A Randomized Pharmacokinetic Study of Generic Tacrolimus Versus Reference Tacrolimus in Kidney Transplant Recipients

Pharmacokinetic analyses comparing generic tacrolimus preparations versus the reference drug in kidney transplant patients are lacking. A prospective, multicenter, open‐label, randomized, two‐period (14 days per period), two‐sequence, crossover and steady‐state pharmacokinetic study was undertaken to compare twice‐daily generic tacrolimus (Sandoz) versus reference tacrolimus (Prograf®) in stable renal transplant patients. AUC_0–12h and peak concentration (C_max) were calculated from 12 h pharmacokinetic profiles at the end of each period (days 14 and 28). Of 71 patients enrolled, 68 provided evaluable pharmacokinetic data. The ratios of geometric means were 1.02 (90% CI 97–108%, p = 0.486) for AUC_0–12h and 1.09 (90% CI 101–118%, p = 0.057) for C_max. Mean (SD) C₀ was 7.3(1.8) ng/mL for generic tacrolimus versus 7.0(2.1) ng/mL for reference tacrolimus based on data from days 14 and 28. Correlations between 12 h trough levels and AUC were r = 0.917 for generic tacrolimus and r = 0.887 for reference drug at day 28. These data indicate that generic tacrolimus (Sandoz) has a similar pharmacokinetic profile to the reference drug and is bioequivalent in kidney transplant recipients according to US Food and Drug Administration and European Medicines Agency guidelines.     

Invasive Pneumococcal Infections in Adult Lung Transplant Recipients

An increased risk of invasive pneumococcal infection (IPI) has been described among kidney or heart transplant recipients, but the epidemiology of IPI among lung transplant recipients has not been previously reported. We undertook a single center, retrospective cohort study to define the incidence, timing, clinical, and microbiologic features of IPI in lung transplant patients. Fourteen out of 220 recipients (6.4%) developed IPI at a median of 1.3 years after transplantation (incidence rate: 22.7 cases per 1000 person-years). All patients were receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis at the time of diagnosis, and 10 (71%) had TMP-SMX-resistant isolates. All isolates were from the 23 valent polysaccharide vaccine-associated serogroups. The high incidence of IPI in lung transplant recipients is similar to that reported in kidney and heart recipients. Alternative prevention strategies, including use of the conjugated pneumococcal vaccine, should be explored in future studies.     

Cardiovascular Risk Profile in Kidney Transplant Recipients Treated With Two Immunosuppressive Regimens: Tacrolimus and Mycophenolate Mofetil Versus Everolimus and Low-Dose Cyclosporine

Objective

The aim of this prospective study was to compare the cardiovascular risk (CVR) profile in patients treated with 2 different immunosuppressive regimens: tacrolimus and mycophenolate mofetil (TAC) compared with everolimus and low-dose cyclosporine (EVL).

Patients and Methods

Sixty consecutive renal transplant recipients prospectively assigned to TAC (n = 30) or to EVL (n = 30) were followed for 6 months. TAC group immunosuppression consisted of basiliximab, tacrolimus, mycophenolate mofetil (MMF), and steroid. EVL group immunosuppression consisted of basiliximab, everolimus, and low doses of cyclosporine and steroid. Main CVR factors analyzed were: hypertension, dyslipidemia, posttransplant diabetes mellitus, and weight gain.

Results

Six months posttransplantation, patients in the EVL group showed significantly higher mean serum cholesterol (P < .003) and serum triglyceride levels (P < .027), as well as a greater number of patients were receiving statin treatment (P < .05). Mean systolic blood pressure, mean diastolic blood pressure, number of patients treated for hypertension, number of antihypertensive medications prescribed per patient, posttransplant weight gain, and posttransplant diabetes mellitus were not significantly different among the EVL and TAC groups after 1, 3, and 6 months posttransplantation.

Conclusions

This study showed that at 6 months posttransplantation, patients on EVL displayed significantly greater dyslipidemia with respect to the TAC group. A longer follow-up will be necessary to discover whether the presence of everolimus in the immunosuppressive regimen provides significant benefits for the CVR of renal transplant recipients.     

