Although immunosuppressive treatments and therapeutic drug monitoring have significantly contributed to the increased success of thoracic transplantation, there is currently no consensus on the best immunosuppressive strategies. Maintenance therapy typically consists of a triple-drug regimen including corticosteroids, a calcineurin inhibitor (cyclosporine or tacrolimus) and either a purine synthesis antagonist (mycophenolate mofetil or azathioprine) or a mTOR inhibitor (sirolimus or everolimus). The incidence of acute and chronic rejection and of mortality after thoracic transplantation is still high compared to other types of solid organ transplantation. The high allogeneicity and immunogenicity of the lungs justify the use of higher doses of immunosuppressants, putting lung transplant recipients at a higher risk for drug-induced toxicities. All immunosuppressants are characterized by a large intra- and inter-individual variability of their pharmacokinetics and by a narrow therapeutic index. It is essential to know their pharmacokinetic properties and to use them for treatment individualization through therapeutic drug monitoring (TDM) in order to improve treatment outcome. Unlike the kidneys and the liver, the heart and the lungs are not directly involved in drug metabolism and elimination, which may be the cause of pharmacokinetic differences between patients from all these transplant groups.
TDM is mandatory for most immunosuppressants, and has become an integral part of immunosuppressive drug therapy. It is usually based on trough concentrations (C0) monitoring, but other TDM tools include the area under the concentration-time curve over the dosing interval (AUC0-12) or over the first 4 hours post-dose (AUC0-4), as well as other single concentration-time points, such as the concentration 2 hours after dosing (C2). Given the peculiarities of thoracic transplantation, a review of the pharmacokinetics and TDM of the main immunosuppressants used in thoracic transplantation is presented in this article. Even more so than in other solid organ transplant populations, their pharmacokinetics is characterized by wide inter- and intra-individual variability in thoracic transplant recipients. The pharmacokinetics of cyclosporine in heart and lung transplant recipients has been explored in a number of studies, but less is known about that of mycophenolate and tacrolimus in these populations, while there are also hardly any studies on the pharmacokinetics of sirolimus and everolimus. Given the increased use of these molecules in thoracic transplant recipients, their pharmacokinetics deserves to be explored more in depth. There is very little data, some of which is conflicting, on the practices and outcomes of the TDM of immunosuppressants after thoracic transplantation. The development of sophisticated TDM tools dedicated to thoracic transplantation are awaited, in order to evaluate accurately and precisely patients’ exposure to drugs in general and in particular, to immunosuppre ssants. Finally, large cohort TDM studies definitely need to be conducted in thoracic transplant patients, in order to identify the most predictive exposure indices, and their target values, and to validate the clinical usefulness of improved TDM in these conditions.
Calcineurin; antagonists & inhibitors; Cyclosporine; pharmacokinetics; therapeutic use; Drug Monitoring; Heart Transplantation; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; pharmacokinetics; therapeutic use; Lung Transplantation; Pediatrics; Tacrolimus; pharmacokinetics; therapeutic use
After renal transplantation, many patients experience adverse effects from maintenance immunosuppressive drugs. When these adverse effects occur, patient adherence with immunosuppression may be reduced and impact allograft survival. If these adverse effects could be prospectively monitored in an objective manner and possibly prevented, adherence to immunosuppressive regimens could be optimized and allograft survival improved. Prospective, standardized clinical approaches to assess immunosuppressive adverse effects by health care providers are limited. Therefore, we developed and evaluated the application, reliability and validity of a novel adverse effects scoring system in renal transplant recipients receiving calcineurin inhibitor (cyclosporine or tacrolimus) and mycophenolic acid based immunosuppressive therapy.
The scoring system included 18 non-renal adverse effects organized into gastrointestinal, central nervous system and aesthetic domains developed by a multidisciplinary physician group. Nephrologists employed this standardized adverse effect evaluation in stable renal transplant patients using physical exam, review of systems, recent laboratory results, and medication adherence assessment during a clinic visit. Stable renal transplant recipients in two clinical studies were evaluated and received immunosuppressive regimens comprised of either cyclosporine or tacrolimus with mycophenolic acid. Face, content, and construct validity were assessed to document these adverse effect evaluations. Inter-rater reliability was determined using the Kappa statistic and intra-class correlation.
A total of 58 renal transplant recipients were assessed using the adverse effects scoring system confirming face validity. Nephrologists (subject matter experts) rated the 18 adverse effects as: 3.1 ± 0.75 out of 4 (maximum) regarding clinical importance to verify content validity. The adverse effects scoring system distinguished 1.75-fold increased gastrointestinal adverse effects (p = 0.008) in renal transplant recipients receiving tacrolimus and mycophenolic acid compared to the cyclosporine regimen. This finding demonstrated construct validity. Intra-class correlation was 0.81 (95% confidence interval: 0.65-0.90) and Kappa statistic of 0.68 ± 0.25 for all 18 adverse effects and verified substantial inter-rater reliability.
This immunosuppressive adverse effects scoring system in stable renal transplant recipients was evaluated and substantiated face, content and construct validity with inter-rater reliability. The scoring system may facilitate prospective, standardized clinical monitoring of immunosuppressive adverse drug effects in stable renal transplant recipients and improve medication adherence.
Immunosuppressive agents; Adverse effects; Renal transplantation; Calcineurin inhibitors; Mycophenolic acid; Tacrolimus; Cyclosporine
In solid organ transplant patients, it is important to maintain a fine balance between preventing rejection and reducing adverse effects. Several immunosuppressive agents such tacrolimus, cyclosporine, sirolimus and everolimus require therapeutic drug monitoring. The study of germline variation of the genome has opened novel opportunities to individualize therapy. Among the currently available immunosuppressive agents, cyclosporine, tacrolimus and mycophenolic acid are in vitro substrates of the UGT1A and 2B families of glucuronidation enzymes. Mycophenolic acid, either given as mycophenolate mofetil or mycophenolate sodium, is the most frequently used antiproliferative immunosuppressant. Mycophenolic acid is a prodrug which is rapidly de-esterified in the gut wall, blood, liver and tissue to the active moiety, mycophenolic acid (MPA). MPA undergoes significant hepatic metabolism to several metabolites. The 7-hydroxyglucuronide MPA is the major metabolite and is inactive. This paper reviews the current status of the genetic associations between germline UGT variants and the pharmacokinetics and pharmacodynamics of mycophenolic acid. Our conclusive assessment of the studies conducted so far is that these germline markers are not ready to be used in the clinic to individualize mycophenolic acid dosing and improve outcome. Novel approaches are required to identify new genetic determinants of outcomes in transplantation.
