Tacrolimus once-daily formulation: in the prophylaxis of transplant rejection in renal or liver allograft recipients

Tacrolimus once-daily (OD) is a new oral formulation of the well established immunosuppressant tacrolimus. Tacrolimus OD provided equivalent steady-state systemic tacrolimus exposure to that achieved with standard oral tacrolimus twice daily in stable renal and liver transplant recipients. The two formulations also provided broadly similar steady-state systemic exposure in de novo renal and liver transplant recipients. In a large, randomised, nonblind, multicentre, three-armed, noninferiority trial in de novo renal transplant recipients, the efficacy failure rates (primary endpoint) [any patient who died, experienced graft failure, had a biopsy-confirmed acute rejection or was lost to follow-up] of tacrolimus OD (14.0%) and standard tacrolimus (15.1%) were noninferior to that of ciclosporin (cyclosporine) microemulsion (17.0%) at 1 year, when each was given in conjunction with corticosteroids, mycophenolate mofetil and basiliximab induction. Data from a pharmacokinetic study suggests that tacrolimus OD has similar efficacy to standard tacrolimus in de novo liver transplant recipients over 6 weeks of treatment. In noncomparative 2-year trials, tacrolimus OD was effective in stable renal and liver transplant recipients converted to tacrolimus OD from standard tacrolimus. The overall tolerability profile of tacrolimus OD appears to be similar to that of standard tacrolimus in de novo and stable renal and liver transplant patients.     

First clinical experience with the new once-daily formulation of tacrolimus

Once-daily tacrolimus is a new oral formulation of the established immunosuppressive agent tacrolimus (Prograf, Astellas Pharma US, Inc., Deerfield, IL), which is administered twice daily. It has been approved in the European Union for prophylaxis of rejection in liver and kidney transplant recipients, where it is registered as Advagraf, and in Canada for the prophylaxis of rejection in kidney transplant recipients, and is currently under review in the United States and Japan. Studies with once-daily tacrolimus have been performed in de novo kidney and liver transplant recipients, and conversion studies have been performed in stable adult kidney and liver transplant recipients and stable pediatric liver transplant recipients, who were converted on an mg:mg basis from twice-daily tacrolimus to a single morning dose of the new formulation. Results of these studies have established the safety and efficacy of this once-daily dosing alternative. Therapeutic regimens for transplant recipients are often complex, contributing to a high incidence of medication noncompliance and its consequences of increased mortality and morbidity. The tacrolimus once-daily regimen may improve compliance while enabling the use of the same patient care strategies, total daily dose, target trough concentrations, and therapeutic monitoring techniques as currently used with the twice-a-day formulation of tacrolimus.     

Immunotherapy for De Novo renal transplantation: what's in the pipeline?

Immunosuppressive drugs have been traditionally developed to prevent acute rejection and to improve short-term kidney transplant outcomes. There is still a medical need to improve outcomes among subgroups of patients at higher risk for graft loss and to reduce cardiovascular, infectious and malignancy-associated morbidity and mortality, and improve long-term adherence. Several new immunosuppressive agents and formulations are undergoing clinical investigation and are discussed in this review.A modified release tacrolimus formulation (MR4) for once-daily administration is undergoing phase III trials. It has been developed to be administered de novo or for maintenance using the same therapeutic target tacrolimus trough concentrations as for the original formulation.Belatacept (LEA29Y), a second generation cytotoxic-T-lymphocyte-associated antigen immunoglobulin (CTLA4-Ig), blocks the interaction between CD80/86 and CD28 costimulatory pathways. In phase II trials, belatacept was as effective as ciclosporin (cyclosporine) when administered in combination with basiliximab, mycophenolate mofetil (MMF) and corticosteroids. Currently, belatacept is undergoing phase III trials including one study in recipients of organs from expanded criteria donors.Inhibitors of the Janus protein tyrosine kinase (JAK)-3 show some selectivity for cells of the lymphoid lineage and have been shown to be effective in late preclinical transplant models. The most frequent adverse effects have been related to nonspecific binding to JAK2 kinases. CP-690550, a JAK3 inhibitor is currently in phase II clinical trials.FK778, is a synthetic malononitrilamide that targets the critical enzyme of the de novo pyrimidine synthesis, dihydroorotic acid dehydrogenase, and receptor-associated tyrosine kinases has completed phase II trials. FK778 also shows antiviral activities that have been tested in patients with polyomavirus nephropathy.Fingolimod (FTY720), a synthetic sphingosine phosphate receptor modulator that reduces the recirculation of lymphocytes to blood and peripheral tissues including inflammatory lesions and graft sites is undergoing phase III trials. Although the efficacy of fingolimod is similar to MMF in patients receiving full doses of ciclosporin, safety issues such as a negative chronotropic effect, macular oedema, pulmonary adverse reactions and graft function resulted in premature discontinuation of the development programme for kidney transplantation. Because there was no clear clinical benefit over treatment options, the clinical development programme of FK778 was discontinued.Finally, a new evolving strategy with powerful induction-induced prolonged T-cell depletion followed by low-dose immunosuppressive monotherapy is showing promising results.     

