Clinical pharmacokinetics of tacrolimus in heart transplantation: new strategies of monitoring

Rubio, María Dolores Mesa; Prado, José María Arizón del; Molina, Mercedes; Aranzana, M. Cárdenas; Saint-Gerons, J Segura; Granados, Amador López; Esteban, E; Rubio, Dolores Mesa; Peñas, Elías Romo; Saint-Gerons, C. Segura

doi:10.1016/s0041-1345(03)00656-0

Cited by 28 publications

(10 citation statements)

References 12 publications

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“…In our opinion, a suitable limited sampling strategy for tacrolimus should consist of two or three time concentration points within a short time post-dose (≤4 h) including a trough level. We selected 24 LLS from the literature [ 12 , 15 , 16 , 18 , 20 , 22 ]. Eighteen of these strategies were based on regression analysis [ 12 , 16 , 18 , 20 , 22 ], and six other strategies were based on Bayesian fitting [ 15 ].…”

Section: Methodsmentioning

confidence: 99%

“…Although tacrolimus C 0 concentrations are generally considered to be a good indication of the total systemic drug exposure [ 1 , 8 ], its usefulness in differentiating graft rejection episodes from nephrotoxicity has been questioned [ 6 , 9 – 11 ]. Recently, the correlation between individual tacrolimus concentrations and AUC 0–12 has been studied in kidney [ 12 – 18 ], liver [ 19 ], heart [ 20 , 21 ] and lung [ 22 ] transplant recipients. In these studies, a poor association was found between the tacrolimus C 0 concentrations and the AUC 0–12 , while tacrolimus concentrations measured at other time points showed much better correlations with the AUC 0–12 .…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, strategies have been developed that included a limited number of sampling time points within a short time post-dose, the so-called limited sampling strategies (LSS). Several two- and three-time-point sampling strategies showed a high correlation with the AUC 0–12 in published studies and were able to predict the AUC 0–12 more accurately than the C 0 concentration alone [ 12 , 15 – 18 , 20 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of limited sampling strategies for tacrolimus

Buijsch

Plas

Stolk

et al. 2007

Eur J Clin Pharmacol

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Objective In literature, a great diversity of limited sampling strategies (LSS) have been recommended for tacrolimus monitoring, however proper validation of these strategies to accurately predict the area under the time concentration curve (AUC 0-12 ) is limited. The aim of this study was to determine whether these LSS might be useful for AUC prediction of other patient populations. Methods The LSS from literature studied were based on regression equations or on Bayesian fitting using MWPHARM 3.50 (Mediware, Groningen, the Netherlands). The performance was evaluated on 24 of these LSS in our population of 37 renal transplant patients with known AUCs. The results were also compared with the predictability of the regression equation based on the trough concentrations C 0 and C 12 of these 37 patients. Criterion was an absolute prediction error (APE) that differed less than 15% from the complete AUC 0-12 calculated by the trapezoidal rule. Results Thirteen of the 18 (72%) LSS based on regression analysis were capable of predicting at least 90% of the 37 individual AUC 0-12 within an APE of 15%. Additionally, all but three LSS examined gave a better prediction of the complete AUC 0-12 in comparison with the trough concentrations C 0 or C 12 (mean 62%). All six LSS based on Bayesian fitting predicted <90% of the 37 complete AUC 0-12 correctly (mean 67%). Conclusions The present study indicated that implementation of LSS based on regression analysis could produce satisfactory predictions although careful evaluation is necessary.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of limited sampling strategies for tacrolimus

Buijsch

Plas

Stolk

et al. 2007

Eur J Clin Pharmacol

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“…Tacrolimus (TAC), the primary immunosuppressive drug for HTx recipients, prevents T cell activation and proliferation by forming a complex with immunophilin, which interacts with intracellular calcineurin that inhibits the expression of genes coding for proinflammatory cytokines . TAC, a narrow therapeutic index drug, demonstrates large pharmacokinetic interindividual variability, partially due to presystemic metabolism by the intestinal cytochrome P450 (CYP)3A system, which may be affected by other CYP3A substrates, inducers, or inhibitors . High variability in TAC trough levels has been related to worse outcomes in both adult and pediatric kidney transplant recipients .…”

