Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This phase IV multicentre study compared the use of LCP-tacrolimus with standard of care (either standard (SR) or prolonged release (PR) tacrolimus depending on centre preference) in de-novo kidney transplant recipients. The authors demonstrated that despite a significantly lower total daily dose in the LCP-tacrolimus group, there was no difference in trough levels or short-term clinical outcomes between groups. The study is fairly well-designed, although the decision to allow the control arm to receive SR or PR tacrolimus at centre discretion is slightly odd as the study is left underpowered to show a difference in comparison to either in isolation. It is not really clear if there is any clinical benefit to an overall dose reduction; trough levels are similar so overall exposure is likely to be equivalent. Certainly, the study provides confirmation that the LCP-tacrolimus formulation is safe and equivalent in clinical efficacy to SR and PR formulations.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
2
Review:
Tacrolimus has become the calcineurin inhibitor (CNI) of choice for maintenance immunosuppression following solid organ transplantation, demonstrating lower risk of acute rejection and improved graft survival compared to cyclosporine (1). It does have some drawbacks, including an increased risk of new-onset diabetes and an unfavourable pharmacokinetic profile with a rapid peak and narrow therapeutic window. There have been a number of attempts to produce a tacrolimus formulation with a flatter pharmacokinetic profile and less pronounced peak, allowing once-daily dosing. Such a profile may have potential to reduce toxicity by reducing peak levels, and once-daily dosing may have an impact on compliance by reducing pill burden. The most-recent of these formulations is LCP-tacrolimus, which is reported to increase bioavailability and reduce first-pass metabolism compared to earlier formulations (2). In a recent, phase 4 multicentre study, Budde and colleagues investigated the role of LCP-tacro in 401 de novo kidney transplant recipients across 10 European countries (3). Recipients were randomised to receive LCP-tacro or “standard care”, which could be immediate-release (IR) or prolonged-release (PR) tacrolimus alongside basiliximab, mycophenolate and corticosteroids. The authors demonstrated a significantly lower daily tacrolimus dose for the LCP-tacrolimus group to achieve slightly higher trough levels, confirming the improved bioavailability seen in earlier studies. However, there were no significant differences in clinical outcomes including rejection rates, graft survival, graft function or toxicity. This large study was well-designed and reported, with central block-randomisation stratified by site and use of a modified intent-to-treat analysis. Whilst reflective of real-world variation in practice, the decision to allow either IR or PR tacrolimus as standard of care does limit the conclusions somewhat, as there is insufficient power to compare LCP-tacrolimus to either alternative formulation in isolation. In reality, this study is unlikely to have much impact on clinical practice. A reduction in daily dose of tacrolimus alone is not sufficient to justify switching to what is presumably a more expensive formulation, although no health economic analysis is presented. Extended follow-up would be required to see if there is any benefit to the flattened pharmacokinetic profile on the risk of CNI toxicity in the longer-term. References 1. Webster A, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. The Cochrane Database of Systematic Reviews 2005; : CD003961. 2. Budde K, Bunnapradist S, Grinyo JM et al. Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of Phase III, double-blind, randomized trial. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2014; 14: 2796. 3. Budde K, Rostaing L, Maggiore U et al. Prolonged-Release Once-Daily Formulation of Tacrolimus Versus Standard-of-Care Tacrolimus in de novo Kidney Transplant Patients Across Europe. Transplant International 2022; 35: 10225.
Aims:
This study aimed to compare the posttransplant outcomes of LCP-tacrolimus (LCPT) versus current standard-of-care tacrolimus (immediate-release tacrolimus (IR-Tac) or prolonged-release tacrolimus (PR-Tac), according to centre preference) in de novo kidney transplant recipients.
Interventions:
Participants were randomly assigned to receive either LCPT or current standard-of-care tacrolimus.
Participants:
403 de novo kidney transplant recipients (≥18 years).
Outcomes:
The primary outcome was the tacrolimus total daily dose (TDD). The secondary clinical outcomes were treatment failure, treatment discontinuation, delayed graft function, local diagnosis of acute rejection requiring treatment, and concomitant immunosuppressive medications.
Follow Up:
6 months
Background: Tacrolimus is the calcineurin inhibitor of choice for preventing acute rejection episodes in kidney transplant patients. However, tacrolimus has a narrow therapeutic range that requires regular monitoring of blood concentrations to minimize toxicity. A new once-daily tacrolimus formulation, LCP-tacrolimus (LCPT), has been developed, which uses MeltDose™ drug-delivery technology to control drug release and enhance overall bioavailability. Our study compared dosing of LCPT with current standard-of-care tacrolimus [immediate-release tacrolimus (IR-Tac) or prolonged-release tacrolimus (PR-Tac)] during the 6 months following de novo kidney transplantation. Comparisons of graft function, clinical outcomes, safety, and tolerability for LCPT versus IR-Tac/PR-Tac were also performed. Methods: Standard immunological risk patients with end-stage renal disease who had received a de novo kidney transplant were randomized (1:1) to LCPT (N = 200) or IR-Tac/PR-Tac (N = 201). Results: Least squares (LS) mean tacrolimus total daily dose from Week 3 to Month 6 was significantly lower for LCPT than for IR-Tac/PR-Tac. Although LS mean tacrolimus trough levels were significantly higher for LCPT than IR-Tac/PR-Tac, tacrolimus trough levels remained within the standard reference range for most patients. There were no differences between the groups in treatment failure measures or safety profile. Conclusion: LCPT can achieve similar clinical outcomes to other tacrolimus formulations, with a lower daily dose. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT02432833.