Tacrolimus: a further update of its use in the management of organ transplantation

Extensive clinical use has confirmed that tacrolimus (Prograf) is a key option for immunosuppression after transplantation. In large, prospective, randomised, multicentre trials in adults and children receiving solid organ transplants, tacrolimus was at least as effective or provided better efficacy than cyclosporin microemulsion in terms of patient and graft survival, treatment failure rates and the incidence of biopsy-proven acute and corticosteroid-resistant rejection episodes. Notably, the lower incidence of rejection episodes after renal transplantation in tacrolimus recipients was reflected in improved cost effectiveness. In bone marrow transplant (BMT) recipients, the incidence of tacrolimus grade II-IV graft-versus-host disease was significantly lower with tacrolimus than cyclosporin treatment. Efficacy was maintained in renal and liver transplant recipients after total withdrawal of corticosteroid therapy from tacrolimus-based immunosuppression, with the incidence of acute rejection episodes at up to 2 years' follow-up being similar with or without corticosteroids. Tacrolimus provided effective rescue therapy in transplant recipients with persistent acute or chronic allograft rejection or drug-related toxicity associated with cyclosporin treatment. Typically, conversion to tacrolimus reversed rejection episodes and/or improved the tolerability profile, particularly in terms of reduced hyperlipidaemia. In lung transplant recipients with obliterative bronchiolitis, conversion to tacrolimus reduced the decline in and/or improved lung function in terms of forced expiratory volume in 1 second. Tolerability issues may be a factor when choosing a calcineurin inhibitor. Cyclosporin tends to be associated with a higher incidence of significant hypertension, hyperlipidaemia, hirsutism, gingivitis and gum hyperplasia, whereas the incidence of some types of neurotoxicity, disturbances in glucose metabolism, diarrhoea, pruritus and alopecia may be higher with tacrolimus treatment. Renal function, as assessed by serum creatinine levels and glomerular filtration rates, was better in tacrolimus than cyclosporin recipients at up to 5 years' follow-up. CONCLUSION: Recent well designed trials have consolidated the place of tacrolimus as an important choice for primary immunosuppression in solid organ transplantation and in BMT. Notably, in adults and children receiving transplants, tacrolimus-based primary immunosuppression was at least as effective or provided better efficacy than cyclosporin microemulsion treatment in terms of patient and graft survival, treatment failure and the incidence of acute and corticosteroid-resistant rejection episodes. The reduced incidence of rejection episodes in renal transplant recipients receiving tacrolimus translated into a better cost effectiveness relative to cyclosporin microemulsion treatment. The optimal immunosuppression regimen is ultimately dependent on balancing such factors as the efficacy of the individual drugs, their tolerability, potential for drug interactions and pharmacoeconomic issues.     