Pharmacokinetics of Tacrolimus in Kidney Transplant Recipients: Twice Daily Versus Once Daily Dosing

Tacrolimus a macrolide immunosuppressant that is routinely given in two equally divided doses every 12 h. However, the time-dependent pharmacokinetics of tacrolimus suggest that once daily morning administration of tacrolimus may produce appropriate drug exposure. The purpose of this pilot study was to compare the pharmacokinetics and safety of twice vs. once daily administration of tacrolimus in stable kidney transplant recipients. Steady-state tacrolimus pharmacokinetic parameters were estimated on two occasions in an open-label, three-arm, two-period sequential study: twice daily dosing (Phase I) and once daily dosing (Phase II). In phase II, 18 patients were assigned to one of three arms: those taking 67%, 85% and 100% of their total twice daily dose once in the morning. In phase I, the mean area under the blood concentration-time curve (AUC) was higher after the morning dose, AUC(0-12) 117 +/- 40 vs. AUC(12-24) 97 +/- 30 ng/h/mL, p=0.012. In the 85% Group, the mean AUC ratio between twice and once daily was 1.0 (95% CI, 0.9-1.1) which predicted the best conversion ratio. Tacrolimus given once daily in the morning, at 85% of the twice daily dose, provides safe and equivalent drug exposure to twice daily dosing. This convenient dosing schedule may help to increase compliance and lower costs.     

Predicted Lifetimes for Adult and Pediatric Split Liver Versus Adult Whole Liver Transplant Recipients

Split liver transplantation allows 2 recipients to receive transplants from one organ. Comparisons of predicted lifetimes for two alternatives (split liver for an adult and pediatric recipient vs. whole liver for an adult recipient) can help guide the use of donor livers. We analyzed mortality risk for 48,888 waitlisted candidates, 907 split and 21,913 whole deceased donor liver transplant recipients between January 1, 1995 and February 26, 2002. Cox regression models for pediatric and adult patients assessed average relative wait list and post-transplant death risks, for split liver recipients. Life years gained compared with remaining on the waiting list over a 2-year period were calculated. Seventy-six splits (152 recipients) and 24 re-transplants resulted from every 100 livers (13.1% [adult] and 18.0% [pediatric] 2-year re-transplant rates, respectively). Whole livers used for 93 adults also utilized 100 livers (re-transplant rate 7.0%). Eleven extra life years and 59 incremental recipients accrued from each 100 livers used for split compared with whole organ transplants. Split liver transplantation could provide enough organs to satisfy the entire current demand for pediatric donor livers in the United States, provide more aggregate years of life than whole organ transplants and result in larger numbers of recipients.     

Tacrolimus Monotherapy in Recipients of Liver Transplant: A Single-Center Experience

IntroductionFollowing liver transplantation (LT), the majority of patients are treated with reduced-dose calcineurin inhibitors (CNIs) in combination with mycophenolate mofetil. The optimal timing for subsequent conversion to CNI monotherapy is not clearly defined. This study aims to evaluate the safety of conversion to CNI monotherapy after LT.MethodsThis was a single-center retrospective study of 100 consecutive patients who received CNI and mycophenolate mofetil combination regimen after LT at Singapore General Hospital from 2006 to 2018. Patient demographics, clinical parameters, and posttransplant complications (ie, rates of graft rejection, de novo malignancy, cytomegalovirus infection and renal impairment) were recorded.ResultsOne hundred patients were recruited and mean follow-up time in months ± standard deviation was 60.36 ± 41.73. Patients were divided into 2 groups based on institution of CNI monotherapy within (group 1) or beyond (group 2) 6 months. Twenty-five (25%) patients were on CNI monotherapy within 6 months post-LT. Overall patient survival was 83.7% at 5-years posttransplant. There was no statistical difference in the rates of posttransplant complications including liver graft rejection (4.0% vs 18.7%, P = .11); de novo malignancy (0.0% vs 8.0%, P = .33); cytomegalovirus infection (4.0% vs 1.3%, P = .44); and renal impairment (20.0% vs 40.0%, P = .069) between the 2 groups.ConclusionsSuccessful institution of CNI monotherapy within 6 months is safe, and does not increase the risk of rejection.     

