Tacrolimus In Heart Transplant Recipients Research Articles

1438-P: Diabetes after Cardiac Transplant with Low-Dose Everolimus and Tacrolimus

Background: Although modern immunosuppressants improve survival post-transplant, they are associated with long-term metabolic complications, such as post-transplant diabetes mellitus (PTDM). Calcineurin inhibitor-sparing regimens using everolimus attenuate some complications such as left ventricular hypertrophy. However, the metabolic effects of everolimus following transplant are less clear. Aims: To compare incidence of diabetes in heart transplant recipients exposed to low-dose everolimus and tacrolimus versus standard-dose tacrolimus. Methods: Post-hoc analysis in participants of a randomised open-label clinical trial of low-dose everolimus and tacrolimus versus standard-dose tacrolimus in heart transplant recipients. Results: There were 39 participants in the trial, mean follow up was 6.4 ± 1.5 years. There was a high rate of pre-existing diabetes (26%) and newly-diagnosed PTDM (36%) during follow-up (Figure 1). Half the patients who developed PTDM in the everolimus-tacrolimus group (n=4/8) ceased diabetes medications during follow-up, which was not observed in patients on standard tacrolimus (n=0/6). Conclusion: This study suggests that treatment with everolimus may improve PTDM outcomes relative to treatment with standard doses of calcineurin inhibitor. These findings should be further studied in prospective randomised trials. Disclosure L.M.Raven: None. C.A.Muir: None. J.Pouliopoulos: None. P.S.Macdonald: Advisory Panel; AstraZeneca, Boehringer Ingelheim Inc., Other Relationship; Novartis. A.Jabbour: None. J.Greenfield: None.

Adaptation of a population pharmacokinetic model to inform tacrolimus therapy in heart transplant recipients.

Existing tacrolimus population pharmacokinetic models are unsuitable for guiding tacrolimus dosing in heart transplant recipients. This study aimed to develop and evaluate a population pharmacokinetic model for tacrolimus in heart transplant recipients that considers the tacrolimus-azole antifungal interaction. Data from heart transplant recipients (n = 87) administered the oral immediate-release formulation of tacrolimus (Prograf®) were collected. Routine drug monitoring data, principally trough concentrations, were used for model building (n = 1099). A published tacrolimus model was used to inform the estimation of Ka , V2 /F, Q/F and V3 /F. The effect of concomitant azole antifungal use on tacrolimus CL/F was quantified. Fat-free mass was implemented as a covariate on CL/F, V2 /F, V3 /F and Q/F on an allometry scale. Subsequently, stepwise covariate modelling was performed. Significant covariates influencing tacrolimus CL/F were included in the final model. Robustness of the final model was confirmed using prediction-corrected visual predictive check (pcVPC). The final model was externally evaluated for prediction of tacrolimus concentrations of the fourth dosing occasion (n = 87) from one to three prior dosing occasions. Concomitant azole antifungal therapy reduced tacrolimus CL/F by 80%. Haematocrit (∆OFV = -44, P < .001) was included in the final model. The pcVPC of the final model displayed good model adequacy. One recent drug concentration is sufficient for the model to guide tacrolimus dosing. A population pharmacokinetic model that adequately describes tacrolimus pharmacokinetics in heart transplant recipients, considering the tacrolimus-azole antifungal interaction was developed. Prospective evaluation is required to assess its clinical utility to improve patient outcomes.

CYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients

High inter-individual variability in tacrolimus clearance is attributed to genetic polymorphisms of CYP3A enzymes. However, due to CYP3A phenoconversion induced by non-genetic factors, continuous changes in tacrolimus-metabolizing capacity entail frequent dose-refinement for optimal immunosuppression. In heart transplant recipients, the contribution of patients’ CYP3A-status (CYP3A5 genotype and CYP3A4 expression) to tacrolimus blood concentration and dose-requirement was evaluated in the early and late post-operative period. In low CYP3A4 expressers carrying CYP3A5*3/*3, the dose-corrected tacrolimus level was significantly higher than in normal CYP3A4 expressers or in those with CYP3A5*1. Modification of the initial tacrolimus dose was required for all patients: dose reduction by 20% for low CYP3A4 expressers, a 40% increase for normal expressers and a 2.4-fold increase for CYP3A5*1 carriers. The perioperative high-dose corticosteroid therapy was assumed to ameliorate the low initial tacrolimus-metabolizing capacity during the first month. The fluctuation of CYP3A4 expression and tacrolimus blood concentration (C0/D) was found to be associated with tapering and cessation of corticosteroid in CYP3A5 non-expressers, but not in those carrying CYP3A5*1. Although monitoring of tacrolimus blood concentration cannot be omitted, assaying recipients’ CYP3A-status can guide optimization of the initial tacrolimus dose, and can facilitate personalized tacrolimus therapy during steroid withdrawal in the late post-operative period.