Cloned enzyme donor immunoassay tacrolimus assay compared with high-performance liquid chromatography-tandem mass spectrometry and microparticle enzyme immunoassay in liver and renal transplant recipients

The immunosuppressant drug tacrolimus has a narrow therapeutic index and is subject to a large variation in individual bioavailability and clearance. With its narrow therapeutic index, therapeutic drug monitoring is standard clinical practice in the management of transplant recipients. In this study, we report the evaluation of the cloned enzyme donor immunoassay (CEDIA) for the determination of whole-blood tacrolimus concentrations compared with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and microparticle enzyme immunoassay (MEIA) using samples obtained from liver (n = 100) and renal (n = 88) transplant recipients. Linear regression analysis showed a relationship of CEDIA = 1.24 HPLC-MS/MS -0.18 (r = 0.81). The mean bias (+/-SEM) for all patients when compared with HPLC-MS/MS was 22.2% (+/-2.1%). The precision of the CEDIA method for all samples showed a root mean square error of 3.1 microg/L. Liver transplant recipient samples showed a mean (+/-SEM) bias compared with HPLC-MS/MS of 12.5% (+/-1.6%). The precision of the CEDIA method for these samples showed a root mean square error of 1.5 microg/L. The data suggest that in the renal transplant group, the CEDIA and MEIA methods have a bias of 33.3% and 20.1%, respectively, compared with HPLC-MS/MS. The CEDIA tacrolimus immunoassay has been shown to be a rapid method for the determination of whole-blood tacrolimus concentrations and may be considered when HPLC-MS/MS is not available. When used in the clinical setting with other parameters, it would be a useful adjunct in the management of liver transplant recipients, but a significant bias in renal transplant patients needs to be further investigated.     

Fabrication and Evaluation of Bi-layer Tablet Containing Conventional Paracetamol and Modified Release Diclofenac Sodium

The objectives of present investigation were to achieve immediate release of paracetamol and tailored release of diclofenac sodium from bi-layer tablets. A 2³ full factorial design was adopted using the amount of polyethylene glycol, microcrystalline cellulose and crospovidone as independent variables for fabricating paracetamol tablets. Diclofenac sodium tablets were prepared using hydroxypropyl methylcellulose as a matrixing agent. The results of analysis of variance showed that the friability of paracetamol was distinctly influenced by the formulation variables. The in vitro drug release behaviour of diclofenac tablets was compared with a marketed formulation. The optimized formulations of paracetamol and diclofenac sodium were used for manufacturing of bi-layer tablets. The bi-layer tablets showed immediate release of paracetamol and modified release of diclofenac.     

Pharmacokinetics of tacrolimus converted from twice-daily formulation to once-daily formulation in Chinese stable liver transplant recipients

Aim:

To evaluate the pharmacokinetics of tacrolimus in Chinese stable liver transplant recipients converted from immediate release (IR) tacrolimus-based immunosuppression to modified release (MR) tacrolimus-based immunosuppression.

Methods:

Open-label, multi-center study with a one-way conversion design was conducted. Eighty-three stable liver recipients (6–24 months post-transplant) with normal renal and stable hepatic function were converted from IR tacrolimus twice-daily treatment to MR tacrolimus once-daily treatment on a 1:1 (mg: mg) total daily dose basis. Twenty-four hour pharmacokinetic studies were carried out on d 0 (pre-conversion), d 1, and d 84 (post-conversion).

Results:

The area under the blood concentration–time curve of MR tacrolimus from 0 to 24 h (AUC_0–24) on d 1 was comparable to that of IR tacrolimus on d 0, with a 90% confidence interval (CI) for MR/IR tacrolimus of 92%–97%. The AUC_0–24 value for MR tacrolimus on d 84 with the daily dose increased by 14% was approximately 17% lower than that for IR tacrolimus. The 90% CI was 77%–90%, outside the bioequivalence range of 80%–125%. There was a good correlation between AUC_0–24 and concentration at 24 h (C₂₄) for IR tacrolimus (d 0, r=0.930) and MR tacrolimus (d 1, r=0.936; d 84, r=0.903).