Prof. Dr. Hans J Schlitt Department of Surgery University of Regensburg Medical Center Regensburg, Germany
Conflicts of Interest:
No
Clinical Impact Rating
3
Review:
The authors have compared standard (twice daily) tacrolimus (TAC) vs. extended-release TAC (once daily) in 2 x 29 de-novo liver transplant recipients. They could show that de-novo use of extended-release TAC is safe in terms of liver function and rejection rate. There was also a somewhat, although not significantly, lower peak level of TAC in blood when using extended-release TAC with the same trough levels. Misfortunately, no data on renal function were provided. There was also a subgroup of patients in whom study drugs were continued for one year, with no relevant differences in adverse reactions in both groups. Thus, extended-release TAC in de-novo liver transplant patients appears to be safe. Although the study group is rather small, these results on safety can be generalized – at least for “standard” patients with rather good liver function after transplantation. Whether this is also the case in patients with bad liver function and high bilirubin, however, remains unclear. In conclusion, the data strongly suggest that extended-release TAC may safely be used in the “standard” situation after liver transplantation starting immediately after transplantation.
The pharmacokinetics of once-daily extended-release tacrolimus tablets (LCPT) in de novo liver transplantation have not been previously reported. In this phase II, randomized, open-label study, de novo liver transplant recipients were randomized to LCPT 0.07-0.13 mg/kg/day (taken once daily; n = 29) or twice-daily immediate-release tacrolimus capsules (IR-Tac) at 0.10-0.15 mg/kg/day (divided twice daily; n = 29). Subsequent doses of both drugs were adjusted to maintain tacrolimus trough concentrations of 5 to 20 ng/mL through day 90, and 5-15 ng/mL thereafter. Twenty-four-hour pharmacokinetic profiles were obtained on days 1, 7, and 14, with trough concentration and efficacy/safety monitoring through year 1. Similar proportions of patients in both groups achieved therapeutic trough concentrations on days 7 and 14 (day 7: LCPT = 78%, IR-Tac = 75%; day 14: LCPT = 86%, IR-Tac = 91%) as well as similar systemic and peak exposure. There was a robust correlation between drug concentration at time 0 and area under the concentration-time curve for both LCPT and IR-Tac (respectively, day 7: r = 0.86 and 0.79; day 14: r = 0.93 and 0.86; P < .0001 for all). Dose adjustments during days 1 to 14 were frequent. Thirty-five patients completed the extended-use period. No significant differences in adverse events were seen between groups. Incidence of biopsy-proven acute rejection (LCPT = 6 and IR-Tac = 4) was similar on day 360. Between formulations, overall exposure was similar at 1 week after transplant with the characteristic delayed-release pharmacokinetic profile of LCPT demonstrated in this novel population. These data support further investigation of the safety and efficacy of LCPT in de novo liver transplantation.
Dr. Liset Pengel, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
The primary objective of this Korean, open-label RCT was to test non-inferiority of Advagraf versus Prograf and review the safety and efficacy of both drugs in living-donor liver transplant recipients. Based on the primary outcome concentration-time curve over 24-hours (AUC0-24) power calculations indicated that 100 patients were needed, although no details of the power calculation was given. A randomisation list was generated and 100 patients were randomised 4 days posttransplant using sealed envelopes. Results showed that higher daily doses of Prograf versus Advagraf were needed to achieve similar exposure. The differences in terms of acute rejections episodes (16% versus 10% for Advagraf and Prograf, respectively) and creatinine clearance (62.9 ± 15.1 and 77.2 ± 23.7 mL/min) are potentially clinically significant but the study was not powered for these outcomes.
Expert Review
Reviewer:
Prof Dr Dirk R J Kuypers, MD PhD, Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Belgium.
Conflicts of Interest:
No
Clinical Impact Rating
3
Review:
The once-daily, prolonged-release formulation of tacrolimus (PR-T) was compared to the bid, immediate-release formulation (IR-T) in a randomized (1:1) open-label pharmacokinetic study (PK) in 100 de novo Korean living-donor liver recipients (LDLT). Safety and efficacy were assessed for 24 weeks while tacrolimus AUC0-24hrs were obtained on Day 6 and 21 after transplantation. Tacrolimus was started intravenously in all patients and switched on postoperative Day 5 to oral PR-T (6-fold iv dose) or IR-T (4-fold iv dose). Similar to kidney transplantation, dose requirements of PR-T remained higher than for IR-T in liver recipients throughout the study. The linear relationship between tacrolimus C24hrs and corresponding AUC0-24hrs was good for both PR-T and IR-T. No significant differences were observed between both study arms in terms of biopsy-proven acute rejection (only one episode in each arm), adverse events and renal function. While the PK profiles obtained on Day 6 were difficult to interpret and compare because of the immediate prior switch to oral PR-T and IR-T on Day 5 (no steady-state), the AUC0-24hrs curves on Day 21 confirmed the known differences in dose-normalized exposure between both formulations. In contrast to kidney transplantation, the combinational donor and recipient genotypes for CYP3A hepatic and intestinal enzymes (and maybe the ABCB1 transporter) do play an important role in early tacrolimus exposure after liver transplantation. The changes noted after 4 weeks with decreasing dose requirements for both formulations (more for PR-T) could, at least in part, be related to the time-dependent interplay between the recipient's intestinal metabolism and the restoration of donor hepatic metabolic capacity, both determined by their respective pharmacogenetic profiles. This study confirms that the use of PR-T in de novo LDLT requires a higher loading dose compared with IR-T and time-related dose adaptations in order to maintain preset target concentration ranges.
