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  • Mulder MB
  • van Hoek B
  • van den Berg AP
  • Polak WG
  • Alwayn IPJ
  • et al.
Liver Transpl. 2023 Feb 1;29(2):184-195 doi: 10.1097/LVT.0000000000000003.
CET Conclusion
Reviewer: Mr Keno Mentor, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: CNI-related chronic kidney disease (CKD) is a common problem following liver transplantation (LT). This unblinded RCT analysed the rates of CKD in patients who underwent LT with normal-dose tacrolimus compared to a combination low-dose tacrolimus/low-dose sirolimus regimen at 3 years post LT. The study reported no difference in the rates of either CKD or acute rejection between the two groups. A major limitation of the study is that nearly half of all patients in both arms had immunosuppression switched by the treating physicians during the follow-up period. In most cases, this switch was made in response to deteriorating renal function. This resulted in a small difference (1ug/l) in the tacrolimus trough levels between the two groups. The authors cite another study with a greater difference in tacrolimus trough level between the control and intervention group, which did demonstrate a renal benefit with a low-dose combination regimen. The high rate of study protocol deviation in this study highlights the fact that immunosuppression regimens are individualised, with physicians making reductions in tacrolimus dose to protect renal function when appropriate. The benefit of investigating a fixed immunosuppression regimen in this clinical setting is thus not clear.
Aims: This study aimed to examine the effect of combining low-dose sirolimus (SRL) and low-dose extended-release tacrolimus (TAC) in comparison to normal-dose extended-release TAC on outcomes following liver transplantation.
Interventions: Participants were randomised to either receive low dose SRL and low-dose extended-release TAC or standard-dose extended-release TAC.
Participants: 196 liver transplant recipients.
Outcomes: The primary outcome was the cumulative incidence of chronic kidney disease (CKD). Secondary outcomes were mean eGFR, treated biopsy-proven acute rejection (tBPAR), retransplantation, incidence of and time to de novo or recurrent malignancy, incidence of de novo diabetes mellitus (NODAT), tolerability and safety outcomes.
Follow Up: 36 months

The aim of this study was to investigate whether the combination of low-dose sirolimus (SRL) and low-dose extended-release tacrolimus (TAC) compared to normal-dose extended-release TAC results in a difference in the renal function and comparable rates of rejection, graft and patient survival at 36 months after transplantation. This study was an open-label, multicenter randomized, controlled trial. Patients were randomized to once-daily normal-dose extended-release TAC (control group) or once-daily combination therapy of SRL and low-dose extended-release TAC (interventional group). The primary endpoint was the cumulative incidence of chronic kidney disease (CKD) defined as grade ≥3 (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2) at 36 months after transplantation. In total, 196 patients were included. CKD at 36 months was not different between the control and interventional group (50.8%, 95% CI: 39.7%-59.9%) vs. 43.7%, 95% CI: 32.8%-52.8%). Only at 6 months after transplantation, the eGFR was higher in the interventional group compared to the control group (mean eGFR 73.1±15 vs. 67.6±16 mL/min/1.73 m2, p=0.02) in the intention-to-treat population. No differences in the secondary endpoints and the number of serious adverse events were found between the groups. Once daily low-dose SRL combined with low-dose extended-release TAC does ultimately not provide less CKD grade ≥3 at 36 months compared to normal-dose extended-release TAC.

  • Mulder MB
  • van der Eijk AA
  • GeurtsvanKessel CH
  • Erler NS
  • de Winter BCM
  • et al.
Gut. 2022 Dec;71(12):2605-2608 doi: 10.1136/gutjnl-2021-326755.
  • Franken LG
  • Francke MI
  • Andrews LM
  • van Schaik RHN
  • Li Y
  • et al.
Eur J Drug Metab Pharmacokinet. 2022 Jul;47(4):523-535 doi: 10.1007/s13318-022-00767-8.
BACKGROUND AND OBJECTIVE:

The tacrolimus concentration within peripheral blood mononuclear cells may correlate better with clinical outcomes after transplantation compared to concentrations measured in whole blood. However, intracellular tacrolimus measurements are not easily implemented in clinical practice. The prediction of intracellular concentrations based on whole-blood concentrations would be a solution for this. Therefore, the aim of this study was to describe the relationship between intracellular and whole-blood tacrolimus concentrations in a population pharmacokinetic (popPK) model.