Conclusion:

The exposure to tacrolimus when administered MR tacrolimus once daily is not equivalent to that for IR tacrolimus twice daily after an 84-day conversion in Chinese stable liver transplant recipients. The dose should be adjusted on the basis of trough levels. The therapeutic drug monitoring for patients treated with IR tacrolimus is considered to be applicable to MR tacrolimus.     

Fabrication and Use of Poly(d,l-lactide-co-glycolide)-Based Formulations Designed for Modified Release of 5-Fluorouracil

5-fluorouracil (5-FU) is a chemotherapeutic agent that has been used for the treatment of a variety of malignancies since its initial introduction to the clinic in 1957. Owing to its short biological half-life, multiple dosings are generally required to maintain effective 5-FU plasma concentrations throughout the therapeutic period. Clinical studies have shown that continuous 5-FU administration is generally superior to bolus injection as exhibited by lower toxicities and increased therapeutic efficacy. Optimal therapeutic efficacy, however, is often compromised by the limiting therapeutic index. Whilst oral formulations are also used, these suffer from the drawbacks of variable bioavailability and first-pass metabolism. As a result, sustained release formulations of 5-FU have been investigated in an effort to mimic the kinetics of continuous infusion particularly for situations where local delivery is considered appropriate. The biocompatible, biodegradable, and highly tunable synthetic polymer, poly(d,l-lactide-co-glycolide) (PLGA), is widely used as a vector for sustained drug delivery, however, issues such as insufficient loading and inappropriate burst release kinetics have dogged progress into the clinic for small hydrophilic drugs such as 5-FU. This review provides introductory information about the mechanism of action, pharmacokinetic and physicochemical properties, and clinical use of 5-FU that have contributed to the development of PLGA-based 5-FU release platforms. In addition, this review provides information on fabrication methods used for a range of 5-FU-loaded PLGA formulations and discusses factors affecting the release kinetics of 5-FU as well as the in vitro and in vivo antitumor or antiproliferative efficacy of these platforms.     

Tacrolimus: in heart transplant recipients

Tacrolimus is a calcineurin inhibitor recently approved in the US and throughout the EU for the prevention of allograft rejection in heart transplant recipients. It is commonly administered orally for long-term immunosuppression. The incidence of mild to severe acute rejection in the first 6 months following heart transplantation was significantly lower in tacrolimus recipients than in ciclosporin recipients (54% vs 66%) in a large, phase III trial conducted in Europe. A large, phase III trial conducted in the US did not show a significant difference between tacrolimus and ciclosporin in the incidence of severe rejection or haemodynamic compromise rejection requiring treatment within the first 6 months post-transplant (22% vs 32%), but did show a significant difference in the incidence at 1 year (23% vs 37%). In phase III trials, 1-year patient survival was similar between tacrolimus and ciclosporin recipients in the EU (93% vs 92%) and the US (95% vs 90%). Tacrolimus was shown to be effective in the prevention of rejection in paediatric and African American heart transplant recipients. The tolerability profile of tacrolimus in heart transplant recipients was broadly similar to that of ciclosporin, although tacrolimus was usually associated with lower incidences of post-transplant hypertension and dyslipidaemia.     

Treating erectile dysfunction in renal transplant recipients

Erectile dysfunction is common in male kidney transplant recipients. Interference with the physiology of erections can be attributed to recipient co-morbidities, the renal transplant operation, medication adverse effects, relationship problems and changes in mental health. A treatment-oriented evaluation of erectile dysfunction allows the development of treatment plans that are patient-specific. Hypo-gonadal men whose hormone parameters do not improve after renal transplantation may respond to testosterone replacement therapy. Use of recommended doses of the phosphodiesterase-5 inhibitor sildenafil does not significantly modify trough concentrations of the calcineurin inhibitors ciclosporin and tacrolimus or result in impaired renal allograft function. Tacrolimus has been shown to increase the peak concentration and prolong the elimination half-life of sildenafil in kidney transplant recipients. Daily administration of sildenafil has resulted in decreased blood pressure in kidney transplant recipients with treated hypertension and tacrolimus immunosuppression. Intracavernosal injections of alprostadil, with or without papaverine and phentolamine, are effective treatments for erectile dysfunction after renal transplantation and have not resulted in alterations of ciclosporin concentrations or in deterioration of renal function. Penile prostheses can be successfully implanted after pelvic organ transplantation without significant risk of infection.     