Aims:
To compare the pharmacokinetics (PK), safety, and efficacy of once- daily, prolonged- release tacrolimus (PR-T) with twice- daily, immediate- release tacrolimus (IR-T) in adult de novo living- donor liver transplant (LDLT) recipients in Korea.
Interventions:
All patients received intravenous tacrolimus from Day 0 (transplantation) for 4 days and were randomized (1:1) to receive oral PR-T or IR-T from Day 5.
Participants:
100 patients (≥20 years and undergoing de novo living-donor liver transplant) were included (PR-T, n = 50; IR-T, n = 50).
Outcomes:
Primary outcome was PK assessment reported as area under the concentration- time curve over 24 hour on Days 6 and 21. Secondary outcomes assessed included tacrolimus concentration at 24 hour, patient/graft survival, biopsy-confirmed acute rejection, and TEAEs.
Follow Up:
Up to Week 24 post transplantation.
Randomized, open-label, comparative, single-center, Phase 4, 24-week study comparing pharmacokinetics (PK), safety, and efficacy of once-daily, prolonged-release tacrolimus (PR-T) with twice-daily, immediate-release tacrolimus (IR-T) in adult de novo living-donor liver transplant (LDLT) recipients in Korea. All patients received intravenous tacrolimus from Day 0 (transplantation) for 4 days and were randomized (1:1) to receive oral PR-T or IR-T from Day 5. PK profiles were taken on Days 6 and 21. Primary endpoint: area under the concentration-time curve over 24 hour (AUC0-24 ). Predefined similarity interval for confidence intervals of ratios: 80%-125%. Secondary endpoints included: tacrolimus concentration at 24 hour (C24 ), patient/graft survival, biopsy-confirmed acute rejection (BCAR), treatment-emergent adverse events (TEAEs). One-hundred patients were included (PR-T, n = 50; IR-T, n = 50). Compared with IR-T, 40% and 66% higher mean PR-T daily doses resulted in similar AUC0-24 between formulations on Day 6 (PR-T:IR-T ratio of means 96.8%), and numerically higher AUC0-24 with PR-T on Day 21 (128.8%), respectively. Linear relationship was similar between AUC0-24 and C24 , and formulations. No graft loss/deaths, incidence of BCAR and TEAEs similar between formulations. Higher PR-T vs IR-T doses were required to achieve comparable systemic exposure in Korean de novo LDLT recipients. PR-T was efficacious; no new safety signals were detected.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This Chinese study investigates the pharmacokinetics of a dispersible formulation of MMF versus standard capsules. The concentration-time profile for dispersible MMF appears flatter, with a lower, later peak. The authors report limited sampling equations to predict the AUC from concentrations within the first 6 hours post-dose. The clinical significance of the difference in shape of the concentration-time profile is unclear as no clinical outcome data are reported. The utility of TDM for MMF is also questionable for the majority of patients, as accurate sample collection for up to 6 hours post-dose is resource intensive and burdensome for patients, with limited evidence for clinical benefit. The equations presented here may not generalise to other populations.
Expert Review
Reviewer:
Dr Rachel Hilton, Guy's & St Thomas' NHS Foundation Trust, United Kingdom.
Conflicts of Interest:
No
Clinical Impact Rating
0
Review:
This is a small study conducted in a single centre in China. The study compares two formulations of mycophenolate mofetil, dispersible tablets and capsules. The study enrolled 40 recipients of deceased donor kidneys and randomised them according to the toss of a coin to receive 750mg twice daily of mycophenolate mofetil either as dispersible tablets or as capsules. At day seven after transplantation, patients underwent twelve-hour concentration time curve sampling (AUC0-12h) for mycophenolic acid. Lower peak concentration (Cmax) was observed in the group that was given dispersible mycophenolate mofetil tablets. Clinical outcomes were not compared and the six patients with adverse outcomes (five with delayed graft function and one with acute rejection) were excluded from the analysis. Thus, it is not possible to say whether there is any clinically relevant difference between the two drug formulations. I think dispersible mycophenolate tablets may only be available in China, so the relevance of this study to a non-Chinese population is unclear.
Aims:
To compare the pharmacokinetic properties of mycophenolate mofetil (MMF) as dispersible tablets, versus capsules in kidney transplant recipients.
Interventions:
Participants were randomised to receive either MMF dispersible tablets or MMF capsules.
Participants:
46 kidney transplant recipients from brain-dead donors receiving the immunosuppressive regimen of of MMF, tacrolimus and prednisone, aged 18 – 55 years.
Outcomes:
Measured outcomes included peak concentration, time to peak concentration, and predicted and measured area under the concentration-time curve.
Follow Up:
7 days
PURPOSE:
To assess the pharmacokinetic properties of mycophenolate mofetil (MMF) dispersible tablets and capsules by the enzyme multiplied immunoassay technique (EMIT) in Chinese kidney transplant recipients in the early post-transplantation phase and to develop the equations to predict mycophenolic acid (MPA) area under the 12-hour concentration-time curve (AUC0-12h) using a limited sampling strategy (LSS).