环孢素A血药浓度监测的临床意义

目的：探讨环孢素A(CsA)血药谷值浓度监测的临床意义。方法：对269例同种肾移植受者术后4081次CsA血药谷值浓度进行了分析。结果：随着移植肾存活时间的延长,CsA治疗浓度水平呈逐渐下降趋势。排斥反应发生时及排斥反应前两周内,CsA浓度不仅低下,而且有一持续约2周的显著下降过程,平均降幅达31％。术后一周内急性排斥反应的发生与CsA浓度关系不大。过高的CsA浓度则与肾中毒’反应有关。CsA治疗浓度与发生排斥反应时的浓度及肾中毒浓度均有一定程度的重叠。结论：认为术后CsA理想的治疗窗浓度应为：术后第1月内为300-450ng／ml,3月内为250～400ng／ml,半年内为200～350ng／ml,以后CsA浓度最好维持在150～250ng／ml。     

One-Year Results with Extended-Release Tacrolimus/MMF, Tacrolimus/MMF and Cyclosporine/MMF in De Novo Kidney Transplant Recipients

Once-daily tacrolimus extended-release formulation (Prograf XL, formerly referred to as MR or MR4) was compared with the twice-a-day tacrolimus formulation (TAC) and cyclosporine microemulsion (CsA), all administered in combination with mycophenolate mofetil (MMF), corticosteroids and basiliximab induction, in a phase 3, randomized (1:1:1), open-label trial in 638 de novo kidney transplant recipients. In combination with MMF and corticosteroids, XL had an efficacy profile comparable to TAC and CsA. XL/MMF and TAC/MMF were statistically noninferior at 1-year posttransplantation to CsA/MMF for the primary efficacy endpoint, efficacy failure (death, graft loss, biopsy-confirmed acute rejection (BCAR) or lost to follow-up). One-year patient and graft survival were 98.6% and 96.7% in the XL/MMF group, 95.7% and 92.9% in TAC/MMF group and 97.6% and 95.7% in CsA/MMF group. The safety profile of XL in comparison with CsA was similar to that observed with TAC in this study and consistent with previously published reports of TAC in comparison with CsA. The results support the safety and efficacy of tacrolimus in combination with MMF, corticosteroids and basiliximab induction, as well as XL as a safe and effective once-daily dosing alternative.     

A Randomized Controlled Trial of Envarsus Versus Immediate Release Tacrolimus in Kidney Transplant Recipients With Delayed Graft Function

BackgroundThe incidence of delayed graft function (DGF) among kidney transplant recipients (KTRs) in the United States continues to increase. The effect of immediate-release tacrolimus (tacrolimus) compared with extended-release tacrolimus (Envarsus) among recipients with DGF is unknown.MethodsThis was a single-center open-label randomized control trial among KTRs with DGF (ClinicalTrials. gov, NCT03864926). KTRs were randomized either to continue on tacrolimus or switch to Envarsus at a 1:1 ratio. Duration of DGF (study period), number of dialysis treatments, and need for adjustment of calcineurin inhibitor (CNI) doses during the study period were outcomes of interest.ResultsA total of 100 KTRs were enrolled, 50 in the Envarsus arm and 50 in the tacrolimus arm; of those, 49 in the Envarsus arm and 48 in the tacrolimus arm were included for analysis. There were no differences in the baseline characteristics, all P > .5, except donors in the Envarsus arm had higher body mass index (mean body mass index 32.9 ± 11.3 vs 29.4 ± 7.6 kg/m² [P = .007]) compared with the tacrolimus arm. The median duration of DGF (5 days vs 4 days, P = .71) and the number of dialysis treatments (2 vs 2, P = .83) were similar between the groups. However, the median number of CNI dose adjustments during the study period in the Envarsus group was significantly lower (3 vs 4, P = .002).ConclusionsEnvarsus patients had less fluctuation in the CNI level, requiring fewer CNI dose adjustments. However, there were no differences in the DGF recovery duration or number of dialysis treatments.     

