Kidney graft failure due to noncompliance

Michelon, Tatiana; Dominguez, V; Losekan, A; Messias, Ana; Bruno, Rosana Mussoi; Bittar, A.E; Keitel, Elizete; Santos, A Ribeiro dos; Goldani, J. C.; Bianchinni, J; Garcia, Clotilde Druck; Neumann, Jorge; Garcı́a, Valter Duro

doi:10.1016/s0041-1345(99)00657-0

Cited by 17 publications

(13 citation statements)

References 4 publications

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“…Maintaining effective immunosuppressive drug levels is essential to preventing rejection, and a lack of adherence to prescribed immunosuppression drug regimens is a barrier to successful transplant outcomes. 11,28 Unfortunately, a lack of adherence has been reported to be common in transplant recipients. [29][30][31] A greater dose frequency is inversely related to medication adherence.…”

Section: Discussionmentioning

confidence: 99%

Conversion from twice daily tacrolimus capsules to once daily extended‐release tacrolimus (LCP‐Tacro): Phase 2 trial of stable liver transplant recipients

et al. 2014

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LCP-Tacro is an extended-release formulation of tacrolimus designed for once-daily dosing. Studies in renal transplantation demonstrate greater bioavailability with similar safety and efficacy vs. twice-daily tacrolimus capsules. In this phase 2 study, adult stable liver transplant patients on tacrolimus capsules (Prograf) twice-daily were converted to tacrolimus tablets (LCPTacro) once-daily; patients continued on LCP-Tacro once-daily for days 8-21; target trough levels were 5-15 ng/mL; 24-hour pharmacokinetic (PK) assessments were done on days 7 (baseline pre-switch), 14, and 21. A 6 month extension study phase evaluated PK and safety following a total of 52 weeks of LCP-Tacro. Fifty-seven patients completed LCP-Tacro dosing in the core study; 43 completed the extension phase. The mean conversion ratio was 0.71 (Prograf:LCP-Tacro). PK data demonstrated consistent exposure (AUC) at the lower conversion dose. C max , C max /C min ratio, percent fluctuation and swing were significantly (P<0.001) lower and T max significantly (P<0.001) longer for LCP-Tacro vs. Prograf. AUC 24 and C min correlation coefficients after 7 and 14 days of therapy were 0.93. There were no significant differences in PK parameters at week 26 vs. 14. One patient experienced an unrelated serious adverse event (SAE) during the core study and discontinued. There were six unrelated SAEs in the extension and 1 possibly related (rejection) that resolved; there were 3 discontinuations due to AEs during the extension. In this study, patients were safely converted from Prograf twice-daily to LCP-Tacro. The greater bioavailability of LCP-Tacro allowed for once-daily dosing and similar (AUC) exposure at a dose approximately 30% less than the total daily dose of Prograf. LCP-Tacro displayed significantly lower peak and peak-trough Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC, area under the curve; AUC 24 , area under the curve at 24 hours; C 24 , concentration at 24 hours; C avg , average concentration; C max , maximum concentration; C min , minimum concentration; CV, coefficient of variation; ECG, electrocardiogram; H&C, hematology and chemistry; PK, pharmacokinetic; RGM, ratio of geometric means; SAE, serious adverse event; SE, standard error; TDD, total daily dose; T max , time of the maximum concentration.Some of the data were presented at the

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Section: Discussionmentioning

confidence: 99%

Conversion from twice daily tacrolimus capsules to once daily extended‐release tacrolimus (LCP‐Tacro): Phase 2 trial of stable liver transplant recipients

et al. 2014

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“…The study by Michelon and colleagues (30) shows an increasing proportion of graft losses attributed to nonadherence during three consecutive time periods. This suggests that the impact of nonadherence is increasing over time.…”