METHODS:
Forty patients who underwent renal transplantation from brain-dead donors were randomly divided into dispersible tablets (Sai KE Ping; Hangzhou Zhongmei Huadong Pharma) and capsules (Cellcept; Roche Pharma, Why, NSW, Australia) groups, and treated with MMF combined with combination tacrolimus and prednisone as a basic immunosuppressive regimen. Blood samples were collected before treatment (0) and at 0.5,1, 1.5, 2, 4, 6, 8, 10, and 12 hours post-treatment and 7 days after renal transplantation. Plasma MPA concentrations were measured using EMIT. LSS equations were identified using multiple stepwise linear regression analysis.
RESULTS:
The peak concentration (Cmax) in the MMF dispersible tablets (MMFdt) group (7.0 ± 2.8) mg/L was reduced compared with that in the MMF capsules (MMFc) group (10.8 ± 6.2 mg/L; P = .012); time to peak concentration in the MMFdt group was 3.2 ± 2.3 hours, which was nonsignificantly elevated compared with that of the MMFc group (2.2 ± 1.7 hours). Three-point estimation formulas were generated by multiple linear regression for both groups: MPA-AUCMMFdt = 3.542 + 3.332C0.5h + 1.117C1.5h + 3.946C4h (adjusted r2 = 0.90, P < .001); MPA-AUCMMFc = 8.149 + 1.442C2h + 1.056C4h + 7.133C6h (adjusted r2 = 0.88, P < .001). Both predicted and measured AUCs showed good consistency.
CONCLUSIONS:
After treatment with MMF dispersible tables or MMF capsules, the Cmax of MPA for the MMFdt group was significantly lower than that of the MMFc group; there was no significant difference in other pharmacokinetic parameters. Three-time point equations can be used as a predictable measure of the AUC0-12h of MPA.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This small but interesting RCT investigates the use of immune monitoring using NFAT-regulated gene expression (NFAT-RE) in stable kidney transplant recipients. All patients received cyclosporine and MMF with/without steroids, and control patients were monitored using standard trough cyclosporine levels. The authors demonstrate a significant improvement in pulse-wave velocity and GFR with NFAT-RE monitoring, with no obvious excess in adverse events or rejection. The small size of this study means that further evidence would be required to demonstrate safety in terms of rejection and graft survival. It appears, however, that NFAT-RE monitoring may allow minimisation of cyclosporine dose safely in these stable, low risk recipients. It is worth noting that trough cyclosporine levels in the standard monitoring arm increased over the 12-month study period, with a corresponding fall in GFR, which does raise the risk of treatment bias in a non-blinded study such as this.
Expert Review
Reviewer:
Professor Ron Shapiro, Kidney/Pancreas Transplantation, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mt. Sinai, USA.
Conflicts of Interest:
No
Clinical Impact Rating
5
Review:
This is an extremely interesting trial of utilizing immunologic monitoring to manage immunosuppression in stable renal transplant recipients. Patients were randomized either to routine PK monitoring (i.e. peak and trough levels) or NFAT-regulated gene expression. Patients randomized to NFAT-regulated gene expression had reduced cardiovascular risk, as assessed by pulse wave velocity, fewer infections, and better renal function than the control group. This is a very important trial. Most immunosuppression is, at some level, an educated guess about what patients should be receiving, based on a composite of clinical and laboratory factors, but without any real immunologic monitoring data. This trial utilized immunologic monitoring to titrate immunosuppressive drug dosing. Even with a very small number of patients, the authors were able to demonstrate a benefit of immunologic monitoring. The study utilized an immunosuppressive agent, cyclosporine that is used in a very small minority of transplant recipients. This work should be repeated by other centers, with larger numbers of patients, utilizing tacrolimus-based immunosuppression. If the findings from this initial experience are replicated, this could lead to a sea change in how patients are managed after transplantation.
Aims:
To compare the monitoring of cyclosporine A (CsA) using nuclear factor of activiated T-cells -regulated gene expression (NFAT-RE), versus standard CsA trough level (C0) monitoring.
Interventions:
Participants were randomly assigned to either standard monitoring (CsA dose adjusted to target a C0 of 80–150 μg/L), or NFAT-RE (CsA adjusted to target a residual NFAT-RE of 15–30%).
Participants:
55 renal allograft recipients from a deceased or living donor ≥6 months prior to study entry, aged ≥18 years with stable renal allograft function, and receiving CsA microemulsion, mycophenolic acid with or without low-dose steroids.
Outcomes:
The primary outcome measured was the change in arterial stiffness, assessed by pulse wave velocity. Secondary outcomes included peripheral and central blood pressure, cardiac augmentation index, biopsy-proven acute rejection, graft loss or death, renal function, safety and tolerability.
Follow Up:
12 months
BACKGROUND:
A new immune monitoring tool which assesses the expression of nuclear factor of activated T cells (NFAT)-regulated genes measures the functional effects of cyclosporine A. This is the first prospective randomized controlled study to compare standard pharmacokinetic monitoring by cyclosporine trough levels to NFAT-regulated gene expression (NFAT-RE).
METHODS:
Expression of the NFAT-regulated genes was determined by qRT-PCR at cyclosporine trough and peak level. Cardiovascular risk was assessed by change of pulse wave velocity from baseline to month 6. Clinical follow-up was 12 months.
