scholarly journals Increased renal function decline in fast metabolizers using extended-release tacrolimus after kidney transplantation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gerold Thölking ◽  
Brigitte Filensky ◽  
Ulrich Jehn ◽  
Katharina Schütte-Nütgen ◽  
Raphael Koch ◽  
...  
Keyword(s):  
Renal Function ◽  
Extended Release ◽  
Estimated Glomerular Filtration Rate ◽  
Patient Survival ◽  
Survival Rates ◽  
Immediate Release ◽  
Immunosuppressive Regimen ◽  
Dose Ratio ◽  
Patients At Risk ◽  
Slow Metabolizers

AbstractFast metabolism of immediate-release tacrolimus (IR-Tac) is associated with decreased kidney function after renal transplantation (RTx) compared to slow metabolizers. We hypothesized, by analogy, that fast metabolism of extended-release tacrolimus (ER-Tac) is associated with worse renal function. We analyzed data from patients who underwent RTx at three different transplant centers between 2007 and 2016 and received an initial immunosuppressive regimen with ER-Tac, mycophenolate, and a corticosteroid. Three months after RTx, a Tac concentration to dose ratio (C/D ratio) < 1.0 ng/ml · 1/mL defined fast ER-Tac metabolism and ≥ 1.0 ng/ml · 1/mL slow metabolism. Renal function (estimated glomerular filtration rate, eGFR), first acute rejection (AR), conversion from ER-Tac, graft and patient survival were observed up to 60-months. 610 RTx patients were divided into 192 fast and 418 slow ER-Tac metabolizers. Fast metabolizers showed a decreased eGFR at all time points compared to slow metabolizers. The fast metabolizer group included more patients who were switched from ER-Tac (p < 0.001). First AR occurred more frequently (p = 0.008) in fast metabolizers, while graft and patient survival rates did not differ between groups (p = 0.529 and p = 0.366, respectively). Calculation of the ER-Tac C/D ratio early after RTx may facilitate individualization of immunosuppression and help identify patients at risk for an unfavorable outcome.

scholarly journals The Tacrolimus Metabolism Rate and Dyslipidemia after Kidney Transplantation

2021 ◽  
Vol 10 (14) ◽  
pp. 3066
Author(s):  
Gerold Thölking ◽  
Christian Schulte ◽  
Ulrich Jehn ◽  
Katharina Schütte-Nütgen ◽  
Hermann Pavenstädt ◽  
...  
Keyword(s):  
Renal Function ◽  
Survival Rates ◽  
Density Lipoprotein ◽  
Immediate Release ◽  
Cardiovascular Death ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Dose Ratio ◽  
Slow Metabolizers

Fast tacrolimus (Tac) metabolism is associated with reduced survival rates after renal transplantation (RTx), mainly due to cardiovascular events. Because dyslipidemia is a leading cause of cardiovascular death, we hypothesized that most RTx patients do not achieve recommended target low-density lipoprotein cholesterol (LDL-C) levels (European cardiology society guidelines) and that fast Tac metabolizers have higher dyslipidemia rates. This study included RTx recipients who received initial immunosuppression with immediate-release tacrolimus (IR-Tac), mycophenolate, and prednisolone. Patients were grouped according to their Tac concentration-to-dose ratio (C/D ratio) 3 months after RTx. Dyslipidemia parameters were analyzed at RTx, 3 months, and 12 months after RTx. Statin use and renal function were documented in a 12-month follow-up, and death was documented in a 60-month follow-up. Ninety-six RTx recipients were divided into two groups: 31 fast Tac metabolizers (C/D ratio < 1.05 ng/mL·1/mg) and 65 slow metabolizers (C/D ratio ≥ 1.05 ng/mL·1/mg). There were no differences in triglyceride or cholesterol levels between groups at RTx, 3, and 12 months after RTx. A total of 93.5% of fast and 95.4% of slow metabolizers did not achieve target LDL-C levels (p = 0.657). Fast metabolizers developed lower renal function compared to slow metabolizers 12 months after RTx (p = 0.009). Fast metabolizers showed a 60 month survival rate of 96.8% compared to 94.7% in the slow metabolizer group (p = 0.811). As most RTx recipients do not reach recommended target LDL-C levels, individualized nutritional counseling and lipid-lowering therapy must be intensified. Fast Tac metabolism is associated with lower renal function after RTx, but does not play a significant role in dyslipidemia.

scholarly journals Conversion from Extended-Dose-Release Tacrolimus to Melt-Dose Tacrolimus in High Metabolizer Patients: Is the New Formulation of LPCT the Best Option for High Metabolizer Kidney Transplanted Patients?