Section: Introductionmentioning

confidence: 99%

High tacrolimus trough level variability is associated with rejections after heart transplant

Gueta

Markovits

Yarden-Bilavsky

et al. 2018

American Journal of Transplantation

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Tacrolimus, the major immunosuppressant after heart transplant (HTx) therapy, is a narrow therapeutic index drug. Hence, achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. Whether high variability in steady state concentrations is associated with poor outcomes is unknown. We investigated the association between tacrolimus trough level variability during the first year post-HTx and outcomes during and beyond the first postoperative year. Overall, 72 patients were analyzed for mortality, of whom 65 and 61 were available for rejection analysis during and beyond the first year post-HTx, respectively. Patients were divided into high (median >28.8%) and low tacrolimus level variability (<28.8%) groups. Mean tacrolimus levels did not differ between the groups (12.7 ± 3.4 ng/mL vs 12.8 ± 2.4 ng/mL, P = .930). Patients in the high variability group exhibited higher long-term rejection rate (median total rejection score: 0.33 vs 0, P = .04) with no difference in rejection scores within the first year post-HTx. Multivariate analysis showed that high tacrolimus trough level variability was associated with >8-fold increased risk for any rejection beyond the first year post-HTx (P = .011). Mortality was associated only with cardiovascular complications (P = .018), with no effect of tacrolimus through level variability.

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“…The validity of this practice, however, has been recently challenged. Several studies in recipients of kidney (25–29), liver (30–32) and heart (33) transplants have shown that Tac concentrations measured 2–4 h postdose were much better correlated with drug exposure than C 0 . Similarly, the current study showed that exposure to Tac, as measured by the AUC 0–12 , was much better correlated with C 3 than with C 0 in either the CF or the non‐CF patients.…”

Section: Discussionmentioning

confidence: 99%

Tacrolimus Pharmacokinetics and Dose Monitoring After Lung Transplantation for Cystic Fibrosis and Other Conditions

Knoop¹,

Thiry

Saint-Marcoux

et al. 2005

American Journal of Transplantation

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In cystic fibrosis (CF), absorption of tacrolimus through the gastrointestinal tract may be impaired due to fat malabsorption. The aim of this pilot study was to compare tacrolimus pharmacokinetics and inter-and intrasubject variability of exposure in stable lung transplant recipients with and without CF, and to determine the best single-time predictors of exposure. The study included 11 lung transplant recipients with CF and 11 without CF who received tacrolimus twice daily. Blood samples were obtained predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 h postdose on 3 separate days within 1 week. Tacrolimus pharmacokinetics and inter-and intrasubject variability of exposure were similar in the two groups, though exposure-per-milligram-dose was ∼50% lower in CF patients. Tacrolimus trough concentration did not accurately predict the area under the concentration curve (AUC 0-12 ), but the concentration measured 3 h postdose (C 3 ) was tightly correlated with the AUC 0-12 in both CF (r 2 = 0.86) and non-CF (r 2 = 0.92) patients. In summary, patients with CF have a higher tacrolimus oral clearance, but nonsignificant differences in short-term inter-and intrasubject variability of exposure compared to patients without CF. C 3 is tightly correlated with AUC 0-12 in lung transplant recipients with and without CF.

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Clinical pharmacokinetics of tacrolimus in heart transplantation: new strategies of monitoring

Cited by 28 publications

References 12 publications

Evaluation of limited sampling strategies for tacrolimus

Evaluation of limited sampling strategies for tacrolimus

High tacrolimus trough level variability is associated with rejections after heart transplant

Tacrolimus Pharmacokinetics and Dose Monitoring After Lung Transplantation for Cystic Fibrosis and Other Conditions

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