UGT; Transplantation; Toxicity; Rejection; Mycophenolic acid; Pharmacogenetics
Immunosuppressants require therapeutic drug monitoring because of their narrow therapeutic index and significant inter-individual variability in blood concentrations. This variability can be because of factors like drug-nutrient interactions, drug-disease interactions, renal-insufficiency, inflammation and infection, gender, age, polymorphism and liver mass. Drug monitoring is widely practiced especially for cyclosporine, tacrolimus, sirolimus and mycophenolic acid.
Therapeutic monitoring of immunosuppressive therapy with cyclosporine is a critical requirement because of intra- and inter-patient variability of drug absorption, narrow therapeutic window and drug induced nephrotoxicity.
Mycophenolic acid (MPA)
Some reasons for therapeutic drug monitoring of MPA during post-transplant period include: relationship between MPA pharmacokinetic parameters and clinical outcomes, Inter-patient pharmacokinetic variability for MPA despite fixed MMF doses, alternations of MPA pharmacokinetics during the first months after transplantation, drug- drug interaction and influence of kidney function on MPA pharmacokinetic.
A recent review of the pharmacokinetics of sirolimus suggested a therapeutic range of 5 to 10 μg l−1 in whole blood. However, the only consensus guidelines published on the therapeutic monitoring of sirolimus concluded that there was not enough information available about the clinical use of the drug to make recommendations.
Sudies have shown, in kidney and liver transplant patients, significant associations of low tacrolimus concentrations with rejection and of high concentrations with nephrotoxicity. Although the feasibility of a limited sampling scheme to predict AUC has been demonstrated, as yet, trough, or pre-dose, whole blood concentration monitoring is still the method of choice.
Cyclosporine; Mycophenolic acid; Sirolimus; Tacrolimus; Therapeutic drug monitoring
Background & objectives:
Kidney transplantation is the best option for patients with end-stage renal disease (ESRD) failure. Prolonged use of immunosuppressive drugs often causes opportunistic infections and malignancies of skin and mucosae, but due to lack of a careful dermatological screening in several transplantation centers the diagnosis and the treatment of dermatological lesions in kidney transplant patients are underestimated. In addition after the introduction of interleukin (IL)-2 -receptor antagonists (basiliximab/daclizumab), mTOR inhibitors and mycophenolate mofetil (MMF)/mycophenolic acid (MPA) in new immunosuppressive protocols only a few studies have analyzed the skin and mucosal lesions in kidney transplant patients. This study was undertaken to evaluate the cutaneous and mucosal diseases after kidney transplantation, and to investigate the association between these and different immunosuppressive protocols and/or demographic features.
A retrospective analysis was done using medical records of kidney transplantation between 2000 and 2009 at the Transplant Unit of Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. The study included 183 patients (M 57.3%, F 42.7%) aged 51.5±11.8 yr) with transplant age 52.3±34.9 months. Induction therapy was basiliximab and steroids based; maintenance therapy included combination-regimes from cyclosporine, tacrolimus, steroids, mycophenolate mofetil (MM), mycophenolic acid (MPA), rapamycin, everolimus. Anti-rejection therapy was steroid and/or thymoglobulines based. Diagnosis of cutaneous disease was made through examination of skin, mucous membranes, nails and hair evaluation. Skin biopsies, specific cultures and serological tests were done when required.
Skin and mucosal diseases were reported in 173 (95.7%) of patients; 88 (50.81%) showed viral lesions; 92 (53.01%) immunosuppression-related lesions; 28 (16.39%) benign tumours; 26 (15.3%) precancers /neoplastic lesions; 24 (14.21%) mycosis; 16 (9.29%) cutaneous xerosis, 15 (8.74%) dermatitis, while absence of cutaneous disease was evident only in 8 (4.37%) cases. An association between drug side effects and anti-rejection treatment (P≤0.01) and/or calcineurin-inhibitors (CNI) exposure (P≤0.01) was found. Longer exposure to immunosuppressive drugs (>60 months) was associated with pre-malignancy and malignancy lesions.
Interpretation & conclusions:
Cutaneous diseases are frequent in kidney transplanted patients. Continuous skin monitoring is necessary to make an early diagnosis and to start appropriate treatment.
Anti-rejection treatment; benign tumour; end-stage renal disease; immunosuppression; kidney transplant; skin lesions
Significantly increasing heart transplantations have been performed in Taiwan in the past decades, but the trends of maintenance immunosuppression for heart transplant recipients have not been well known. In this study, we aimed to explore the trends of maintenance immunosuppressive therapy and common complications for heart transplant recipients.
We retrospectively analyzed ambulatory prescriptions in 488 heart transplant recipients for the period 2000–2009. Patient complications after heart transplantation were also identified.
The annual number of new heart transplant recipients ranged from 18 to 68. The 5-year survival rate was 77.9%. The total number of regimens was 10 in 2000, and increased to 28 in 2009. Most prescriptions were immunosuppressive combinations (95.5%–89.5%). The majority of immunosuppressive regimens were a triple regimen: cyclosporine, mycophenolic acid and corticosteroid in 2009. Cyclosporine was a predominant calcineurin inhibitor with a decreasing trend from 73.9% to 59.1%, whereas the use of tacrolimus significantly increased from 11.9% to 38.4%. Mycophenolic acid was the most frequently used antimetabolite (60.1%–80.3%), while the use of azathioprine was reduced (21.6%–2.3%). From 2008, the launch of everolimus initiated a new era in the utilization of mammalian target of rapamycin inhibitors for maintenance immunosuppression.