Section: Impact Of Nonadherencementioning

confidence: 96%

“…Results of case series of subjects with failed grafts Using the values given for transplants that functioned at least 6 months in the study byMichelon et al 1999 for transplants performed between 1977 and 1998.b Excluding death with function if data available, compares to a median of 11.4% in the same studies but including subjects who died with function.Tx, transplantation.…”

mentioning

confidence: 99%

Frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review

Butler

Roderick²,

Mullee³

et al. 2004

Transplantation

488

372

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Nonadherence to immunosuppressants is recognized to occur after renal transplantation, but the size of its impact on transplant survival is not known. A systematic literature search identified 325 studies (in 324 articles) published from 1980 to 2001 reporting the frequency and impact of nonadherence in adult renal transplant recipients. Thirty-six studies meeting the inclusion criteria for further review were grouped into cross-sectional and cohort studies and case series. Meta-analysis was used to estimate the size of the impact of nonadherence on graft failure. Only two studies measured adherence using electronic monitoring, which is currently thought to be the most accurate measure. Cross-sectional studies (n=15) tended to rely on self-report questionnaires, but these were poorly described; a median (interquartile range) of 22% (18%-26%) of recipients were nonadherent. Cohort studies (n=10) indicated that nonadherence contributes substantially to graft loss; a median (interquartile range) of 36% (14%-65%) of graft losses were associated with prior nonadherence. Meta-analysis of these studies showed that the odds of graft failure increased sevenfold (95% confidence interval, 4%-12%) in nonadherent subjects compared with adherent subjects. Standardized methods of assessing adherence in clinical populations need to be developed, and future studies should attempt to identify the level of adherence that increases the risk of graft failure. However, this review shows nonadherence to be common and to have a large impact on transplant survival. Therefore, significant improvements in graft survival could be expected from effective interventions to improve adherence.

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“…High intra-individual variability and variable drug exposure are associated with increased risk for graft deterioration and loss (6). In addition, multipledaily dosing is associated with an increased risk for nonadherence (7)(8)(9), which can lead to acute rejection (10) and, in serious cases, graft failure (11). Therefore, a oncedaily tacrolimus-dosing regimen could potentially positively affect patient medication adherence.…”

Section: Introductionmentioning

confidence: 99%

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

Budde

Bunnapradist

Grinyó

et al. 2014

American Journal of Transplantation

104

141

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This Phase III randomized trial examined efficacy and safety of a novel once-daily extended-release tacrolimus formulation (LCP-Tacro [LCPT]) versus twice-daily tacrolimus in de novo kidney transplantation. Primary efficacy end point was proportion of patients with treatment failure (death, graft failure, biopsy-proven acute rejection or lost to follow-up) within 12 months. Starting doses were, LCPT: 0.17 mg/kg/day and tacrolimus twice-daily: 0.1 mg/kg/day; 543 patients were randomized, LCPT: n ¼ 268; tacrolimus twice-daily: n ¼ 275. At 12 months treatment failure was LCPT: 18.3% and tacrolimus twice-daily: 19.6%; the upper 95% CI of the treatment difference was þ5.27%, below the predefined þ10% noninferiority criteria. There were no significant differences in the incidence of individual efficacy events or adverse events. Target tacrolimus trough levels were more rapidly achieved in the LCPT group. Following initial dose, 36.6% of patients in the LCPT group had rapidly attained trough levels within 6-11 ng/mL versus 18.5% of tacrolimus twice-daily patients; majority of tacrolimus twice-daily patients (74.7%) had troughs <6 ng/mL compared with 33.5% in the LCPT group. Overall, cumulative study dose was 14% lower for LCPT. Results suggest that use of oncedaily LCPT in de novo kidney transplantation is efficacious and safe. Lower LCPT dose reflects the improved absorption provided by the novel formulation.

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Kidney graft failure due to noncompliance

Cited by 17 publications

References 4 publications

Conversion from twice daily tacrolimus capsules to once daily extended‐release tacrolimus (LCP‐Tacro): Phase 2 trial of stable liver transplant recipients

Conversion from twice daily tacrolimus capsules to once daily extended‐release tacrolimus (LCP‐Tacro): Phase 2 trial of stable liver transplant recipients

Frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review

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

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