METHODS:

Pharmacokinetic analysis was performed using non-linear mixed effects modelling software (NONMEM). The final model was evaluated using goodness-of-fit plots, visual predictive checks, and a bootstrap analysis.

RESULTS:

A total of 590 tacrolimus concentrations from 184 kidney transplant recipients were included in the study. All tacrolimus concentrations were measured in the first three months after transplantation. The intracellular tacrolimus concentrations (n  = 184) were best described with an effect compartment. The distribution into the effect compartment was described by the steady-state whole-blood to intracellular ratio (RWB:IC) and the intracellular distribution rate constant between the whole-blood and intracellular compartments. Lean body weight was negatively correlated [delta objective function value (ΔOFV) -8.395] and haematocrit was positively correlated (ΔOFV = - 6.752) with RWB:IC, and both lean body weight and haematocrit were included in the final model.

CONCLUSION:

We were able to accurately describe intracellular tacrolimus concentrations using whole-blood concentrations, lean body weight, and haematocrit values in a popPK model. This model may be used in the future to more accurately predict clinical outcomes after transplantation and to identify patients at risk for under- and overexposure. Dutch National Trial Registry number NTR2226.

  • Mulder MB
  • Busschbach JV
  • van Hoek B
  • van den Berg AP
  • Polak WG
  • et al.
Transplantation. 2020 May;107(12):2545-2553.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This multicentre RCT randomised liver recipients at 90 days after transplant to once-daily standard dose tacrolimus or once daily low-dose sirolimus and tacrolimus. This manuscript reports findings in generic quality of life (QOL) and fatigue severity score, with no differences seen between the groups over 36 months post-transplant. For a study of this type, response rates were good with over 2/3 patients completing the 36-month questionnaires. Nearly half of patients in each group switched immunosuppression during follow-up, so in intent-to-treat analysis any true effect of immunosuppression on QOL is likely to be diluted. However, the authors do present a per-protocol analysis showing similar results. Whilst the study is essentially negative, it does give some useful insights into QOL in the liver transplant population, showing that QOL post-transplant approaches that of the general population.
Aims: This study aimed to compare the impact of two different immunosuppression regimens (sirolimus (SRL) versus tacrolimus (TAC)-based regimen) on the health-related quality of life (HRQoL) and the severity of fatigue in liver transplant recipients.
Interventions: Participants were randomised to either the TAC group or the TAC+SRL group.
Participants: 196 liver transplant recipients.
Outcomes: The main outcomes of interest were the assessment of health-related quality of life (HRQoL) using the EQ-5D-5L questionnaire (Dutch version), and severity of fatigue using the Fatigue Severity Score (FSS) questionnaire.
Follow Up: 3 years posttransplantation.
BACKGROUND: The impact of different immunosuppression regimes on the health-related quality of life (HRQoL) and the severity of fatigue in liver transplant recipients is largely unknown. We investigated the impact of a sirolimus-based regimen compared with a tacrolimus (TAC)-based regimen on the HRQoL and the severity of fatigue. METHODS: In this multicenter, open-label, randomized, controlled trial, 196 patients were randomized 90 d after transplantation to (1) once daily normal-dose TAC or (2) once daily combination therapy of low-dose sirolimus and TAC. HRQoL was measured with the EQ-5D-5L questionnaire, the EQ-visual analog scale, and the severity of fatigue questionnaire Fatigue Severity Score (FSS). The EQ-5D-5L scores were translated to societal values. We examined the HRQoL and the FSS over the course of the study by fitting generalized mixed-effect models. RESULTS: Baseline questionnaires were available for 87.7% (172/196) of the patients. Overall, patients reported the least problems in the states of self-care and anxiety/depression and the most problems in the states of usual activities and pain/discomfort. No significant differences in HrQol and FSS were seen between the 2 groups. During follow-up, the societal values of the EQ-5D-5L health states and the patient's self-rated EQ-visual analog scale score were a little lower than those of the general Dutch population in both study arms. CONCLUSIONS: The HRQoL and FSS were comparable in the 36 mo after liver transplantation in both study groups. The HRQoL of all transplanted patients approximated that of the general Dutch population, suggesting little to no residual symptoms in the long term after transplantation. Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