Cyclosporine remained the most frequently used calcineurin inhibitors, and tacrolimus increased gradually. Mycophenolic acid was the most popular antimetabolite rather than azathioprine. The rapidly increased everolimus combined regimen may change the patterns of maintenance immunosuppression. The increasing number of combination therapies indicates an active role of everolimus and a tendency of complex tailored individual therapies. © 2014 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.
heart transplantation; immunosuppressive therapy; prescription patterns; pharmacoepidemiology
Long term therapeutic drug monitoring and assessment of renal function are required in renal transplant recipients on immunosuppressant therapy such as tacrolimus. Dry blood spots (DBS) have been used successfully in the clinic for many years and offers a convenient, simple and non-invasive method for repeated blood tests. We developed and performed a preliminary validation of a method for the analysis of tacrolimus and creatinine from a single DBS using liquid chromatography-tandem mass spectrometric (LC–MS/MS). Tacrolimus and creatinine were extracted from a 6 mm punch with a mixture of methanol/acetonitrile containing ascomycin and deuterated creatinine as internal standards. A 10 μl aliquot of the extract was analyzed directly after dilution for creatinine with normal phase high performance liquid chromatography and multiple reaction monitoring. The remainder of the extract was processed and analyzed for tacrolimus. The lower limit of quantification for tacrolimus was 1 ng/ml with accuracy of 0.34% bias and precision (CV) of 11.1%. The precision ranged from 1.33% to 7.68% and accuracy from −4.44% to 11.6% bias for the intra- and inter-day analysis. The lower limit of quantification of creatinine was 0.01 mg/dL with precision of 7.94%. Accuracy was based on recovery of additional creatinine spiked into whole blood samples and ranged from −2.45% bias at 5 mg/dL to 3.75% bias at 0.5 mg/dL. Intra- and inter-day precision was from 3.48 to 4.11%. The assay was further validated with DBS prepared from pediatric renal transplant recipients. There was excellent correlation between the levels of tacrolimus and creatinine obtained from the clinical laboratory and the DBS method developed. After additional validation, this assay may have a significant impact on compliance with medication intake as well as potentially lowering the cost associated with intravenous blood draws in clinical laboratories.
Creatinine; Tacrolimus; Therapeutic drug monitoring; Liquid chromatography tandem mass; spectrometry (LC–MS/MS); Dried blood spot (DBS)
In this study a new principle of measurement in LC-MS/MS (liquid chromatography mass spectrometry) for determination of the immunosuppressive drugs sirolimus, everolimus, tacrolimus, and cyclosporin A has been introduced by using the Cs+ ion as the product ion in the multiple reaction monitoring mode (MRM).
Separation of the immunosuppressive agents was achieved using a phenyl-hexyl-RP column together with a ternary gradient elution profile, consisting of water, methanol and acetonitrile combined with 0.1% v/v formic acid and 0.1 mmol/l Cs+.
Quantification was performed using cyclosporin D, ascomycin and 32-desmethoxy-rapamycin as internal standards.
The inter-run precision of this new method, expressed as the coefficient of variation, was 2.57% for sirolimus, 2.11% for everolimus, 2.31% for tacrolimus and 2.11% for cyclosporin A.
immunosuppressive drugs; LC-MS/MS; Cs+ adducts
During the last 5 decades, liver transplantation has witnessed rapid development in terms of both technical and pharmacologic advances. Since their discovery, calcineurin inhibitors (CNIs) have remained the standard of care for immunosuppression therapy in liver transplantation, improving both patient and graft survival. However, adverse events, particularly posttransplant nephrotoxicity, associated with long-term CNI use have necessitated the development of alternate treatment approaches. These include combination therapy with a CNI and the inosine monophosphate dehydrogenase inhibitor mycophenolic acid and use of mammalian target of rapamycin (mTOR) inhibitors. Everolimus, a 40-O-(2-hydroxyethyl) derivative of mTOR inhibitor sirolimus, has a distinct pharmacokinetic profile. Several studies have assessed the role of everolimus in liver transplant recipients in combination with CNI reduction or as a CNI withdrawal strategy. The efficacy of everolimus-based immunosuppressive therapy has been demonstrated in both de novo and maintenance liver transplant recipients. A pivotal study in 719 de novo liver transplant recipients formed the basis of the recent approval of everolimus in combination with steroids and reduced-dose tacrolimus in liver transplantation. In this study, everolimus introduced at 30 days posttransplantation in combination with reduced-dose tacrolimus (exposure reduced by 39%) showed comparable efficacy (composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, or death) and achieved superior renal function as early as month 1 and maintained it over 2 years versus standard exposure tacrolimus. This review provides an overview of the efficacy and safety of everolimus-based regimens in liver transplantation in the de novo and maintenance settings, as well as in special populations such as patients with hepatocellular carcinoma recurrence, hepatitis C virus-positive patients, and pediatric transplant recipients. We also provide an overview of ongoing studies and discuss potential expansion of the role for everolimus in these settings.
mTOR inhibitors; everolimus; liver transplantation; efficacy; safety
Despite the advances in the treatment of chronic hepatitis B virus (HBV) infection, liver transplantation (LT) remains the only hope for many patients with end-stage liver diseases resulting from HBV.
The aim of this study was to investigate the rate of HBV recurrence in cases that had undergone LT due to the HBV related liver cirrhosis.
Patients and Methods
Forty-nine patients who underwent LT due to HBV related cirrhosis since 2001 to 2009 in Shiraz Organ Transplantation Center were enrolled in the present study. They were asked to complete the planned questionnaire and also to sign the informed consent in order to take part in this study. Post-transplant prophylaxis protocol against HBV recurrence was based on a hundred milligrams of lamivudine daily plus intramuscular injections of hepatitis B immune globulin (HBIG) with appropriate dosage to keep anti-HBs antibody titer above 300 IU/L and 100 IU/L in the first six months and afterwards, respectively. Blood samples were obtained and checked for HBsAg, HBeAg, and the titers of Anti -HBsAb as well as Anti- HBeAb with ELISA. A quantitative HBV DNA assay was also done on all samples (GENE-RAD® Real-time PCR).