Generic maintenance immunosuppression in solid organ transplant recipients

Survival after solid organ transplantation has increased in the era of tacrolimus and mycophenolate. This increased survival could be due in part to the broad clinical use of these potent and specific agents for maintenance immunosuppression. These drugs have enhanced specificity and potency for T and B lymphocytes compared with their predecessors, cyclosporine and azathioprine. Between 2008 and 2010, the United States Food and Drug Administration approved several generic formulations of both tacrolimus and mycophenolate mofetil. Deciding whether generic products can be safely substituted for the innovator product is a clinical dilemma similar to that which occurred when generic formulations of cyclosporine became available. We describe the concerns regarding generic immunosuppression use, summarize expert opinion and consensus statements in transplantation, analyze the potential impact of generic substitution, and provide estimates of populations affected based on generic drug market penetration. Formulary considerations such as cost, availability, and potential drug ordering and drug selection errors are described, and transplant coordinator and patient perspectives are reviewed. Finally, general recommendations about the use of generic maintenance immunosuppression in solid organ transplant recipients are provided. Although more research is needed to confirm clinical and therapeutic equivalence and pharmacoeconomic benefit, generic immunosuppressants can be safely substituted for innovator products as long as patients consistently receive the same product, patients and clinicians are aware of when substitutions occur, and enhanced therapeutic drug monitoring is provided during the transition.     

他克莫司群体药动学在儿童肝移植中的研究进展

他克莫司治疗窗窄，药动学个体差异大，临床难以建立儿童受者的个体化治疗方案。群体药动学（PPK）在个体化给药研究方面有巨大优势。为了实现他克莫司在儿童肝移植受者中的个体化治疗，国内外学者致力于儿童肝移植受者的PPK研究，但各研究的结果存在差异。本文通过检索PubMed、Web of Science及Scopus数据库中的相关文献，着重分析了既往他克莫司PPK在儿童肝移植受者中的研究，总结影响他克莫司PPK参数的主要因素，期望应用PPK方法为构建儿童肝移植受者的个体化治疗方案奠定基础。     

Tacrolimus dosing in Chinese renal transplant recipients: a population-based pharmacogenetics study

Objectives

The aims of this study were to examine the effects of genetic and clinical factors on the maintenance dose of tacrolimus in patients following renal transplantation and to develop a tacrolimus-dosing model that could be combined with associated factors.

Patients and methods

This study included 142 renal transplant recipients who received tacrolimus as immunosuppressive agent. CYP3A5, MDR1 and NR1I2 gene polymorphisms were identified based on the SNaPshot assay. The relationship between the genetic and clinical factors and tacrolimus maintenance dose as well as between dose-corrected tacrolimus concentration was examined.

Results

CYP3A5 genotype, body weight, haematocrit, haemoglobin and total bilirubin significantly influenced the maintenance tacrolimus dose. The tacrolimus-dosing model derived from linear regression model accounted for 40.5% of total variations in the tacrolimus maintenance dose.

Conclusions

A pharmacogenetics-based dosing model has been developed for the prediction of the tacrolimus maintenance dose in renal transplant recipients. This model may be useful in helping clinicians prescribe the initial tacrolimus dose with greater safety and effectiveness.     

