率为78%,他克莫司胶囊组为86%,两组比较差异无统计学意义(P>0.05),环孢素A胶囊组的不良反应发生率较他克莫司胶囊组低。成本/效果比(C/E):环孢素A胶囊组为55.81,他克莫司胶囊组为46.19。结论与环孢素A胶囊比较,他克莫司胶囊用于肝移植受者更为经济有效。     

Rabbit antithymocyte globulin induction therapy in adult renal transplantation

Rabbit antithymocyte globulin (rATG) and horse antithymocyte globulin (horse ATG) are the polyclonal antithymocyte agents available for use in solid organ transplantation in the United States. Horse ATG is indicated for induction immunosuppression and for treatment of acute rejection episodes after kidney transplantation; rATG is indicated for treatment of acute rejection only. However, rATG is commonly used in clinical practice as an induction immunosuppressive agent, instigating many questions regarding appropriate dosing, tolerability, safety, and efficacy. Available evidence supports the use of rATG as an induction agent in adult renal transplant recipients. The use of this product for induction therapy has been studied in conjunction with a full-dose, triple-therapy maintenance regimen (sequential quadruple immunosuppression) consisting of a calcineurin inhibitor, an antimetabolite, and corticosteroids. Rabbit ATG has a proven safety and efficacy profile both as treatment of acute rejection and as induction therapy in patients undergoing kidney transplantation. The most common adverse events associated with rATG are cytokine release syndrome, thrombocytopenia, and lymphopenia. Results of early studies showed an increased rate of cytomegalovirus disease associated with rATG treatment, but recent studies indicate that routine administration of modern antiviral prophylaxis can reduce this risk. Current practice with rATG is evolving to minimize lifelong exposure to calcineurin inhibitors and corticosteroids.     

Tacrolimus toxicity associated with concomitant metoclopramide therapy

Subtherapeutic tacrolimus trough concentrations were noted in a 52-year-old woman who had undergone liver transplantation. Her tacrolimus dosage was increased from 7 to 28 mg twice/day, and ketoconazole therapy was added; however, her tacrolimus concentration remained undetectable. Metoclopramide 10 mg 4 times/day was begun to control the patient's new-onset nausea and vomiting. Within 48 hours of increasing the dosage to 20 mg 4 times/day, her tacrolimus trough concentration exceeded 30 ng/ml. Signs and symptoms were suggestive of tacrolimus nephrotoxicity and neurotoxicity. According to the Naranjo scale, this adverse drug event was probably the result of improved absorption of tacrolimus secondary to metoclopramide therapy. The patient's subtherapeutic tacrolimus concentration at baseline was probably secondary to poor absorption due to impaired gastric emptying. Coadministration of metoclopramide significantly improved gastric motility and delivery of tacrolimus to the small intestine, increasing tacrolimus bioavailability, thus resulting in acute-onset tacrolimus toxicity. When tacrolimus is administered with metoclopramide in patients with gastric dysmotility, tacrolimus concentrations should be monitored closely to minimize the risk of toxicity.     

The role of tacrolimus in renal transplantation

Tacrolimus gained FDA approval for use in liver transplantation in 1994 and, approximately 3 years later, was approved for the prevention of acute rejection in kidney transplantation. Over the last decade tacrolimus has become the calcineurin inhibitor of choice for the prevention of rejection in renal transplantation. The objective of this study was to provide a review and update of the literature on the use of tacrolimus in renal transplantation. Numerous clinical trials have shown tacrolimus to be superior to cyclosporine in the prevention of acute rejection and recent trials have demonstrated superiority of tacrolimus over cyclosporine in terms of allograft survival. Post-transplant diabetes remains more common with tacrolimus than cyclosporine, despite lower doses of both tacrolimus and corticosteroids. A novel once-daily dosage form of tacrolimus has recently been developed and is approved for use in Europe. Tacrolimus remains an important immunosuppressant for the prevention of acute rejection. The prolonged-release formulation may improve compliance and possibly long-term outcomes.     