There were 91.8% males and 8.2% females enrolled in the study. The duration of post-transplant prophylaxis ranged from 3 months to 8 years (mean 18.9 ± 19.3 months). HBsAg and HBeAg were positive in 24.5% and 2% of cases, respectively. Real-time PCR for HBV DNA were zero copies/mL in 91.8% of patients, none of which represented a positive value for HBV recurrence (Positive > 10,000 copies/mL). The mean Anti-HBs Ab titer was 231.7 ± 135.9 IU/L; it was above 100 IU/L in 71.4% of patients. Thirty-seven (75.5%) of the patients were taking tacrolimus plus mycophenolate mofetil, 6 (12.2%) were on cyclosporine plus mycophenolate mofetil, and 6 (12.2%) were taking sirolimus plus mycophenolate mofetil. HBsAg was detectable in seven patients taking tacrolimus plus mycophenolate mofetil (18.9%), in four patients taking cyclosporine plus mycophenolate mofetil (66.7%), and in one patient among the six who were taking sirolimus plus mycophenolate mofetil (16.7%). There was no significant statistical correlation between the presence of a positive value for HBsAg and the immunosuppression regimen or Anti HBsAb titer (P ˃ 0.05). Presence of a positive value for HBsAg was not predictive of a positive HBV DNA or its level in blood (P ˃ 0.05).
Post-transplant HBV prophylaxis with lamivudine and intramuscular HBIG with appropriate dosage to keep anti-HBs antibody titer above 300 IU/L in the first six months and above 100 IU/L afterwards is effective for prevention of HBV recurrence after LT.
Hepatitis B Virus; Liver Transplant; Immunosuppression; Recurrence
The aim of this study was to analyze the distribution of malignancies in patients after heart transplantation (HTX) and to evaluate the risk factors including immunosuppressive therapy with regard to the development of malignancies and survival. Special emphasis was placed on the effects of a mammalian target of rapamycin (mTOR) containing immunosuppressive regimen.
A total of 381 patients (age ≥18 years) receiving HTX were included in the present analysis. All patients were followed-up at the University of Heidelberg Heart Center, Heidelberg, Germany. Data were retrieved from the Heidelberg Registry for Heart Transplantation being collected between 1989 and 2014. According to center standard, all patients received induction therapy with anti-thymocyte globulin guided by T-cell monitoring since 1994. The initial immunosuppressive regimen consisting of cyclosporine A (CsA) and azathioprine (AZA) was replaced by CsA and mycophenolate mofetil (MMF) in 2001 and by tacrolimus (TAC) and MMF in 2006. Additionally, mTOR inhibitors (everolimus/sirolimus) were applied since 2003.
Mean recipient age at HTX was 51.2±10.5 years and the mean follow-up period after HTX was 9.7±5.9 years. During follow-up, 130 patients developed a neoplasm (34.1% of total). Subgroup analysis revealed 58 patients with cutaneous malignancy only (15.2%), 56 patients with noncutaneous malignancy only (14.7%), and 16 patients with both cutaneous and noncutaneous malignancy (4.2%). Statistically significant risk factors associated with an increased risk of malignancy after HTX were older age (P<0.0001), male recipients (P=0.0008), dyslipidemia (P=0.0263), diabetes mellitus (P=0.0003), renal insufficiency (P=0.0247), and >1 treated rejection episode (TRE) in the first year after HTX (P=0.0091). Administration of CsA (P=0.0195), AZA (P=0.0008), or steroids (P=0.0018) for >1 year after HTX was associated with increased development of malignancy, whereas administration of MMF (P<0.0001) or mTOR inhibitors (P<0.0001) was associated with a lower risk for development of malignancy. Additionally, 5-year follow-up of cutaneous malignancy recurrence (P=0.0065) and noncutaneous malignancy mortality (P=0.0011) was significantly lower in patients receiving an mTOR inhibitor containing therapy after the development of a malignancy.
This study highlights the complexity of risk factors including immunosuppression with regard to the development of malignancies after HTX. mTOR-inhibitor-based immunosuppression is associated with a better outcome after HTX, particularly in cases with noncutaneous malignancy.
immunosuppression; risk factors; cyclosporine A; tacrolimus; azathioprine; mycophenolate mofetil; mTOR inhibitor; steroids
Kidney transplantation improves quality of life and reduces the risk of mortality. A majority of the success of kidney transplantation is attributable to the calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, and their ability to reduce acute rejection rates. However, long-term graft survival rates have not improved over time, and although controversial, evidence does suggest a role of chronic CNI toxicity in this failure to improve outcomes. Consequently, there is interest in reducing or removing CNIs from immunosuppressive regimens in an attempt to improve outcomes. Several strategies exist to spare calcineurin inhibitors, including use of agents such as mycophenolate mofetil (MMF), mycophenolate sodium (MPS), sirolimus, everolimus or belatacept to facilitate late calcineurin inhibitor withdrawal, beyond 6 mo post-transplant; or using these agents to plan early withdrawal within 6 mo; or to avoid the CNIs all together using CNI-free regimens. Although numerous reviews have been written on this topic, practice varies significantly between centers. This review organizes the data based on patient characteristics (i.e., the baseline immunosuppressive regimen) as a means to aid the practicing clinician in caring for their patients, by matching up their situation with the relevant literature. The current review, the first in a series of two, examines the potential of immunosuppressive agents to facilitate late CNI withdrawal beyond 6 mo post-transplant, and has demonstrated that the strongest evidence resides with MMF/MPS. MMF or MPS can be successfully introduced/maintained to facilitate late CNI withdrawal and improve renal function in the setting of graft deterioration, albeit with an increased risk of acute rejection and infection. Additional benefits may include improved blood pressure, lipid profile and serum glucose. Sirolimus has less data directly comparing CNI withdrawal to an active CNI-containing regimen, but modest improvement in short-term renal function is possible, with an increased risk of proteinuria, especially in the setting of baseline renal dysfunction and/or proteinuria. Renal outcomes may be improved when sirolimus is used in combination with MMF. Although data with everolimus is less robust, results appear similar to those observed with sirolimus.