Clinical experience with itraconazole in systemic fungal infections

The broad spectrum antifungal itraconazole is an effective and well tolerated agent for the prophylaxis and treatment of systemic fungal infections. The recent development of an itraconazole oral solution and an intravenous itraconazole solution has increased the options for the use of this drug and increased the oral bioavailability in a variety of at-risk patients. Reliable absorption of the itraconazole oral solution has been demonstrated in patients with HIV infection, neutropenic patients with haematological malignancy, bone marrow transplant recipients and neutropenic children. In clinical trials, itraconazole oral solution (5 mg/kg/day) was more effective at preventing systemic fungal infection in patients with haematological malignancy than placebo, fluconazole suspension (100 mg/day) or oral amphotericin-B (2 g/kg/day) and was highly effective at preventing fungal infections in liver transplant recipients. There were no unexpected adverse events with the itraconazole oral solution in any of these trials. In addition, intravenous itraconazole solution is at least as effective as intravenous amphotericin-B in the empirical treatment of neutropenic patients with systemic fungal infections, and drug-related adverse events are more frequent in patients treated with amphotericin-B. A large proportion of patients with confirmed aspergillosis also respond to treatment with intravenous itraconazole followed by oral itraconazole. The new formulations of itraconazole are therefore effective agents for prophylaxis and treatment of most systemic fungal infections in patients with haematological malignancy.     

Effects of hematocrit value on microparticle enzyme immunoassay of tacrolimus concentration in therapeutic drug monitoring

The effects of hematocrit (Ht) value on microparticle enzyme immunoassay (MEIA) of tacrolimus concentration were examined in 1063 whole-blood samples from 42 transplant recipients (13 liver, 20 kidney, and 9 bone marrow transplantations). MEIA guarantees the test's assay quality for blood tacrolimus in samples with Ht values of 25% to 45%. However, 129 samples (29.3%) obtained from liver transplant recipients and 107 samples (61.5%) from bone marrow transplant recipients had lower Ht (<25%). Further, 81 blood samples (18.1%) with Ht > 45% were observed in kidney transplant patients. Twenty-five whole-blood samples with low Ht were tested by 3 assay methods for tacrolimus: MEIA, modified, corrected MEIA (cMEIA), and enzyme-linked immunosorbent assay (ELISA). MEIA gave higher blood concentrations of tacrolimus than ELISA (16.1 versus 11.0 ng/mL, P < 0.001). This difference was generated by overestimation in MEIA and was not observed in samples with normal Ht. This overestimation was eliminated by using cMEIA on samples with low Ht values: there was no difference in blood tacrolimus concentration between cMEIA and ELISA (12.3 versus 11.0 ng/mL). ELISA or cMEIA should be used for tacrolimus assay in samples obtained from bone marrow transplant recipients with anemia and from liver and kidney transplant recipients with unstable Ht values.     

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.     

Combination treatment with sirolimus and ciclosporin in clinical renal transplantation: A comprehensive review

Sirolimus is a potent new immunosuppressive agent that has been shown to reduce the incidence of acute rejection episodes among renal transplant recipients as well as provide a unique approach to optimize treatment outcomes in difficult transplant situations. Owing to its properties as a critical-dose drug, therapeutic concentration monitoring of sirolimus readily compensates for intra- and interpatient variability and drug interactions with a variety of other agents such as ciclosporin. This review summarizes the results that demonstrate the efficacy of sirolimus in combination treatment with ciclosporin in human renal transplantation, as well as its potential in alternative therapeutic modalities in a broad range of transplant recipients. The clinical trials for SDZ-RAD, a macrocyclic lactone immunosuppressant structurally similar to sirolimus, also are reviewed herein. SDZ-RAD was developed in an attempt to improve the pharmacokinetic characteristics of sirolimus, particularly to increase the extent and reproducibility of its oral bioavailability and to reduce the extensive tissue distribution by virtue of its greater polarity. (c) 2001 Prous Science. All rights reserved.     