RESULTS:
In total, 55 stable kidney allograft recipients were enrolled. Mean baseline residual NFAT-RE was 13.1 ± 9.1%. Patients in the NFAT-RE group showed a significant decline in pulse wave velocity from baseline to month 6 versus the standard group (-1.7 ± 2.0 m/s vs 0.4 ± 1.4 m/s, P < 0.001). Infections occurred more often in the standard group compared with the immune monitoring group. No opportunistic infections occurred with NFAT-RE monitoring. At 12 months of follow-up, renal function was significantly better with NFAT-RE versus standard monitoring (Nankivell glomerular filtration rate: 68.5 ± 17.4 mL/min vs 57.2 ± 19.0 mL/min; P = 0.009).
CONCLUSIONS:
NFAT-RE as translational immune monitoring tool proved efficacious and safe in individualizing cyclosporine therapy, with the opportunity to reduce the cardiovascular risk and improve long-term renal allograft function.
Professor Stuart J. Knechtle, Duke Transplant Center, USA.
Conflicts of Interest:
No
Clinical Impact Rating
3
Review:
This comparative pharmacokinetic trial evaluates factors which affect AUC and trough levels between two tacrolimus formulations in kidney transplant recipients, twice daily Prograf and once daily Advagraf. The studied population was predominantly Caucasian males with BMI averages of 27, possibly making this comparison less applicable to a more diverse population with respect to gender, obesity, or different metabolic enzyme polymorphisms. This study confirms the challenge of clinical monitoring, that the use of a trough level for estimating tacrolimus exposure is only as accurate as the drug administration and lab sampling times. Drug formulation, time from transplant, diurnal variation and gene expression of metabolic enzymes are likely to affect tacrolimus dose requirements, and increase the discordance between trough levels and AUC. Pharmacokinetic comparison trials such as this continue to be important to allow us to better predict dose requirements of tacrolimus, especially as the number of available tacrolimus formulations increases in the market. Unfortunately, even as we understand more about pharmacogenomic and pharmacokinetic variances between individuals, we still lack clinical tools to assess the impact of drug exposure and the level of immunosuppression or risk for drug toxicities.
BACKGROUND:
Several studies found differences in tacrolimus whole blood trough levels (C0) or area-under-the curve (AUC) between the twice-daily (Tac-BID) and once-daily (Tac-OD) formulations given to kidney transplant recipients at equal doses. As C0 is widely used as a surrogate of the AUC for individual dose adjustment, this study investigated the correlation and proportionality between C0 and the 24h-AUC, depending on the formulation, time post-transplantation, pharmacogenetics traits and other individual characteristics.
METHODS:
45 adult kidney transplant recipients were randomized to receive either Tac OD or Tac BID. On days 8±1 (D8) and 90±3 (month 3, M3), blood samples were collected over 24h in both groups. Tacrolimus concentrations were determined using HPLC-MS/MS and common CYP3A5, CYP3A4 and ABCB1 genotypes characterized using allelic discrimination assays. Tacrolimus population pharmacokinetics was studied in the two patient groups using the Iterative Two Stage (ITS) technique, considering a one-compartment model with two gamma laws to describe the absorption phase. Bayesian estimation based on the C0, C1h and C3h concentrations was employed to estimate individual Tac AUC0-12h and AUC12-24h (for Tac BID), or AUC0-24h (for Tac OD). Multiple linear regression was used to evaluate the influence of Tac formulation, post-transplantation period, recipient gender, existing glucose metabolism disorders, and CYP3A5, CYP3A4 and ABCB1 genotypes on C0, AUC0-24h and the AUC-to-trough concentration ratios.
RESULTS:
The Full Analysis Set comprised 22 patients on Tac OD and 20 on Tac BID. Tac exposure indices as well as their time evolution were similar in the two groups. Multi-linear modeling analysis showed that the Tac dose was higher with Tac-OD than Tac-BID, on D8 than at M3 and in CYP3A5 expressors (p<0.0001 for all). No such influence was found on C0 or C24h, while the AUC0-24h was significantly higher on D8 than at M3. The AUC0-24h/C0 ratio was not affected by the drug formulation and the polymorphisms studied, but it was significantly lower on D8 than at M3 (p=7.8×10-5). In contrast, both the post-transplantation period (p=1.53×10-4), and CYP3A5 expression (p=0.003) had a significant influence on the AUC0-24h/C24h ratio, explaining 19% and 12% of its variability, respectively. Consistently, for both Tac formulations, the AUC0-24h was better correlated with C24h than C0, and for Tac-BID the AUC0-12h was better correlated with C12h than C0.
CONCLUSIONS:
This study confirms that the precisely timed 12h- or 24h-post-dose blood concentration (as opposed to the vaguely defined 'trough level') is a convenient surrogate of the 24h-AUC of tacrolimus for the two TAC formulations over the first 3 months post-transplantation. Still, for a given C24h value, AUC0-24h was higher on D8 and in CYP3A5 expressors. Bayesian estimation of AUC0-12h for TAC BID and AUC0-24h for TAC OD is feasible using only 3 time points within the first 3h, thus giving access to the actual overall exposure.
Professor Josep M Grinyó, University of Barcelona, Spain.