Kidney transplantation; Calcineurin inhibitor; Withdrawal; Sparing; Cyclosporine; Tacrolimus; Renal function; Graft survival
The art of administering immunosuppression lies in the ability to achieve a delicate balance between rejection and infection, thus maximizing patient survival and minimizing morbidity.
To analyze the effect of immunosuppression strategies following liver transplant on the incidence of acute rejection, bile leak, renal dysfunction and posttransplant graft unrelated infection.
Settings and Design
A retrospective analysis of immunosuppression regimens in 57 liver transplant recipients between Jan 1998 to July 2004 at a single institution.
Methods and Material
For the purpose of study, the patients were divided into two groups: A — Cyclosporine based therapy (n=37), and B — Tacrolimus based therapy (n=20). In addition, both groups received Azathioprine or Mycophenolate mofetil with steroids. There were two subgroups in each Group A and B: Group C — Received induction using IL2Rab (n=5), and D — Where Sirolimus was used instead of Mycophenolate mofetil (N=7). The subgroups were equally distributed among the basic groups. The regimen was started based on one of the standard protocols but changes were made according to the clinical status of each patient.
Statistical analysis used
The statistical analysis was done using Chi square test on SPSS12.
A lower incidence of rejection was observed in Tacrolimus group compared to Cyclosporine group. There was an unacceptably high incidence of bile leak in patients where Sirolimus was used as an adjunct. IL2Rab enabled us to maintain a lower trough level of Tacrolimus for maintenance and enabled us to discontinue steroids earlier.
Based on this study we dropped Sirolimus from our immunosuppression protocol and the encouraging results obtained with tacrolimus based therapy have supported its use as standard therapy in our immunosuppression regimens.
Immunosuppression; Transplant; Rejection
AIM: To assess the advantages and disadvantages of immunosuppression monotherapy after transplantation and the impact of monotherapy on hepatitis C virus (HCV) recurrence.
METHODS: Articles from Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded, including non-English literature identified in these databases, were searched up to January 2013. We included randomized clinical trials comparing various immunosuppression monotherapy and prednisone-based immunosuppression combinations for liver transplantation. The modified Jadad scale score or the Oxford quality scoring system was used. Meta-analyses were performed with weighted random-effects models.
RESULTS: A total of 14 randomized articles including 1814 patients were identified. Eight trials including 1214 patients compared tacrolimus monotherapy (n = 610) vs tacrolimus plus steroids or triple therapy regarding acute rejection and adverse events (n = 604). Five trials, including 285 patients, compared tacrolimus monotherapy (n = 143) vs tacrolimus plus steroids or triple therapy regarding hepatitis C recurrence (n = 142). Four trials including 273 patients compared cyclosporine monotherapy (n = 148) vs cyclosporine and steroids regarding acute rejection and adverse events (n = 125). Two trials including 170 patients compared mycophenolate mofetil monotherapy (n = 86) vs combinations regarding acute rejection (n = 84). There were no significant differences in the acute rejection rates between tacrolimus monotherapy (RR = 1.04, P = 0.620), and cyclosporine monotherapy (RR = 0.89, P = 0.770). Mycophenolate mofetil monotherapy had a significant increase in the acute rejection rate (RR = 4.50, P = 0.027). Tacrolimus monotherapy had no significant effects on the recurrence of hepatitis C (RR = 1.03, P = 0.752). More cytomegalovirus infection (RR = 0.48, P = 0.000) and drug-related diabetes mellitus (RR = 0.54, P = 0.000) were observed in the immunosuppression combination therapy groups.
CONCLUSION: Tacrolimus and cyclosporine monotherapy may be as effective as immunosuppression combination therapy. Mycophenolate mofetil monotherapy was not considerable. Tacrolimus monotherapy does not increase recurrence of HCV.
Liver transplantation; Immunosuppression monotherapy; Cytomegalovirus; Diabetes; Meta-analysis
Promising data regarding the safety and efficacy of gastric bypass surgery (GBS) as an option to address obesity in the transplant population are emerging. The data lack on how GBS may alter the pharmacokinetics (PK) of modern immunosuppression. The objective of this study was to describe the alterations in the PK of modern immunosuppressants and the GBS population.
Data are presented on six subjects who participated in this trial – four were on dialysis and two were renal transplant recipients. Dialysisdependent bypass subjects received a single dose of 6 mg of sirolimus, two 4-mg doses of tacrolimus and two 1000-mg doses of mycophenolate mofetil (MMF) over the 24-h study period. Transplant recipients continued their current regimen. Maximum plasma concentration (Cmax), time to reach the maximum plasma concentration (Tmax) and the area under the plasma concentration vs. time curve (AUC0–12 and AUC0–∞ where appropriate) were calculated for tacrolimus, sirolimus, mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG).
Significant inter-patient variability in the Cmax, Tmax and AUC of tacrolimus, sirolimus MPA and MPAG was observed. A notable difference in the AUC:dose ratio for tacrolimus was seen when comparing data with published data in the non-bypass population. Similar differences in PK were seen with sirolimus, MPA and MPAG.