Prolonged Release Tacrolimus Has Comparable Safety and Efficacy Profile as Standard Release Tacrolimus in Heart Transplant Recipients

Prolonged Release Tacrolimus Has Comparable Safety and Efficacy Profile as Standard Release Tacrolimus in Heart Transplant Recipients

Prolonged Release Tacrolimus Has Comparable Safety and Efficacy Profile as Standard Release Tacrolimus in Heart Transplant Recipients

Current data on safety and efficacy of prolonged release tacrolimus (PRT, Advagraf) in heart transplant (HTX) recipients is scarce. We sought to compare standard release tacrolimus (SRT) to PRT in this patient population. In a prospective cross-over single-center study we enrolled 70 HTX recipients transplanted between 2014 and 2017. In Phase 1 all patients received SRT and were followed for 6 months. Then SRT was switched for PRT (Phase 2) and the patients were followed for another 6 months. Target tacrolimus trough values for SRT and PRT in Phases 1 and 2 were 5-8 ng/mL. Renal dysfunction was defined as estimated glomerular filtration rate (eGFR)<90mL/min/1.73m2. Of 70 patients enrolled, 56 (80%) were male with the average age of 56±10 years, 40 (57%) had renal dysfunction, 16 (23%) had diabetes and 41 (59%) had hypertension. When comparing the two treatment strategies we found no differences regarding tacrolimus trough levels (7.1±1.4 ng/mL in SRT vs. 7.2±1.6 ng/mL in PRT, P=0.57) or cumulative drug dose (3.1±1.6 mg vs. 3.6±1.8 mg, P=0.11). Furthermore, we found no differences in eGFR (75±14 mL/min/1.73m2 in SRT vs. 73±18 mL/min/1.73m2 in PRT, P=0.69), Cystatin C levels (1.11±0.27 mg/dL vs. 1.08±0.33 mg/dL, P=0.68), glucose metabolism (HbA1c: 5.9±0.9% vs. 5.8±1.0%, P=0.68), allograft left ventricular ejection fraction (65±7% vs. 66±6%, P=0.84) or right ventricular function (TAPSE: 1.7±0.7 cm vs. 1.8±0.3 cm, P=0.39). Troponin levels (0.01±0.01 pg/mL in SRT vs. 0.01±0.02 pg/mL in PRT, P=0.29) and allograft rejection rates (0% in SRT vs. 1% in PRT, P=0.32) remained comparable. When stratifying patients according to the baseline eGFR no decline was observed in patients with either normal renal function (ΔeGFR -2.2±5.1 mL/min/1.73m2 in SRT vs. +0.6±5.6 mL/min/1.73m2 in PRT, P=0.19) or decreased renal function (ΔeGFR -0.9±7.7 mL/min/1.73m2 in SRT vs. -0.7±8.9 mL/min/1.73m2 in PRT, P=0.95). Prolonged-release tacrolimus may represent a safe and effective alternative to standard-release tacrolimus in heart transplant recipients.

Targeted Aspergillus Prophylaxis With Voriconazole in Heart Transplant Patients: A Focus on the Interaction With Tacrolimus.