  • Andrews LM
  • de Winter BC
  • Tang JT
  • Shuker N
  • Bouamar R
  • et al.
Transplant Direct. 2017 Jan 19;3(2):e129 doi: 10.1097/TXD.0000000000000644.
CET Conclusion
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion: This paper represents a post hoc analysis of a previously published RCT, which had studied the interaction between CYP3A5 genotype and Tacrolimus clearance. This study aimed to investigate the relationship between bodyweight and Tacrolimus dose-response in overweight patients when commenced on bodyweight-calculated Tacrolimus dose. In the standard dosing group, overweight and obese patients had a significantly higher trough Tacrolimus level on Day 3. In fact, the median serum level was 15ng/ml, with 60% of these patients overexposed to Tacrolimus. The authors used their calculations to develop a dosing guideline considering BMI and CYP3A5 genotype, which was subsequently validated in another cohort. The new dosing guideline reduced the proportion of overexposed higher BMI patients significantly. This study is important with the increase in global obesity, however the population included were overwhelmingly of white ethnic origin, and the target Tacrolimus level may be considered high in some units (10-15ng/ml).
Expert Review
Reviewer: Dr Rainer Oberbauer, Department of Nephrology, Medical University of Vienna, Austria.
Conflicts of Interest: No
Clinical Impact Rating 1
Review: Experts from Erasmus University in Rotterdam studied the exposure of TAC in 203 patients after renal transplantation, randomized to standard dosing according to body weight, or to dosing according to their CYP3A5 genotype. The main finding was that overweight and obese patients had a TAC trough concentration above target, CYP3A5 non-expressors showed a similar trend. Based on these findings the authors proposed dosing guidelines for obese patients with starting doses as low as 60% of the standard dose. The main conclusion was that TAC dosing in obese patients tends to overshoot. Since TDM is the gold standard, dose adjustments are common and performed every day in the first week.
Aims: To investigate whether a Tacrolimus (Tac) starting dose based on bodyweight leads to the achievement of Tac target whole-blood predose concentrations (C0) in overweight patients on day 3 after transplantation.
Interventions: Participants were randomized to receive Tac in either the standard, bodyweight-based dose of 0.20 mg/kg per day, versus a dose based on their CYP3A5 genotype. CYP3A5 expressers received 0.30 mg/kg per day, whereas the nonexpressers received 0.15 mg/kg per day.
Participants: 203 kidney transplant recipients who participated in a previous randomized-controlled trial* who had Tac C0 available on day 3 after transplantation.
Outcomes: The primary outcome measured was Tac C0. Other outcomes measured were Tac overexposure, Tac underexposure and Tac on target.
Follow Up: Day 3
BACKGROUND:

Bodyweight-based dosing of tacrolimus (Tac) is considered standard care, even though the available evidence is thin. An increasing proportion of transplant recipients is overweight, prompting the question if the starting dose should always be based on bodyweight.

METHODS:

For this analysis, data were used from a randomized-controlled trial in which patients received either a standard Tac starting dose or a dose that was based on CYP3A5 genotype. The hypothesis was that overweight patients would have Tac overexposure following standard bodyweight-based dosing.

RESULTS:

Data were available for 203 kidney transplant recipients, with a median body mass index (BMI) of 25.6 (range, 17.2-42.2). More than 50% of the overweight or obese patients had a Tac predose concentration above the target range. The CYP3A5 nonexpressers tended to be above target when they weighed more than 67.5 kg or had a BMI of 24.5 or higher. Dosing guidelines were proposed with a decrease up to 40% in Tac starting doses for different BMI groups. The dosing guideline for patients with an unknown genotype was validated using the fixed-dose versus concentration controlled data set.

CONCLUSIONS:

This study demonstrates that dosing Tac solely on bodyweight results in overexposure in more than half of overweight or obese patients.