Everolimus: a proliferation signal inhibitor targeting primary causes of allograft dysfunction

Allograft dysfunction remains a major problem for long-term graft survival after kidney and heart transplantation. Current immunosuppressive regimens do not completely address the causes of allograft dysfunction which include acute rejection episodes, complications of immunodeficiency (for example, cytomegalovirus infection), nephrotoxicity from calcineurin inhibitors (cyclosporine and tacrolimus) and vascular remodeling and vasculopathy. Everolimus is a potent immunosuppressor that inhibits growth factor-stimulated proliferation of hematopoietic and nonhematopoietic cells, including vascular smooth muscle. Everolimus is indicated for the prophylaxis of acute rejection in kidney and heart transplant patients in a combined regimen with cyclosporine microemulsion and corticosteroids. Everolimus is formulated as both a tablet and a tablet for oral solution. It is rapidly absorbed and displays dose-proportional, stable pharmacokinetics. Everolimus has equivalent efficacy to mycophenolate mofetil in reducing the incidence of acute rejection after renal transplantation and superior efficacy to azathioprine after heart transplantation. Combination of everolimus with cyclosporine allows dose-reduction of cyclosporine while maintaining efficacy due to the synergistic immunosuppressive effects of the combination. Everolimus reduces intimal thickening of blood vessels to the graft and the incidence of allograft vasculopathy in heart transplantation. In both kidney and heart transplantation, the incidence of cytomegalovirus infection was lower in everolimus-treated patients compared with patients receiving the control treatment. Everolimus-related adverse events include elevated cholesterol and triglycerides, which respond to treatment, and decreased platelet count, which is transient. Nephrotoxicity may result from the combination of everolimus with full-dose cyclosporine but is mitigated by reducing the dose of cyclosporine. Everolimus is initiated at 0.75 mg b.i.d. with dose adjustments guided by therapeutic drug monitoring of predose blood levels. In clinical development trials, everolimus has demonstrated the ability to reduce the incidence of acute rejection episodes, cytomegalovirus infection and cardiac vasculopathy, thus addressing the primary causes of allograft dysfunction.     

他克莫司诱发移植后新发糖尿病高于环孢素A的机制研究进展

目的:综述近年来国内外学者对环孢素A和他克莫司诱发移植后新发糖尿病的机制研究,为临床合理用药提供依据。方法:检索国内外相关文献,进行整理和综合分析。结果:NODAT(new-onset diabetes after transplantation)即移植后新发糖尿病,也称PTDM(post-transplant diabetes mellitus),是器官移植患者常见、严重的并发症。NODAT发病的危险因素包括年龄、性别、高剂量类固醇、体重指数、家族史和免疫抑制剂,其中免疫抑制剂的使用是发病的高危因素。环孢素A和他克莫司是两种主要的免疫抑制剂,应用免疫抑制剂可以减少移植后急性排斥反应的发生率,提高患者的生存率,但使用免疫抑制剂会诱发NODAT,他克莫司导致NODAT发生率高于环孢素A,具体机制目前尚无定论。结论:临床医生可以根据他克莫司导致NODAT发生率高于环孢素A的机制,制定合理的给药方案。     

Exenatide

The immunosuppressive drugs used in organ transplantation have a narrow therapeutic index, with rejection occurring as a consequence of underdosing and infection, malignancy and a number of drug-specific side effects with excessive dosing. Significant heterogeneity in the dose of drug required to achieve therapeutic blood concentrations adds to the complexity of the problem, which has been partly resolved by therapeutic drug monitoring. Single nucleotide polymorphisms have been identified in genes encoding metabolic enzymes, drug efflux pumps and drug targets for most of the drugs in widespread use. A pharmacogenetic approach to immunosuppressive drug prescribing remains to be tested. Based on current evidence, the most promising strategy would be use of the cytochrome P450 3A5 expresser genotype to guide initial dosing with tacrolimus.     

Pharmacogenetics in transplant patients: can it predict pharmacokinetics and pharmacodynamics?