Clinical Impact Rating
3
Review:
The ASERTAA study is a prospective, randomized, multicentre, open, crossover study to assess in African American (AA) transplant recipients the influence of CYP3A5 genotype on tacrolimus exposure and the pharmacogenetic differences between CYP3A5 expressers (high tacrolimus metabolisers) and non-expressers in patients receiving immediate-release tacrolimus formulation (IR-TAC) or extended-release LCP tacrolimus (LCP-TAC), which have distinct pharmacokinetic profiles. The main findings of the study are that overall in a conversion ratio from IR-TAC to LCP-TAC of 1:0.85, the AA population showed higher exposures of tacrolimus mainly in Cmin and AUC0-24h, even after dose normalization, and that the overall PK profiles of both formulations are similar to those described in other kidney and liver transplant populations. Interestingly, CYP3A5 expressers treated with LCP-TAC displayed lower Cmax (31%), and higher AUC0-24h (12%) than patients under IR-TAC. In contrast, non-expressers had similar Cmax and AUC with both formulations, but higher Cmin with LCP-TAC. These differences might derive from the decreasing CYP3A5 enzymatic activity along the intestinal tract, as LCP-TAC is also absorbed in the distal segments of the gut. Despite the small numbers, the findings of this study may suggest to review the recommended conversion ratios from IR-TAC to LCP-TAC in AA patients and that this last formulation may attenuate the impact of high tacrolimus metabolism in AA CYP3A5 expressers, which might result in a more predictable drug exposure and lower peak concentrations, with potential better clinical tolerance. Larger studies with higher numbers of patients including additional SNPs and their possible clustering might be of interest.
BACKGROUND:
Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile.
STUDY DESIGN:
Randomized prospective crossover study.
SETTING & PARTICIPANTS:
50 African American maintenance kidney recipients on stable IR-Tac dosing.
INTERVENTION:
Recipients were randomly assigned to continue IR-Tac on days 1 to 7 and then switch to LCPT on day 8 or receive LCPT on days 1 to 7 and then switch to IR-Tac on day 8. The LCPT dose was 85% of the IR-Tac total daily dose.
OUTCOMES:
Tacrolimus 24-hour AUC (AUC0-24), peak and trough concentrations (Cmax and Cmin), time to peak concentration, and bioavailability of LCPT versus IR-Tac, according to CYP3A5 genotype.
∼80% of participants carried the CYP3A5*1 allele (CYP3A5 expressers). There were no significant differences in AUC0-24 or Cmin between CYP3A5 expressers and nonexpressers during administration of either IR-Tac or LCPT. With IR-Tac, tacrolimus Cmax was 33% higher in CYP3A5 expressers compared with nonexpressers (P=0.04): With LCPT, this difference was 11% (P=0.4).
LIMITATIONS:
This was primarily a pharmacogenetic study rather than an efficacy study; the follow-up period was too short to capture clinical outcomes.
CONCLUSIONS:
Achieving therapeutic tacrolimus trough concentrations with IR-Tac in most African Americans results in significantly higher peak concentrations, potentially magnifying the risk for toxicity and adverse outcomes. This pharmacogenetic effect is attenuated by delayed tacrolimus absorption with LCPT.
TRIAL REGISTRATION:
Registered at ClinicalTrials.gov, with study number NCT01962922.
This is a nicely done randomised prospective crossover study in stable recipients of simultaneous pancreas and kidney (SPK) transplants who were on Prograf together with mycophenolate and steroids. The patients, of whom there were 21, had stable renal and pancreatic function and were randomised to either continue on Prograf or convert to Advagraf over a period of 12 weeks, and then they converted on a one and one basis to Prograf or Advagraf. There was no change in mycophenolate acid levels and tacrolimus blood levels and mycophenolate acid levels remained unchanged regardless of whether they were on Prograf or Advagraf. Cylex levels as a measure of immune response were unchanged and there were no episodes of rejection during the six month study. The authors conclude that this is sound evidence that it is safe to convert between Prograf and Advagraf on a one-to-one basis without any major impact on pharmacokinetic or pharmacodynamics in SPK recipients.
Expert Review
Reviewer:
Dr Claudio Ponticelli, Past Director Nephrology Division Ospedale Maggiore, Milano, Italy.
Conflicts of Interest:
No
Clinical Impact Rating
2
Review:
This is a randomized, prospective, cross-over study aimed to assess the impact of switching 21 stable pancreas and kidney transplant (P/K) recipients from twice-a-day Prograf to once-a-day Advagraf. No difference in tacrolimus or mycophenolic acid levels was noted. ImmuKnow (Cylex) levels, serum creatinine, and blood sugar levels remained unchanged. Even with a small number of participants, the study showed that converting stable P/K recipients from Prograf to Advagraf (1/1) is safe. However, the study cannot provide information about the possibility of converting patients in the early post-transplant period. More important, one may wonder whether the same results can be obtained by giving the same daily dose of Prograf once a day instead of twice a day. Long-term follow-up of a larger number of patients is also needed to evaluate whether Advagraf can actually improve the adherence to prescriptions and to reduce gastro-intestinal troubles.
Aims:
To examine the effect of conversion from standard tacrolimus (Prograf) to long-acting tacrolimus (Advagraf) in stable simultaneous pancreas-kidney (SPK) recipients.
Interventions:
This was a crossover design and participants were randomised to receive either once a day Advagraf or to continue with twice-daily Prograf for 3 months, and then switch to the other formulation for the next 3 months.
Participants:
21 SPK recipients >1 year post-transplant receiving Prograf twice-daily and mycophenolate mofetil (MMF), with an eGFR >30 mL/min/1.72 m2, stable renal and pancreas allograft function and stable tacrolimus trough levels of 3-10 ng/ mL.
Outcomes:
Measured outcomes included tacrolimus, mycophenolic acid and Cylex CD4 + ATP levels, pancreas and renal function, rejection episodes and side effects.
Follow Up:
6 months
INTRODUCTION:
We assessed the pharmacokinetic and pharmacodynamic impact of converting stable simultaneous pancreas-kidney (SPK) recipients from standard tacrolimus (Prograf) to long-acting tacrolimus (Advagraf).