When comparing the PK of sirolimus, tacrolimus, MPA and MPAG to published PK data in the non-bypass population, significant differences are observed. It is likely that transplant recipients with GBS would need higher doses of tacrolimus, sirolimus and MMF to provide similar exposure to a non-bypass patient.
gastric bypass; immunosuppression; pharmacokinetics
Sirolimus (rapamycin, RAPAMUNE, RAPA) is an immunosuppressive agent used for the prophylaxis of renal allograft rejection and exhibits an immunosuppressive mechanism that is distinct from that for cyclosporine and tacrolimus. The purpose of this manuscript is to discuss the exposure-response relationships and drug interactiosn of sirolimus. The various factors affecting sirolimus whole blood exposure included first-pass extraction, formulation, food, demographics, liver disease, assay method, and interacting drugs. Clinically significant effects caused by food, pediatric age, hepatic impairment, and interacting drugs require recommendations for the safe and efficacious use of sirolimus in renal allograft patients. An exposure-response model based on multivariate logistic regression was developed using the interstudy data from 1832 renal allograft patients. The analysis revealed an increased probability of acute rejection for sirolimus troughs <5 ng/mL, cyclosporine troughs <150 ng/mL, human leukocyte antigen (HLA) mismatches ≥4, and females. The outcomes suggested that individualization of sirolimus doses immediately after transplantation, based on HLA mismatch and sex, would likely decrease the probability of acute rejections in renal allograft recipients who receive concomitant sirolimus, cyclosporine (full-dose), and corticosteroid therapy. Sirolimus is a substrate for both Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) and undergoes extensive first-pass extraction. Drugs that are known to inhibit or induce these proteins may potentially affect sirolimus whole blood exposure. In healthy volunteers, cyclosporine, diltiazem, erythromycin, ketoconazole, and verapamil significantly increased sirolimus whole blood exposure, and rifampin significantly decreased sirolimus exposure. However, sirolimus whole blood exposure was not affected by acyclovir, atorvastatin, digoxin, ethinyl estradiol/norgestrel, glyburide, nifedipine, or tacrolimus. Among the 15 drugs studied, sirolimus significantly increased the exposures of only erythromycin and S-(−)verapamil.
sirolimus; exposure-response relationship; drug interactions
Pharmacokinetic monitoring has been insufficiently studied in paediatric solid organ transplantation, especially because some agents are relatively new to paediatric use, are of new formulation modification or are being used in combinations not previously well studied. The choice of immunosuppressive drugs after paediatric renal transplantation is increasing. Cyclosporine A (CyA), tacrolimus and mycophenolate mofetil (MMF) use has become routine. While pharmacokinetic monitoring of CyA and tacrolimus is routine, few paediatric data on tacrolimus pharmacokinetics exist, and, for MMF, pharmacokinetic monitoring is performed in only a few Canadian centres. The aim of the present article is to provide guidelines for the use of these three drugs by using a large number of full pharmacokinetic profiles in children.
One hundred forty-nine full pharmacokinetic 10-point profiles on cyclosporine microemulsion, 103 on the classic cyclosporine, 118 on tacrolimus and 114 on MMF were retrospectively analyzed. All pharmacokinetic profiles were obtained from paediatric renal transplant patients in steady state.
For pharmacokinetic monitoring of the classic cyclosporine formulation, evaluation of the trough levels suffices to estimate the area under the curve (AUC). For microemulsified cyclosporine, the trough levels do not provide a useful tool, and blood concentrations at 2 or 3 h (C2 or C3) after intake should be measured instead. Tacrolimus trough levels sufficiently estimate the AUC, but measuring the C4 yields the best prediction of the AUC. Nonetheless, C2 also provides a superior tool than the trough levels. Tacrolimus and CyA AUCs change substantially over time after renal transplantation. There is only a poor correlation between the trough level and the AUC for mycophenolic acid (MPA). No single time point provides a surrogate marker of the AUC. At least three time points are required to accurately estimate the AUC, and C1, C2 and C6 serve as the best markers. The article also describes the interaction between MPA and differing concomitant immunosuppression, as well as the variation of the MPA AUC with differing concentrations of cyclosporine.
Pharmacokinetic monitoring of these three drugs is mandatory in paediatric renal transplantation because it is impossible to predict the drug interactions and blood levels from a given dose. Target AUCs for a given time point after transplantation remain to be established.
Area under the curve; Cyclosporine; Mycophenolate mofetil; Mycophenolic acid; Pharmacokinetics; Tacrolimus
Graft-versus-host Disease (GvHD) prophylaxis after allogeneic hematopoietic stem-cell transplantation (HSCT) is an ongoing effort but relative effects of different policies are not systematically explored.
We systematically reviewed 30-year evidence on GvHD prophylaxis and quantified the relative effect of different policies using a network meta-analysis. We searched PubMed and the Cochrane Library for randomized studies on the topic. The primary outcome of interest was grade II-IV acute GvHD over 0 or I (with odds ratio OR <1 denoting benefit).
Thirty-three eligible studies that enrolled 3,440 patients (published up to June 2014), provided data on seven immunosuppressive drugs namely cyclosporin A (CsA), methotrexate (MTX), anti-thymocyte globulin (ATG), mycophenolate mofetil (MMF), tacrolimus, sirolimus or corticosteroids and their combinations to calculate 14 direct and 21 indirect effects. The majority of trials (32/33) referred to myeloablative conditioning and sibling transplants (25/33). Tacrolimus/MTX (OR 0.44; 95% 0.27–0.70, number needed to treat to benefit, i.e. to avert a case of II-IV GvHD, NNTB = 5) and ATG/CsA/MTX (OR 0.45; 95%CI 0.26–0.78; NNTB = 5) were superior over CsA/MTX. ATG/CsA/MTX did not differ from tacrolimus/MTX (indirect evidence). Sirolimus-based prophylaxis outperformed CsA/MTX (OR 0.10; 95%CI 0.02–0.49, NNTB = 4) and marginally outperformed tacrolimus/MTX (OR 0.22; 95%CI 0.05–1.11). Add-on corticosteroids had no benefit over CsA/MTX.
Tacrolimus/MTX and ATG/CsA/MTX were the outperformers over CsA/MTX, but sirolimus-based regimens showed also potential. More randomized data are needed for reduced-intensity conditioning, as well as for MMF and sirolimus-containing regimens.
Despite use of a lower mycophenolate dose in Thai kidney transplant patients, acceptable graft and patient outcomes can be achieved. We therefore examined the pharmacokinetics of mycophenolic acid (MPA) by area under the curve (AUC) and investigated genetic contribution in mycophenolate metabolism in this population.