Background: Voriconazole is a commonly used agent for the treatment and prophylaxis of invasive aspergillosis (IA) in heart transplant recipients. Complicating its use with this population is its significant interaction with the calcineurin inhibitors tacrolimus and cyclosporine. Most primary literature pertaining to this interaction focuses on use of voriconazole in allogeneic hematopoietic stem cell recipients. There is little information pertaining to the efficacy of voriconazole for IA prophylaxis or its effects on tacrolimus pharmacokinetics in heart transplant patients. Objective: Evaluate the use of voriconazole for invasive Aspergillus (IA) targeted prophylaxis in heart transplant recipients with a focus on the drug-drug interaction between voriconazole and tacrolimus and its impact on tacrolimus dose after discontinuation of voriconazole. Methods: This single-center, nonrandomized, retrospective, sequential study reviewed the use of targeted prophylaxis protocol in heart transplant recipients at Abbott Northwestern Hospital from January 2015 through May 2017. Results: Patients screened for targeted prophylaxis protocol from 2015 through 2017 had a 0% incidence of IA. This was in comparison to a 7% incidence of IA for a historical group of recipients from 2010 to 2014 prior to the use of the protocol. Additionally, patients on voriconazole needed on average a 67% reduction in tacrolimus dose (mg/kg/day) while on voriconazole compared with similar patients not on voriconazole to stay within the tacrolimus trough level protocol range. On discontinuation of voriconazole, a preemptive 100% tacrolimus dose increase resulted in 55% of tacrolimus trough levels within protocol range on first check. Overall, after 1-month post-voriconazole discontinuation, a 215% average increased tacrolimus dose was needed to maintain a level within the protocol trough range. Conclusion and Relevance: This study corroborates that targeted IA prophylaxis with oral voriconazole for up to 90 days is associated with a reduction in the incidence of IA in new heart transplant recipients. The pharmacokinetic analysis was able to provide more details on the effects of the interaction between voriconazole and tacrolimus in heart transplant recipients. Application of these data will better aid transplant centers to handle the effects of voriconazole discontinuation on patients on tacrolimus.

Safety and Efficacy of Extended-Release Tacrolimus in De Novo Heart Transplant Recipients: Preliminary Results from a Phase-II Trial

Purpose Medication non-compliance after cardiac transplantation may be improved by simplifying dosing frequency to once-a-day extended-release tacrolimus, potentially reducing rejection rate and improving patient outcomes. Of the 2 distinct proprietary formulations for extended-release tacrolimus that are FDA approved for renal transplant patients, Meltdose tacrolimus tablets (LCP-Tacro or LCPT) has enhanced bioavailability, including in rapid metabolizers. There is limited data supporting the use of extended release tacrolimus in heart transplant recipients. Here we report initial safety and efficacy findings with extended-release tacrolimus in this population. Methods In an ongoing, phase II, single-center, open-label study (NCT03373227), 20 de novo adult heart transplant recipients have been enrolled to receive LCPT. Primary endpoints included incidence of rejection and graft failure. Secondary endpoints included compliance, incidence of adverse effects, infections, re-admissions, and survival. Therapeutic tacrolimus levels were monitored for overall drug compliance. A CYP3A5 genotype sub-study has been added to examine the associations between genotype and efficacy and safety. Results Demographics and findings are shown in Table 1. During a median post-transplant follow-up of 22 weeks (range 2-45), no serious drug related adverse events were observed and no safety issues identified. Percent of time in therapeutic range was consistent with low incidence of rejection; 2 patients had an episode of treated rejection, which resolved with steroid therapy. Conclusion Our findings demonstrate favorable early safety and efficacy profile of LCPT in heart transplant recipients.

CYP3A5*3 and POR*28 genetic variants influence the required dose of tacrolimus in heart transplant recipients.

After heart transplantation (HTx), the interindividual pharmacokinetic variability of immunosuppressive drugs represents a major therapeutic challenge due to the narrow therapeutic window between over-immunosuppression causing toxicity and under-immunosuppression leading to graft rejection. Although genetic polymorphisms have been shown to influence pharmacokinetics of immunosuppressants, data in the context of HTx are scarce. We thus assessed the role of genetic variation in CYP3A4, CYP3A5, POR, NR1I2, and ABCB1 acting jointly in immunosuppressive drug pathways in tacrolimus (TAC) and ciclosporin (CSA) dose requirement in HTx recipients. Associations between 7 functional genetic variants and blood dose-adjusted trough (C0) concentrations of TAC and CSA at 1, 3, 6, and 12 months after HTx were evaluated in cohorts of 52 and 45 patients, respectively. Compared with CYP3A5 nonexpressors (*3/*3 genotype), CYP3A5 expressors (*1/*3 or *1/*1 genotype) required around 2.2- to 2.6-fold higher daily TAC doses to reach the targeted C0 concentration at all studied time points (P ≤ 0.003). Additionally, the POR*28 variant carriers showed higher dose-adjusted TAC-C0 concentrations at all time points resulting in significant differences at 3 (P = 0.025) and 6 months (P = 0.047) after HTx. No significant associations were observed between the genetic variants and the CSA dose requirement. The CYP3A5*3 variant has a major influence on the required TAC dose in HTx recipients, whereas the POR*28 may additionally contribute to the observed variability. These results support the importance of genetic markers in TAC dose optimization after HTx.