METHODS:
In a randomized prospective crossover study, stable SPK recipients on Prograf were assigned to Prograf with 1:1 conversion to Advagraf or vice versa. Demographics, tacrolimus, mycophenolic acid levels, and Cylex CD4 + ATP levels were taken at specified intervals in addition to standard blood work.
RESULTS:
Twenty-one patients, who were a minimum of 1 year post-transplant, were entered into the study. No difference in tacrolimus or mycophenolic acid levels was noted between patients who were first assigned to Prograf or Advagraf. Additionally, Cylex levels as well as serum creatinine, lipase, and blood sugar levels were unchanged. There were no episodes of rejection during the 6-month study.
CONCLUSIONS:
It is safe to convert between Prograf and Advagraf 1:1, without major impact on pharmacokinetics or pharmacodynamics in SPK recipients.
Dr Ben Sprangers, University Hospitals Leuven, Leuven, Belgium.
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
In this study, Alloway et al. address the question whether innovator tacrolimus is bioequivalent to generic tacrolimus, and whether generics of tacrolimus are bioequivalent to each other. This is an important issue as it has been argued in the past that for drugs with a narrow therapeutic index such as tacrolimus, clinicians should be cautious switching from innovator tacrolimus to generic tacrolimus. In this well-designed 8-week study, 35 kidney transplant recipients and 36 liver transplant recipients received treatment with innovator tacrolimus and two generic formulations of tacrolimus (tacrolimus Sandoz and tacrolimus Dr Reddy), and pharmacokinetic evaluation was performed. The authors demonstrated that the different tacrolimus formulations were bioequivalent according to the FDA average bioequivalence acceptance criteria, and within-subject variability was similar for AUC and Cmax for all products. In addition, the more stringent SCABE acceptance criteria were met for all product comparisons for AUC and Cmax. There are several limitations of this study: 1. Only a limited number of patients were included and the study was of short duration, 2. No evaluation of specific subgroups were performed (CYP3A5 genotype, ABCB1 genotype), 3. Selection of generic high and generic low tacrolimus formulations based abbreviated new drug applicants data from healthy individuals, 4. It is not an evaluation of all available generic tacrolimus formulations. In conclusion, this study demonstrates that innovator tacrolimus and generic tacrolimus formulations are bioequivalent and can be used interchangeably in clinical practice.
BACKGROUND:
Although the generic drug approval process has a long-term successful track record, concerns remain for approval of narrow therapeutic index generic immunosuppressants, such as tacrolimus, in transplant recipients. Several professional transplant societies and publications have generated skepticism of the generic approval process. Three major areas of concern are that the pharmacokinetic properties of generic products and the innovator (that is, "brand") product in healthy volunteers may not reflect those in transplant recipients, bioequivalence between generic and innovator may not ensure bioequivalence between generics, and high-risk patients may have specific bioequivalence concerns. Such concerns have been fueled by anecdotal observations and retrospective and uncontrolled published studies, while well-designed, controlled prospective studies testing the validity of the regulatory bioequivalence testing approach for narrow therapeutic index immunosuppressants in transplant recipients have been lacking. Thus, the present study prospectively assesses bioequivalence between innovator tacrolimus and 2 generics in individuals with a kidney or liver transplant.
METHODS AND FINDINGS:
From December 2013 through October 2014, a prospective, replicate dosing, partially blinded, randomized, 3-treatment, 6-period crossover bioequivalence study was conducted at the University of Cincinnati in individuals with a kidney (n = 35) or liver transplant (n = 36). Abbreviated New Drug Applications (ANDA) data that included manufacturing and healthy individual pharmacokinetic data for all generics were evaluated to select the 2 most disparate generics from innovator, and these were named Generic Hi and Generic Lo. During the 8-week study period, pharmacokinetic studies assessed the bioequivalence of Generic Hi and Generic Lo with the Innovator tacrolimus and with each other. Bioequivalence of the major tacrolimus metabolite was also assessed. All products fell within the US Food and Drug Administration (FDA) average bioequivalence (ABE) acceptance criteria of a 90% confidence interval contained within the confidence limits of 80.00% and 125.00%. Within-subject variability was similar for the area under the curve (AUC) (range 12.11-15.81) and the concentration maximum (Cmax) (range 17.96-24.72) for all products. The within-subject variability was utilized to calculate the scaled average bioequivalence (SCABE) 90% confidence interval. The calculated SCABE 90% confidence interval was 84.65%-118.13% and 80.00%-125.00% for AUC and Cmax, respectively. The more stringent SCABE acceptance criteria were met for all product comparisons for AUC and Cmax in both individuals with a kidney transplant and those with a liver transplant. European Medicines Agency (EMA) acceptance criteria for narrow therapeutic index drugs were also met, with the only exception being in the case of Brand versus Generic Lo, in which the upper limits of the 90% confidence intervals were 111.30% (kidney) and 112.12% (liver). These were only slightly above the upper EMA acceptance criteria limit for an AUC of 111.11%. SCABE criteria were also met for the major tacrolimus metabolite 13-O-desmethyl tacrolimus for AUC, but it failed the EMA criterion. No acute rejections, no differences in renal function in all individuals, and no differences in liver function were observed in individuals with a liver transplant using the Tukey honest significant difference (HSD) test for multiple comparisons. Fifty-two percent and 65% of all individuals with a kidney or liver transplant, respectively, reported an adverse event. The Exact McNemar test for paired categorical data with adjustments for multiple comparisons was used to compare adverse event rates among the products. No statistically significant differences among any pairs of products were found for any adverse event code or for adverse events overall. Limitations of this study include that the observations were made under strictly controlled conditions that did not allow for the impact of nonadherence or feeding on the possible pharmacokinetic differences. Generic Hi and Lo were selected based upon bioequivalence data in healthy volunteers because no pharmacokinetic data in recipients were available for all products. The safety data should be interpreted in light of the small number of participants and the short observation periods. Lastly, only the 1 mg tacrolimus strength was utilized in this study.