Kidney transplant recipients with stable graft function who were receiving mycophenolate mofetil 1,000 mg/d in combination with either cyclosporine or tacrolimus, and prednisolone were studied. The MPA concentration was measured by fluorescence polarization immunoassay (FPIA), at predose and 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after dosing. Genetic polymorphisms in UGT1A8, UGT1A9, and UGT2B7 were examined by denaturing high-performance liquid chromatography (DHPLC)-based single-base extension (SBE) analysis.
A total 138 patients were included in study. The mean AUC was 39.49 mg-h/L (28.39–89.58 mg-h/L), which was in the therapeutic range. The correlation between the predose MPA concentration and AUC was poor. The mean AUC in the tacrolimus group was higher than that in the cyclosporine group. Polymorphisms in UGT2B7 showed significant association with AUC.
Most of our patients with reduced mycophenolate dose had the AUC within the therapeutic range. Genetic polymorphisms in UGT2B7 may play a role in MPA metabolism in Thai kidney transplant patients.
UGT; MPA; pharmacokinetic; immunosuppressive
Kidney transplant recipients receiving calcineurin inhibitor-based immunosuppression incur increased long-term risks of cancer and kidney fibrosis. Switch to mammalian target of rapamycin (mTOR) inhibitors may reduce these risks. Steroid or Cyclosporin Removal After Transplant using Everolimus (SOCRATES), a 36-month, prospective, multinational, open-label, randomized controlled trial for de novo kidney transplant recipients, assessed whether everolimus switch could enable elimination of mycophenolate plus either steroids or CNI without compromising efficacy. Patients received cyclosporin, mycophenolate and steroids for the first 14 days then everolimus with mycophenolate and CNIwithdrawal (CNI-WD); everolimus with mycophenolate and steroid withdrawal (steroid-WD); or cyclosporin, mycophenolate and steroids (control). 126 patients were randomized. The steroid WD arm was terminated prematurely because of excess discontinuations. Mean eGFR at month 12 for CNI-WD versus control was 65.1 ml/min/1.73 m2 vs. 67.1 ml/min/1.73 m2 by ITT, which met predefined noninferiority criteria (P = 0.026). The CNI-WD group experienced a higher rate of BPAR(31% vs. control 13%, P = 0.048) and showed a trend towards higher composite treatment failure (BPAR, graft loss, death, loss to follow-up). The 12 month results from SOCRATES show noninferiority in eGFR, but a significant excess of acute rejection when everolimus was commenced at week 2 to enable a progressive withdrawal of mycophenolate and cyclosporin in kidney transplant recipients.
cyclosporin; everolimus; kidney transplantation; mammalian target of rapamycin; steroids
End-stage renal disease is the irreversible final stage of chronic kidney disease and is fatal when not managed by either transplantation or dialysis. Transplantation is generally preferred over dialysis. However, to prevent graft rejection or loss, lifelong immunosuppression is required. Tacrolimus is currently the cornerstone of post-transplantation immunosuppression. The study aim was to carry out an economic evaluation of immunosuppression, including more recent agents such as a once-daily prolonged-release formulation of tacrolimus (Advagraf™) and belatacept, relative to a twice-daily immediate-release formulation of tacrolimus (Prograf™).
A model was constructed comprising six states: onset of biopsy-confirmed acute rejection, functioning graft with or without a biopsy-confirmed acute rejection, non-functioning graft (dialysis), re-transplantation, and death. Data on clinical effectiveness were derived from a systematic literature review and the model captured the effects of patient adherence to immunosuppressant therapy on graft survival using relative risk of graft survival and published data on adherence in patients using Advagraf and Prograf. In the base case, the time horizon was 25 years and one-way and probabilistic sensitivity analyses were conducted.
The analysis demonstrated that Prograf was cost-effective when compared with cyclosporin and belatacept and was more effective than sirolimus, but would not be considered cost-effective against sirolimus. The modeled improvement in the adherence profile of patients using Advagraf relative to Prograf resulted in both improved clinical outcomes and reduced costs.
Prograf was more clinically effective than cyclosporin, belatacept, and sirolimus, supporting its current positioning as the mainstay of immunosuppressive therapy in renal transplant recipients. Based on improved patient adherence with Advagraf, the model projected that Advagraf would be both more effective and less costly than Prograf. Replacing Prograf with Advagraf as the standard of care for post-transplant immunosuppression could likely result in both cost savings and improved clinical outcomes.
tacrolimus; costs; cost-effectiveness; Great Britain
Regular immunosuppressant drug monitoring is important for maintaining the drug concentrations of organ recipients within the therapeutic range. The standardized liquid chromatography-tandem mass spectrometry (LC-TMS) technique has been used for the accurate analysis of immunosuppressive drugs. In the present study, the performance of the recently developed high-throughput, rapid ultra-performance liquid chromatography combined with tandem mass spectrometry (UPLC-TMS) method was validated for the simultaneous measurement of cyclosporin A and tacrolimus in whole blood. The method of measuring cyclosporin A and tacrolimus using UPLC-TMS was established and the precision, limit of detection (LOD), limit of quantitation (LOQ) and matrix effect were validated. In addition, the performance of UPLC-TMS was compared with that of a chemiluminescence immunoassay (CLIA) in >3,400 clinical specimens. The UPLC-TMS revealed a within-run and between-run precision of <8% and showed a bias of <5%. The LOD and LOQ were 2.0 and 2.5 ng/ml for cyclosporin A, and 0.3 and 0.4 ng/ml for tacrolimus, respectively. Interference from the matrix was not observed. The CLIA measurements of cyclosporin A and tacrolimus showed correlations corresponding with the formulae: Concentration(CLIA) = 1.18 × UPLC-TMS – 5.85; [95% CI: proportional, 1.16–1.19; constant, −6.86–(−4.81)] and Concentration(CLIA) = 1.14 × UPLC-TMS – 0.38; [(95% CI: proportional, 1.13–1.14; constant, −0.35–(−0.43)], respectively. The majority of results were higher for the immunoassay than for the UPLC-TMS. The newly developed rapid UPLC-TMS method was suitable for use with a large therapeutic concentration range of the analyzed immunosuppressive drugs. Sample preparation was simple and it was possible to detect several immunosuppressants simultaneously, thus significantly lowering the cost of analysis. In conclusion, this method may contribute to improved accuracy and may be preferred to immunoassays for the routine clinical measurement of immunosuppressive drug concentrations in whole blood.