Cyclosporine versus Tacrolimus Treated Liver Transplant Recipients with Chronic Hepatitis C: Outcomes Analysis of the UNOS/OPTN Database

Recurrent hepatitis C virus (HCV) remains a problematic cause of morbidity and mortality for liver transplant patients. Immunosuppression including calcineurin‐inhibitors has been implicated in the acceleration of recurrent HCV. Recent studies suggest that outcomes may be better with cyclosporine (CSA‐ME) compared to tacrolimus (TAC), but the data are inconclusive. We retrospectively analyzed data received from the United Network for Organ Sharing on 8809 chronic HCV liver transplant recipients receiving either cyclosporine microemulsion (CSA‐ME) or tacrolimus (TAC) as maintenance immunosuppression prior to discharge. We analyzed patient death, graft failure, failure due recurrent disease and acute cellular rejection (ACR) for CSA‐ME versus TAC treated patients. Three‐year unadjusted patient and graft survival rates were 76.8% and 71.5%, respectively, in the CSA‐ME group versus 79.9% and 75.0% in the TAC group. Propensity score‐adjusted results suggest CSA‐ME treated patients are at increased risk of patient death and graft failure [Hazards ratio (HR) = 1.17; 95% CI = 1.01–1.36 and HR = 1.19; 95% CI = 1.04–1.35, respectively] and biopsy‐confirmed AR (HR = 2.03; 95% CI = 1.54–2.67) compared to TAC treated patients. These results provide evidence to reconsider the targeted administration of CSA‐ME to HCV‐infected liver transplant recipients.     

A 1-Year Randomized Controlled Study of Everolimus Versus Mycophenolate Mofetil With Reduced-Dose Cyclosporine in Maintenance Heart Transplant Recipients

Background

The aim of this study was to demonstrate noninferiority of everolimus with reduced cyclosporine (CsA) vs mycophenolate mofetil (MMF) with reduced CsA in improving renal function.

Methods

In this 1-year randomized, open-label, noninferiority study in maintenance heart transplant recipients with impaired renal function 70 patients received everolimus (n = 36) or MMF (n = 34) in combination with reduced CsA. The planned sample size was not reached as the study was prematurely discontinued due to slow recruitment.

Results

Noninferiority of the everolimus regimen could not be shown: In the total population MMF seemed to be favorable on renal function assessed by serum creatinine and filtration rates, but not in the subset of patients who reached the intended reduced CsA level. Incidence rates of rejection episodes were significantly higher under MMF at month 6 (P = .0332).

Conclusions

Overall, the results of this trial using reduced CsA in combination with either everolimus or MMF show that there is evidence to reduce the CsA level when everolimus is given concomitantly and that the benefit of MMF with reduced CsA levels is limited due to insufficient immunosuppression.     

Chickenpox in Adult Renal Transplant Recipients

Five of 610 adults developed chickenpox between 35 days and9.2 years after renal transplantation, and only one patientsurvived. All patients received prednisolone and azathioprineduring the incubation period. Corticosteroid therapy was continued,but azathioprine was stopped after diagnosis. Four patientswere treated with acyclovir, but three were given suboptimaldoses. The patient who survived had been taking the lowest doseof azathioprine and was given the recommended dose of acyclovir.All patients who died developed disseminated intravascular coagulation,and at postmortem examination were found to have had cerebralhaemorrhage. None of the patients treated with acyclovir hadevidence of active varicella-zoster virus infection at postmortem examination, but two had disseminated bacterial and fungalinfections. Chickenpox follows a severe and often fatal course in adultswith renal transplants. Prompt acyclovir therapy can be effective,provided an adequate dose is given. Attention should be directedtowards prevention by the identification and immunisation ofat risk patients prior to transplantation.