Pharmacogenetics holds the potential to allow individualized dosing of immunosuppressive agents to optimize their therapeutic effect while minimizing adverse effects. As more pharmacogenetic information accumulates, the prospect of reducing or discontinuing the intensive therapeutic drug monitoring of immunosuppressants looks attractive. However, the long process of developing useful clinical information from basic information on the genes of interest is at a very early stage, and our present information does not supercede pharmacokinetic or blood concentration monitoring of immunosuppressants. The most extensive blood concentration/dose information available is on tacrolimus and its dosing related to CYP3A5 and ABCB1 gene polymorphisms. Although CYP3A5 genotype is definitely associated with tacrolimus dosing, the only recommendation presently published is for an arbitrary doubling of the starting tacrolimus dose in CYP3A5 expressors. For cyclosporine, sirolimus, and corticosteroids, the presently available pharmacogenetic information does not permit pharmacokinetic predictions. The pharmacodynamics of immunosuppressants, as evidenced by effects on acute rejection or adverse drug effects, have considerably more potential for prediction by pharmacogenetic models. Drug-resistant rejection, nephrotoxicity, steroid resistance and osteonecrosis, and even patient survival may ultimately be predicted by models incorporating multiple gene polymorphisms and other critical patient information. At this point, treatment algorithms can be developed that will allow us to individualize a transplant patient's immunosuppressive therapy.     

Does pharmacogenetics have the potential to allow the individualisation of immunosuppressive drug dosing in organ transplantation?

The immunosuppressive drugs used in organ transplantation have a narrow therapeutic index, with rejection occurring as a consequence of underdosing and infection, malignancy and a number of drug-specific side effects with excessive dosing. Significant heterogeneity in the dose of drug required to achieve therapeutic blood concentrations adds to the complexity of the problem, which has been partly resolved by therapeutic drug monitoring. Single nucleotide polymorphisms have been identified in genes encoding metabolic enzymes, drug efflux pumps and drug targets for most of the drugs in widespread use. A pharmacogenetic approach to immunosuppressive drug prescribing remains to be tested. Based on current evidence, the most promising strategy would be use of the cytochrome P450 3A5 expressor genotype to guide initial dosing with tacrolimus.     

新型免疫抑制剂构效关系的研究进展

自从1986年环孢菌素首次用于控制器官移植中的免疫排斥反应以来,多种新型免疫抑制剂相继进入临床实践.与环孢菌素相比,这些新型免疫抑制药物的疗效卓著、不良反应较小.其中,他克莫司、西罗莫司、FTY720和15-脱氧精胍菌素的应用更为广泛.从作用机制、构效关系和不良反应对这几种新型免疫抑制剂在控制器官移植排斥反应研究领域的最新进展进行了较为详细的介绍.     

Basiliximab: a review of its use as induction therapy in renal transplantation

Basiliximab (Simulect), a chimeric (human/murine) monoclonal antibody, is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents.Basiliximab significantly reduced acute rejection compared with placebo in renal transplant recipients receiving dual- (cyclosporin microemulsion and corticosteroids) or triple-immunotherapy (azathioprine- or mycophenolate mofetil-based); graft and patient survival rates at 12 months were similar. Significantly more basiliximab than placebo recipients were free from the combined endpoint of death, graft loss or acute rejection 3 years, but not 5 years, after transplantation.The incidence of adverse events was similar in basiliximab and placebo recipients, with no increase in the incidence of infection, including cytomegalovirus (CMV) infection. Malignancies or post-transplant lymphoproliferative disorders after treatment with basiliximab were rare, with a similar incidence to that seen with placebo at 12 months or 5 years post-transplantation. Rare cases of hypersensitivity reactions to basiliximab have been reported.The efficacy of basiliximab was similar to that of equine antithymocyte globulin (ATG) and daclizumab, and similar to or greater than that of muromonab CD3. Basiliximab was as effective as rabbit antithymocyte globulin (RATG) in patients at relatively low risk of acute rejection, but less effective in high-risk patients. Numerically or significantly fewer patients receiving basiliximab experienced adverse events considered to be related to the study drug than ATG or RATG recipients. The incidence of infection, including CMV infection, was similar with basiliximab and ATG or RATG.Basiliximab plus baseline immunosuppression resulted in no significant differences in acute rejection rates compared with baseline immunosuppression with or without ATG or antilymphocyte globulin in retrospective analyses conducted for small numbers of paediatric patients. Limited data from paediatric renal transplant recipients suggest a similar tolerability profile to that in adults. Basiliximab appears to allow the withdrawal of corticosteroids or the use of corticosteroid-free or calcineurin inhibitor-sparing regimens in renal transplant recipients.Basiliximab did not increase the overall costs of therapy in pharmacoeconomic studies.CONCLUSION: Basiliximab reduces acute rejection without increasing the incidence of adverse events, including infection and malignancy, in renal transplant recipients when combined with standard dual- or triple-immunotherapy. The overall incidence of death, graft loss or acute rejection was significantly reduced at 3 years; there was no significant difference for this endpoint 5 years after transplantation. Malignancy was not increased at 5 years. The overall efficacy, tolerability, ease of administration and cost effectiveness of basiliximab make it an attractive option for the prophylaxis of acute renal transplant rejection.     