cyclosporin A; tacrolimus; ultra-performance liquid chromatography; tandem mass spectrometry; chemiluminescence immunoassay
Mycophenolic acid (MPA) is used as an immunosuppressant after organ transplantation and for the treatment of immune diseases. There is increasing evidence that therapeutic drug monitoring and plasma concentration-guided dose adjustments are beneficial for patients to maintain immunosuppressive efficacy and to avoid toxicity. The major MPA metabolite that can be found in high concentrations in plasma is MPA glucuronide (MPAG). A metabolite usually present at lower concentrations, MPA acyl-glucuronide (AcMPAG), has been implicated in some of the adverse effects of MPA.
We developed and validated an automated high-throughput ultra-high performance chromatography-tandem mass spectrometry (U-HPLC-MS/MS) assay using liquid-handling robotic extraction for the quantification of MPA, MPAG, and AcMPAG in human EDTA plasma and urine.
The ranges of reliable response were 0.097 (lower limit of quantitation) to 200 μg/mL for MPA and MPAG and 0.156– 10 μg/mL for AcMPAG in human urine and plasma. The inter-day accuracies were 94.3–104.4%, 93.8–105.0% and 94.4–104.7% for MPA, MPAG and AcMPAG, respectively. Inter-day precisions were 0.7–7.8%, 0.9–6.9% and 1.6–8.6% for MPA, MPAG and AcMPAG. No matrix interferences, ion suppression/enhancement and carry-over were detected. The total assay run time was 2.3 min.
The assay met all predefined acceptance criteria and the quantification of MPA was successfully cross-validated with an LC-MS/MS assay routinely used for clinical therapeutic drug monitoring. The assay has proven to be robust and reliable during the measurement of samples from several pharmacokinetics trials.
Mycophenolic Acid; Mycophenolic Acid Glucuronide; Mycophenolic Acid Acyl-Glucuronide; U-HPLC-MS/MS; immunosuppressant
Only a minority of islet transplant recipients maintain insulin independence at 5 years under the Edmonton protocol of immunosuppression. New immunosuppressive strategies are required in order to improve long term outcomes.
Materials and Methods
Three subjects with unstable type 1 DM underwent islet transplantation with alemtuzumab induction and sirolimus-tacrolimus maintenance for three months then sirolimus-mycophenolic acid maintenance thereafter. Follow-up was >2 years. Comparison was with sixteen historical subjects transplanted under the Miami version of the Edmonton protocol.
Insulin independence was achieved in 2/3 alemtuzumab and 14/16 historical subjects. Those who did not achieve insulin independence only received a single islet infusion. Insulin independence rates remained unchanged in the Alemtuzumab group, but decreased from 14/16 (88%) to 6/16 (38%) in the Historical group over two years. Insulin requirements increased in the Historical group while remaining stable in the Alemtuzumab group. Comparison of functional measures at 3 months suggested better engraftment with alemtuzumab (NS). Further comparison of Alemtuzumab versus Historical groups, up to 24 months, demonstrated significantly better: Mixed Meal Stimulation Index (24 months 1.0±0.08 n=3 vs 0.5±0.06 pmol/mL n=6, p<0.01), Mixed Meal peak C-peptide (24 months 5.0±0.5 n=3 vs 3.1±0.3 nmol/mL n=6, p<0.05), HbA1c (24 months 5.4±0.15 n=3 vs 6.3±0.12pmol/mL n=10, p<0.01).
Administration of alemtuzumab was well tolerated. There was no increased incidence of infections in alemtuzumab subjects despite profound, prolonged lymphocyte depletion.
Islet transplantation with alemtuzumab induction was well tolerated and resulted in improved short and long term outcomes. Further investigation is underway for validation.
Corticosteroid therapy has been the time-honoured treatment for autoimmune hepatitis; however, the emergence of new immunosuppressive agents has afforded opportunities to improve or replace the standard regimens.
To describe technological advances and feasible treatment interventions that promise to supplant the current generation of corticosteroids.
A review of the MEDLINE database for published experiences from 1984 to 2011 was conducted.
Cyclosporine and tacrolimus have been uniformly successful as salvage therapies for steroid-refractory autoimmune hepatitis. Ten reports of cyclosporine therapy involving 133 patients had positive outcomes in 93%, whereas therapy with tacrolimus in three reports involving 41 patients had positive outcomes in 98%. Salvage therapy with mycophenolate mofetil had a favourable outcome in 47%, especially in patients with azathioprine intolerance. Front-line therapy with mycophenolate mofetil normalized liver parameters in 88% and allowed corticosteroid tapering in 58%. Front-line therapy with budesonide combined with azathioprine for six months normalized liver parameters more frequently (47% versus 18%) and with fewer side effects (28% versus 53%) than prednisone combined with azathioprine. Monoclonal antibodies to CD3 and recombinant cytotoxic T lymphocyte antigen 4 fused with immunoglobulin represent feasible molecular interventions for study in autoimmune hepatitis.
Nonstandard drug therapies must be used in highly selected clinical situations including steroid failure (calcineurin inhibitors), azathioprine intolerance (mycophenolate mofetil), and mild disease or fragile patients (budesonide combined with azathioprine). Molecular interventions for autoimmune hepatitis are feasible for study because of their use in other immune-mediated diseases.
Opportunities to improve or replace standard corticosteroid regimens have emerged.
Autoimmune; Front-line; Hepatitis; Molecular; Salvage; Therapy