(17) - De-Novo Low TAC/Low SIR Immunosuppression after HTx - 10 Year Results of a Prospective Trial

s S15 Conclusion: This was the first study to demonstrate a lower rate of CMV infection in patients treated with Tac vs. those treated with CsA after HTx.

(712) - Tacrolimus in Heart Transplant Recipients With Chagas Disease. Initial Experience

Heart transplant (HTx) is the treatment of choice in Chagasic advanced heart failure. CsA is the main immunosuppressant reported, but there is lack of information about of Tacrolimus use in this patient (p) group. Our aim was to analyze early and long term outcomes in Chagasic HTx p, comparing two different de novo immunosuppressive strategies.

134: A Randomized Study Using Humanized Monoclonal Antibody Against Cd52 (Campath-1h) and Tacrolimus in Heart Transplant Recipients

134: A Randomized Study Using Humanized Monoclonal Antibody Against Cd52 (Campath-1h) and Tacrolimus in Heart Transplant Recipients

Long-Term Efficacy and Safety of Conversion to Tacrolimus in Heart Transplant Recipients with Ongoing or Recurrent Acute Cellular Rejection

Despite the widespread use of potent immunosuppressive drugs, such as cyclosporin A and mycophenolate mofetil, ongoing and recurrent cellular rejection remain a common problem after heart transplantation. We aimed to describe the long-term effects of conversion from cyclosporine A to tacrolimus in patients with ongoing and recurrent cellular rejection. This was a single-centre retrospective analysis of 17 heart transplant recipients who were switched from cyclosporine A to tacrolimus due to ongoing (5 patients) or recurrent cellular rejection (12 patients). We studied long-term efficacy and safety of this approach. 167 endomyocardial biopsies were performed during a mean follow-up of 69.1 +/- 12.7 months. Thirteen biopsies (7.8%) in eight patients (47%) revealed higher grades of acute cellular rejection (Banff 2). However, they were not hemodynamically significant and did not require intravenous antirejection therapy. The mean rejection score was reduced significantly. Conversion to tacrolimus was tolerated in 82% pts without any significant side effects during a long-term follow-up. In conclusion, the conversion to tacrolimus in heart transplant recipients with ongoing or recurrent acute cellular rejection was safe and effective also during a long-term follow-up.

Účinnost a bezpečnost kombinované léčby atorvastatinem a tacrolimem u pacientů po transplantaci srdce

Úvod: Inhibitory HMG-CoA jsou běžnou součástí standardního léčebného protokolu po ortotopické transplantaci srdce (OHTx). Na druhé straně je jejich použití potenciálně nebezpečné vzhledem k jejich interakci s cyklosporinem A (CsA). Cílem této studie bylo zhodnotit účinnost a bezpečnost kombinované léčby atorvastatinem a tacrolimem (TAC) u pacientů po transplantaci srdce.Metody: Sledovali jsme skupinu 31 pacientů po OHTx s opakovaně dokumentovanými plazmatickými koncentracemi celko-vého cholesterolu vyššími než 5,5 mmol/l při současném podávání fluvastatinu. Hlavním imunosupresivem byl CsA. Následně byli pacienti převedeni na kombinaci TAC a atorvastatinu se zahajovací dávkou 20 mg. Pro nežádoucí účinky bylo nutno u čtyř pacientů tuto léčbu vysadit. Dále bylo sledováno zbývajících 27 pacientů po OHTx. Klinické vyšetření včetně vyšetření krve bylo provedeno jeden měsíc a čtyři měsíce po změně léčebného protokolu. U podskupiny 19 pacientů bylo provedeno kontrolní vyšetření i po sedmi měsících.Výsledky: Nebyl zjištěn ani jeden případ myalgie nebo zvýšení koncentrace kreatinkinázy v plazmě. Po prvním měsíci léčby došlo ke statisticky významnému snížení koncentrace celkového cholesterolu (6,06 &plusmn; 0,89 mmol/l oproti 4,74 &plusmn; 0,70 mmol/l; p &lt; 0,0001). Podobný trend byl pozorován u LDL-cholesterolu a apolipoproteinu-B. účinky léčby byly po celou dobu sledování stabilní.Závěry: U nemocných po OHTx vedlo převedení na kombinaci TAC a atorvastatinu ke statisticky významnému snížení koncentrací celkového cholesterolu, LDL-cholesterolu a apolipoproteinu-B.