CONCLUSIONS:
Using an innovative, controlled bioequivalence study design, we observed equivalence between tacrolimus innovator and 2 generic products as well as between 2 generic products in individuals after kidney or liver transplantation following current FDA bioequivalence metrics. These results support the position that bioequivalence for the narrow therapeutic index drug tacrolimus translates from healthy volunteers to individuals receiving a kidney or liver transplant and provides evidence that generic products that are bioequivalent with the innovator product are also bioequivalent to each other.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This small post-hoc study investigates the role of phospho-specific flow cytometry for pharmacodynamic monitoring after renal transplantation. The authors retrospectively analysed samples from participants of a randomised trial comparing tacrolimus and Belatacept based immunosuppression, finding greater inhibition of downstream T-cell signalling pathways with tacrolimus than Belatacept. They also higher levels of p-ERK (part of the T-cell signalling pathway) in Belatacept-treated patients experiencing acute rejection at some timepoints. These data are interesting and point to a potential mechanism for the increased rates of acute rejection seen in trials of Belatacept to date. However, significant differences in expression were only seen in a small subset of timepoints, and it is unclear how useful this would be as a prospective monitoring tool as no relationship is described between inhibition and clinical endpoints.
Expert Review
Reviewer:
Afiliate Professor Helio Tedesco Silva Junior, Nephrology Division-Kidney Transplant Unit, Hospital do Rim-Escola Paulista de Medicina-UNIFESP, Brazil.
Conflicts of Interest:
No
Clinical Impact Rating
1
Review:
This study investigated the phosphorylation status of 3 signalling proteins involved in T cell activation as a pharmacodynamic biomarker of immunosuppression in patients receiving TAC-based (n=20) or BELA-based (n=20) immunosuppressive regimens. The incidence of biopsy-proven acute rejection was 10% and 55% respectively. The phosphorylation status of p38MAPK, ERK and Akt in unstimulated and stimulated CD8+ and CD4+ T cells were generally inhibited in blood samples of kidney transplant patients receiving TAC compared to BELA. Higher p-ERK levels in both CD4+ and CD8+ T cells were observed in patients receiving BELA who developed biopsy-proven acute rejection. In addition, only p-ERK expression at the time of rejection was higher compared to patients without a rejection in patients receiving BELA. Unfortunately, the authors were unable to compare the phosphorylation status of these signalling proteins in patients with and without biopsy-proven acute rejection receiving TAC, due to the low number of patients with acute rejection (n=2). This initial exploratory data suggest an association between the phosphorylation status of signalling proteins involved in T cell activation and acute rejection. Yet, far more studies are required to determine whether the phosphorylation status of signalling proteins involved in T cell activation provide further discriminatory prediction for patients at risk for acute rejection who are receiving TAC-based immunosuppressive regimens and showing similar TAC blood concentrations.
Aims:
To determine whether phospho-specific flow cytometry could be used as a tool for pharmacodynamic monitoring of tacrolimus (TAC) based immunosuppression after kidney transplantation.
Interventions:
This was a post-hoc analysis of a previous randomised controlled trial* which randomised participants to receive either a belatacept based immunosuppressive treatment, versus a TAC-based immunosuppressive treatment.
Participants:
40 recipients of a kidney transplant from a living donor, aged ≥18 years.
Outcomes:
The primary outcome measured was the inhibition of key T-cell activation pathways. Biopsy-proven acute rejection was also measured.
Follow Up:
1 year
Pharmacokinetic immunosuppressive drug monitoring poorly correlates with clinical outcomes after solid organ transplantation. A promising method for pharmacodynamic monitoring of tacrolimus (TAC) in T cell subsets of transplant recipients might be the measurement of (phosphorylated) p38MAPK, ERK1/2 and Akt (activated downstream of the T cell receptor) by phospho-specific flow cytometry. Here, blood samples from n = 40 kidney transplant recipients (treated with either TAC-based or belatacept (BELA)-based immunosuppressive drug therapy) were monitored before and throughout the first year after transplantation. After transplantation and in unstimulated samples, p-p38MAPK and p-Akt were inhibited in CD8+ T cells and p-ERK in CD4+ T cells but only in patients who received TAC-based therapy. After activation with PMA/ionomycin, p-p38MAPK and p-AKT were significantly inhibited in CD4+ and CD8+ T cells when TAC was given, compared to pre-transplantation. Eleven BELA-treated patients had a biopsy-proven acute rejection, which was associated with higher p-ERK levels in both CD4+ and CD8+ T cells compared to patients without rejection. In conclusion, phospho-specific flow cytometry is a promising tool to pharmacodynamically monitor TAC-based therapy. In contrast to TAC-based therapy, BELA-based immunosuppression does not inhibit key T cell activation pathways which may contribute to the high rejection incidence among BELA-treated transplant recipients.
CET Conclusion