Bayesian forecasting and prediction of tacrolimus concentrations in pediatric liver and adult renal transplant recipients

AIM: To test the predictive capacity of two recently derived population pharmacokinetic models and the usefulness of Bayesian forecasting to predict tacrolimus blood concentrations in pediatric liver and adult kidney transplant recipients. MATERIALS AND METHODS: New databases were added to the Abbottbase PKS (Bayesian dosage prediction) program to incorporate the population pharmacokinetic models developed for tacrolimus. Two independent populations of transplant recipients were used to predict tacrolimus trough concentrations. Pharmacokinetic, demographic, and covariate data were collected from patient records. Different time weighting factors were tested (1, 1.005, 1.01) and the influence of excluding data collected in the first 5 days post-transplant examined. Concentrations were predicted until the 10th tacrolimus measurement. Actual tacrolimus concentrations were compared with those predicted by the PKS program and bias and precision determined. RESULTS: Tacrolimus concentrations predicted by the PKS program were, on average, unbiased for the pediatric liver population, but were over-predicted (9%) for the adult renal population. In both populations predictions were not precise (imprecision ranged from 39 to 50%). CONCLUSIONS: Due to the imprecision seen in this study, these models could not be used in clinical practice in the immediate post-transplant period. Poor precision may be due to reliance on routine drug monitoring data alone, difficulties with expression of covariates in continuous modeling relationships in the PKS program, lack of accurate quantitative measures of liver function, or large, random intraindividual variability in the bioavailability of tacrolimus.     

Release behavior of drugs from various natural gums and polymers

Polymers are the high molecular weight compounds of natural or synthetic origin, widely used in drug delivery of formulations. These polymers are further classified as hydrophilic or hydrophobic in nature. Depending upon this characteristic, polymers exhibit different release behavior in different media. This property plays an important role in the selection of polymers for controlled, sustained or immediate release formulations. The review highlights the literatures related to the research made on several polymers regarding the release kinetics which made them a novel approach for modifying the action of the particular formulation.     

Immunosuppressive drugs in paediatric liver transplantation

Orthotopic liver transplantation is established treatment for children with acute and chronic liver failure. Despite advances in pre- and postoperative management, innovative surgical techniques and new immunosuppressive drugs, acute and chronic rejection remains a problem. In addition, well established adverse effects of commonly used immunosuppressive drugs are no longer accept able. More potent, but less toxic, immunosuppressive agents have been developed and some novel compounds are now entering routine practice. Cyclosporin was the cornerstone of immunosuppressive therapy until the introduction of its novel pharmaceutical form (Neoral) with improved bioavailability, lower inter- and intraindividual pharmacokinetic variability and improved graft survival. Recently, tacrolimus, a macrolide drug with a similar mode of action, but much higher potency, was introduced and, at present, is the only agent which can successfully replace cyclosporin as a first-line immunosuppressive drug. Mycophenolate mofetil has recently been approved for use in adult and paediatric renal transplant recipients. It has a similar mode of action to cyclosporin and tacrolimus, but acts at a later stage of the T cell activation pathway. Administration with standard immunosuppressive drugs reduces the incidence of acute rejection and enables cyclosporin and tacrolimus dose reduction, thus reducing the risk of associated toxic effects. Phase I and II trials with sirolimus (rapamycin), a macrolide antibiotic, have shown comparable immunosuppressive action, when administered in conjunction with standard immunosuppressants. Further clinical trials need to be carried out to establish efficacy, tolerability and pharmacokinetics in paediatric transplant recipients. Monoclonal antibody therapy (daclizumab and basiliximab) is an exciting new development whereby T cell proliferation is inhibited by selective blockade of interleukin (IL)-2 receptors. Preliminary results, when used in combination with a standard immunosuppressive regimen, are good with respect to incidence of acute graft rejection, host immune response and adverse effects. FTY720 is a novel synthetic immunosuppressive compound which induces a reduction in peripheral blood lymphocyte count through apoptotic T cell death or accelerated trafficking of T cells into lymphatic tissues. Experimental animal studies demonstrated synergistic action in combination with low dose cyclosporin or tacrolimus, potentiating their immunosuppressive effects. Further studies are being carried out to determine its potential for application in organ transplantation. Despite this rapid development of novel compounds, it will take many years before they may become part of standard protocols in paediatric transplantation medicine. Further development and research of efficacy and tolerability of existing drugs is, therefore, vital.