2020 ◽  
Vol 4 (1) ◽  
pp. 18-21
Author(s):  
Paolo Carta ◽  
Federica Curci ◽  
Leonardo Caroti ◽  
Larti Aida ◽  
Lorenzo Di Maria ◽  
...  
Keyword(s):  
Renal Function ◽  
Kidney Transplantation ◽  
Kidney Transplant ◽  
Dose Level ◽  
Extended Release ◽  
Blood Levels ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Dose Ratio ◽  
New Formulation

Tacrolimus (FK506) is the most widely used anti-rejection drug in kidney transplantation, especially its extended release Tacrolimus formulation (ER-Tac, Advagraf), which is used when target blood levels can be difficult to reach in high metabolizer patients. In this retrospective monocentric study, we analyzed the effect of a switch from ER-Tac to LifeCycle Pharma Tacrolimus (LPCT, Envarsus) on the dose/level ratio of FK506 in high metabolizer patients that cannot achieve target blood levels in the first 6 months after transplantation.We observed a statistically significant improvement in the level to dose ratio after the switch. Renal function remained stable. We also observed a reduction in the development of tremors. Our data suggest that LPCT can be used in a safer way in high metabolizer kidney transplant recipients.

scholarly journals Dosing Patterns during Conversion to IPX066, Extended-Release Carbidopa-Levodopa (ER CD-LD), in Parkinson’s Disease with Motor Fluctuations

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
John C. Morgan ◽  
Rohit Dhall ◽  
Robert Rubens ◽  
Sarita Khanna ◽  
Suneel Gupta
Keyword(s):  
Extended Release ◽  
Immediate Release ◽  
Oral Formulation ◽  
Study Entry ◽  
Dose Ratio ◽  
Dose Frequency ◽  
Open Label ◽  
Two Phase ◽  
Treatment Regimens ◽  
Link Type

Background. IPX066 is an extended-release (ER) oral formulation of carbidopa-levodopa (CD-LD). Following an initial peak at about one hour, plasma LD concentrations are maintained for about 4-5 hours. Objective. To present dosing factors that may affect the successful conversion to ER CD-LD from other LD formulations. Methods. Two-phase 3 studies of ER CD-LD vs. immediate-release (IR) CD-LD (ADVANCE-PD) and vs. CD-LD + entacapone (CLE; ASCEND-PD) in subjects with advanced PD included a 6-week, open-label conversion to ER CD-LD prior to treatment randomization. The “converted” daily LD dose ratio and dose frequency for ER CD-LD were compared to the prior LD treatment regimens at study entry. Results. The average daily LD dose ratio at the end of dose conversion to ER CD-LD was approximately 2.1 for IR CD-LD and 2.8 for CLE. The final dose ratios tended to be slightly higher for participants taking lower LD doses at study entry but independent of dose frequency. ER CD-LD dose frequency increased with increasing LD dose and dose frequency at study entry. Participants on higher baseline LD doses ≥800 mg and dose frequencies ≥6 tended to have higher rates of discontinuation during conversion to ER CD-LD. Conclusions. Converting participants from other LD formulations to ER CD-LD is based on their current LD regimen. For the most common daily doses (≤1250 mg) and dose frequencies (<7) of LD, final mean dose ratios were within tight ranges of 2.1 to 2.4 for IR CD-LD (ADVANCE-PD) and 2.4 to 2.8 for CLE (ASCEND-PD) and were generally independent of the LD dosing frequency at study entry. These trials are registered with NCT00974974, NCT01130493.

scholarly journals Tacrolimus: Influence of the Posttransplant Concentration/Dose Ratio on Kidney Graft Function in a Two-Year Follow-Up

2019 ◽  
Vol 44 (5) ◽  
pp. 1075-1088 ◽  
Author(s):  
Maja Nowicka ◽  
Monika Górska ◽  
Zuzanna Nowicka ◽  
Krzysztof Edyko ◽  
Piotr Edyko ◽  
...  
Keyword(s):  
Graft Function ◽  
Total Daily Dose ◽  
Kidney Graft ◽  
Dose Ratio ◽  
Metabolism Rate ◽  
Patients At Risk ◽  
Recipient Age ◽  
The Relationship ◽  
Slow Metabolizers

Introduction: Tacrolimus (TAC) metabolism rate has the potential to impact graft function after kidney transplantation (KTx). We aimed to analyze the relationship between the early post-KTx TAC C/D ratio (blood trough concentration normalized by total daily dose) and kidney graft function in a 2-year follow-up. Methods: We retrospectively analyzed data from 101 post-KTx patients at 3, 6, 12, and 24 months after KTx to identify the C/D ratio cutoff value optimal for dividing patients into fast and slow TAC metabolizers. We investigated the relationship between their TAC metabolism rate and graft function. Results: Patients were divided based on the TAC C/D ratio at 6 months after KTx of 1.47 ng/mL * 1 mg. Fast metabolizers (C/D ratio <1.47 ng/mL * 1 mg) presented with significantly worse graft function throughout the whole study period (p < 0.05 at each timepoint) and were significantly less likely to develop good graft function (estimated glomerular filtration rate ≥45 mL/min/1.73 m2) than slow metabolizers. Our model based on donor and recipient age, recipient sex and slow/fast metabolism status allowed for identification of patients with compromised graft function in 2-year follow-up with 66.7% sensitivity and 94.6% specificity. Conclusion: Estimating TAC C/D ratio at 6 months post-KTx might help identify patients at risk of developing deteriorated graft function in a 2-year follow-up.