Tacrolimus in Heart Transplant Recipients

The development of cyclosporine was pivotal in allowing cardiac transplantation to become an accepted treatment for patients with end-stage heart disease. More recently, tacrolimus has become available as a useful alternative to cyclosporine, and has been successfully combined with either azathioprine or the newer anti-proliferative agents, mycophenolate mofetil or sirolimus. Numerous randomized clinical trials have demonstrated that tacrolimus is comparable to cyclosporine in terms of overall patient survival and at least equally effective in preventing acute rejection. In addition, tacrolimus has been particularly effective as a rescue treatment in cases where recurrent rejection has occurred with cyclosporine. The adverse effects of tacrolimus differ from those of cyclosporine, and the drug particularly shows an improved profile with respect to hypertension, dyslipidemia, and long-term renal function. These data have recently led to the regulatory approval of tacrolimus for primary immunosuppression in patients undergoing cardiac transplantation in the US.

Konverze na tacrolimus u pacientů po transplantaci srdce s rekurentní rejekcí

Konverze na tacrolimus u pacientů po transplantaci srdce s rekurentní rejekcí

359: Sirolimus or mycophenolate mofetil (MMF): Which is the better partner for Tacrolimus in heart transplant recipients?

359: Sirolimus or mycophenolate mofetil (MMF): Which is the better partner for Tacrolimus in heart transplant recipients?

Tacrolimus

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.

Sirolimus and tacrolimus in clinical cardiac transplantation

Aim: The nephrotoxicity associated with calcineurin-inhibitors is dose dependent. The goal of this study is to determine whether a combination of tacrolimus and sirolimus will allow us to reduce the level of tacrolimus in heart transplant recipients, thus reduce the degree of tacrolimus-induced renal toxicity. Methods: Since March 2000, we have treated 12 consecutive primary heart transplant recipients with a combination of tacrolimus, sirolimus and steroids (Group I). The clinical data of these patients were compared with those of 10 patients who received tacrolimus, mycophenolate mofetil and steroids (Group II). The levels of sirolimus (24 hour trough) amd MMF were maintained at 8.0-12.0 ng/ml, and 1.5-3.0 ng/ml, respectively. A steroids tapering schedule was similar between groups. Results: The number of rejection episodes, tacrolimus doses and levels, serum creatinine, platelet counts, cholesterol and triglycerides of the two groups are presented in the table. There is no difference in the freedom from rejection (grade 2; Gr I: 72 13%, Gr II: 71 13%) or patient survival; however the rejection (grade 2) episode/patient, serum creatinine (at 2 weeks) and mean tacrolimus levels (at 3 months) are higher in group II (see Table). Conclusion: The short-term outcome of cardiac recipients under tacrolimus/sirolimus/steroids immunosuppressive regimen compares favorably with those under the tacrolimus/mycophenolate mofetil/steroids regimen. The lower tacrolimus level in the sirolimus group may translate into less nephrotoxicity.

Sirolimus and tacrolimus in clinical heart transplantation

Aim: The nephrotoxicity associated with calcineurin-inhibitors is dose dependent. The goal of this study is to determine whether a combination of tacrolimus and sirolimus will allow us to reduce the level of tacrolimus in heart transplant recipients, thus reduce the degree of tacrolimus-induced renal toxicity.