Cyclosporine

Cyclosporine is an immunosuppressant used to prevent the rejection of transplanted kidneys, hearts, and livers. Cyclosporine suppresses T-lymphocyte function without causing myelosuppression, and its pharmacokinetics are highly variable. Compared with conventional immunosuppressive drug therapy, both patient and graft survival improved in patients treated with cyclosporine. Patients treated with cyclosporine also had less complicated hospital courses than patients receiving conventional immunosuppressants. The adverse effects from cyclosporine are reversible but include nephrotoxicity, hepatotoxicity, malignancies, hirsutism, and minor neurologic complications. Intravenous cyclosporine doses range from 2-9 mg/kg/d and oral doses range from 10-50 mg/kg/d; the dosage should be individualized based on the clinical status of the patient as well as blood concentrations of the drug. Monitoring cyclosporine blood concentrations is necessary in the postoperative management of transplant patients. Cyclosporine has contributed to the improved success of transplantation and the recognition of transplantation as a new therapeutic option for several diseases.     

The tolerability of newer immunosuppressive medications in a patient with acute intermittent porphyria

Acute intermittent porphyria results from a deficiency of the porphobilinogen deaminase enzyme of heme biosynthesis and is commonly exacerbated by a wide variety of medications. When referred a patient with acute intermittent porphyria for a renal transplant, only steroids and azathioprine were discovered as safe in patients with acute intermittent porphyria. The administration of many newer immunosuppressive medications, including calcineurin inhibitors, has not been documented in acute intermittent porphyria. Actually, cyclosporine is presently considered contraindicated in acute intermittent porphyria. To determine if calcineurin inhibitors would be tolerated in acute intermittent porphyria, cyclosporine and tacrolimus were administered pretransplant and were documented not to exacerbate acute intermittent porphyria. A successful renal transplant was then performed using tacrolimus. This is the first reported patient with documented acute intermittent porphyria to tolerate safely several of the newer immunosuppressive medications, including tacrolimus, mycophenolate, and rabbit antithymocytic globulin following renal transplantation. This patient's pretransplant evaluation also suggested that cyclosporine may be safe for some patients with acute intermittent porphyria.     

Pharmacodynamic monitoring of calcineurin phosphatase activity in transplant patients treated with calcineurin inhibitors

Calcineurin inhibitors, tacrolimus and cyclosporine, have been widely used to prevent the rejection or graft-versus-host disease after transplantations. Since these drugs have a narrow therapeutic range and show large inter- and intraindividual pharmacokinetic variability, frequent therapeutic drug monitoring is required to control their blood concentrations. Even with blood concentrations within the therapeutic range, some patients still experience acute rejection or infections. Tacrolimus and cyclosporine form a complex with their respective binding proteins, immunophilins, which in turn inhibit the phosphatase activity of calcineurin, a key enzyme in the activation of T lymphocytes. Pharmacodynamic assessment of calcineurin phosphatase activity in combination with the monitoring of blood concentrations has been studied. The inhibitory effects on calcineurin activity in peripheral blood mononuclear cells differed between tacrolimus and cyclosporine in transplant patients. The pharmacodynamics of both drugs shows great inter- as well as intraindividual variation, and acute rejection was associated with calcineurin activity. Calcineurin activity at trough time points was suggested as a single surrogate predictor for overall calcineurin activity throughout dosing periods. Monitoring of calcineurin phosphatase activity might be useful to determine the therapeutic range of tacrolimus and cyclosporine concentrations for an individual patient treated with a calcineurin inhibitor.