scholarly journals Fast Tac Metabolizers at Risk – It is Time for a C/D Ratio Calculation

2019 ◽  
Vol 8 (5) ◽  
pp. 587 ◽  
Author(s):  
Schütte-Nütgen ◽  
Thölking ◽  
Steinke ◽  
Pavenstädt ◽  
Schmidt ◽  
...  
Keyword(s):  
At Risk ◽  
Graft Survival ◽  
Graft Function ◽  
Rejection Rate ◽  
Immunosuppressive Regimen ◽  
Metabolism Rate ◽  
Daily Dose ◽  
Patients At Risk ◽  
Slow Metabolizers ◽  
Patient And Graft Survival

Tacrolimus (Tac) is a part of the standard immunosuppressive regimen after renal transplantation (RTx). However, its metabolism rate is highly variable. A fast Tac metabolism rate, defined by the Tac blood trough concentration (C) divided by the daily dose (D), is associated with inferior renal function after RTx. Therefore, we hypothesize that the Tac metabolism rate impacts patient and graft survival after RTx. We analyzed all patients who received a RTx between January 2007 and December 2012 and were initially treated with an immunosuppressive regimen containing Tac (Prograf®), mycophenolate mofetil, prednisolone and induction therapy. Patients with a Tac C/D ratio <1.05 ng/mL × 1/mg at three months after RTx were characterized as fast metabolizers and those with a C/D ratio ≥1.05 ng/mL×1/mg as slow metabolizers. Five-year patient and overall graft survival were noticeably reduced in fast metabolizers. Further, fast metabolizers showed a faster decline of eGFR (estimated glomerular filtration rate) within five years after RTx and a higher rejection rate compared to slow metabolizers. Calculation of the Tac C/D ratio three months after RTx may assist physicians in their daily clinical routine to identify Tac-treated patients at risk for the development of inferior graft function, acute rejections, or even higher mortality.

scholarly journals Conversion to Everolimus was Beneficial and Safe for Fast and Slow Tacrolimus Metabolizers after Renal Transplantation

2020 ◽  
Vol 9 (2) ◽  
pp. 328 ◽  
Author(s):  
Gerold Thölking ◽  
Nils Hendrik Gillhaus ◽  
Katharina Schütte-Nütgen ◽  
Hermann Pavenstädt ◽  
Raphael Koch ◽  
...  
Keyword(s):  
Renal Function ◽  
Risk Factor ◽  
Renal Transplantation ◽  
Filtration Rate ◽  
Calcineurin Inhibitor ◽  
Estimated Glomerular Filtration Rate ◽  
Graft Function ◽  
Observation Time ◽  
Slow Metabolizers

Fast tacrolimus (TAC) metabolism (concentration/dose (C/D) ratio <1.05 ng/mL/mg) is a risk factor for inferior outcomes after renal transplantation (RTx) as it fosters, e.g., TAC-related nephrotoxicity. TAC minimization or conversion to calcineurin-inhibitor free immunosuppression are strategies to improve graft function. Hence, we hypothesized that especially patients with a low C/D ratio profit from a switch to everolimus (EVR). We analyzed data of 34 RTx recipients (17 patients with a C/D ratio <1.05 ng/mL/mg vs. 17 patients with a C/D ratio ≥1.05 ng/mL/mg) who were converted to EVR within 24 months after RTx. The initial immunosuppression consisted of TAC, mycophenolate, prednisolone, and basiliximab induction. During an observation time of 36 months after changing immunosuppression from TAC to EVR, renal function, laboratory values, and adverse effects were compared between the groups. Fast TAC metabolizers were switched to EVR 4.6 (1.5–21.9) months and slow metabolizers 3.3 (1.8–23.0) months after RTx (p = 0.838). Estimated glomerular filtration rate (eGFR) did not differ between the groups at the time of conversion (baseline). Thereafter, the eGFR in all patients increased noticeably (fast metabolizers eGFR 36 months: + 11.0 ± 11.7 (p = 0.005); and slow metabolizers eGFR 36 months: + 9.4 ± 15.9 mL/min/1.73 m2 (p = 0.049)) vs. baseline. Adverse events were not different between the groups. After the switch, eGFR values of all patients increased statistically noticeably with a tendency towards a higher increase in fast TAC metabolizers. Since conversion to EVR was safe in a three-year follow-up for slow and fast TAC metabolizers, this could be an option to protect fast metabolizers from TAC-related issues.

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