High Initial Blood Levels of Tacrolimus in Overweight Renal Transplant Recipients

Rodrigo, Emilio; Cossío, María Ángeles de Cos; Sánchez, Blanca; Ruiz, J.C.; Piñera, Celestino; Fernández‐Fresnedo, Gema; Palomar, Rosa; Pérez-Ceballos, M.A.; Cotorruelo, J.G; Zubimendi, J.A; Francisco, A.L.M. de; Arias, Manuel

doi:10.1016/j.transproceed.2005.02.055

Cited by 35 publications

(22 citation statements)

References 5 publications

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“…Our data also confirm literature reports on clinical factors associated with slow tacrolimus metabolizers: male sex [40], age [41,42], HCV positivity [43], and higher BMI [44].…”

Section: Discussionsupporting

confidence: 91%

The interactions of age, sex, body mass index, genetics, and steroid weight-based doses on tacrolimus dosing requirement after adult kidney transplantation

Stratta

Quaglia²,

Cena³

et al. 2011

Eur J Clin Pharmacol

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Our results demonstrate the importance of the interaction among genetic and clinical factors in conditioning tacrolimus disposition, with corticosteroid weight-based dose being the only modifiable risk factor for tacrolimus requirement. As the tacrolimus dosing requirement increases with increasing tacrolimus clearance through concomitant steroid use, undesirable changes in tacrolimus levels may occur when steroid doses are tapered, predominantly in slow metabolizers. This often neglected drug interaction has to be monitored to optimize tacrolimus exposure in kidney transplant patients.

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“…Our data also confirm literature reports on clinical factors associated with slow tacrolimus metabolizers: male sex [40], age [41,42], HCV positivity [43], and higher BMI [44].…”

Section: Discussionsupporting

confidence: 91%

The interactions of age, sex, body mass index, genetics, and steroid weight-based doses on tacrolimus dosing requirement after adult kidney transplantation

Stratta

Quaglia²,

Cena³

et al. 2011

Eur J Clin Pharmacol

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“…We minimized the effects of these confounding factors by selecting and adjusting for those factors that have significant impact on the mixed-effects model. Among all significant covariates, BMI correlated positively with SRL log (C/D), similar to a previous finding showing higher initial tacrolimus blood levels in overweight renal transplant recipients (22). Additionally, SRL concentration/dose ratios were increased during clotrimazole or statins co-administration and were decreased during tacrolimus or prednisone co-administration, suggesting CYP3A enzyme competition between substrates (statins and tacrolimus) as well as CYP3A induction and inhibition by corticosteroids (23,24) and clotrimazole, respectively (25,26).…”

Section: Discussionsupporting

confidence: 88%

Associations of ABCB1 3435C>T and IL-10-1082G>A Polymorphisms With Long-Term Sirolimus Dose Requirements in Renal Transplant Patients

et al. 2011

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Backgrounds SRL absorption and metabolism are affected by Pgp-mediated transport and CYP3A enzyme activity, which are further under the influences of cytokine concentrations. This retrospective study determined the associations of ABCB1 1236C>T, 2677 G>T/A, and 3435C>T, CYP3A4 -392A>G, CYP3A5 6986A>G and 14690G>A, IL-10 -1082G>A, and TNF -308G>A polymorphisms with SRL dose-adjusted, weight-normalized trough concentrations (C/D) at 7 days, and at 1, 3, 6, and 12 months post initiation of SRL. Methods Genotypes for 86 renal transplant patients who received SRL-based maintenance immunosuppressive therapy were determined using polymerase chain reaction followed by chip-based mass spectrometry. The changes of log-transformed C/D over the days post transplantation were analyzed using a linear mixed-effects model, with adjustments for body mass index and weight-normalized doses of tacrolimus, prednisone, clotrimazole, and statins. Results ABCB1 3435C>T and IL-10 -1082G>A were significantly associated with log C/D (p=0.0016 and 0.0394, respectively). Mean SRL C/D was 48% higher in patients with ABCB1 3435CT/TT genotype than those with 3435CC genotype, and was 24% higher in IL-10 -1082GG compared to -1082AG/AA. Conclusions ABCB1 3435C>T and IL-10 -1082G>A were significantly associated with long-term SRL dose requirements. Genetics can play a significant role in SRL dosing and may be useful in therapeutic monitoring of SRL in renal transplantation. Future replication studies are needed to confirm these associations.

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“…To our knowledge, only 2 studies have investigated the relationship between bodyweight or BMI and Tac exposure at first steady state. Rodrigo et al 9 concluded that overweight renal transplant recipients are more prone to develop initial high exposure (ie, a C 0 > 15 ng/mL) compared with nonoverweight recipients. Rodrigo et al 9 demonstrated that the first Tac C 0 tended to be higher than 15 ng/mL in overweight, older kidney transplant recipients.…”

Section: Discussionmentioning

confidence: 99%

“…Rodrigo et al 9 concluded that overweight renal transplant recipients are more prone to develop initial high exposure (ie, a C 0 > 15 ng/mL) compared with nonoverweight recipients. Rodrigo et al 9 demonstrated that the first Tac C 0 tended to be higher than 15 ng/mL in overweight, older kidney transplant recipients. Sawamoto et al 18 demonstrated that the average Tac maintenance dose in patients with a BMI greater than 25 kg/m 2 is significantly lower compared with that in patients with a BMI of 25 kg/m 2 or less.…”

Section: Discussionmentioning

confidence: 99%

Overweight Kidney Transplant Recipients Are at Risk of Being Overdosed Following Standard Bodyweight-Based Tacrolimus Starting Dose

Andrews

Winter

Tang

et al. 2017

Transplantation Direct

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BackgroundBodyweight-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.MethodsFor 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.ResultsData 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.ConclusionsThis study demonstrates that dosing Tac solely on bodyweight results in overexposure in more than half of overweight or obese patients.

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High Initial Blood Levels of Tacrolimus in Overweight Renal Transplant Recipients

Cited by 35 publications

References 5 publications

The interactions of age, sex, body mass index, genetics, and steroid weight-based doses on tacrolimus dosing requirement after adult kidney transplantation

The interactions of age, sex, body mass index, genetics, and steroid weight-based doses on tacrolimus dosing requirement after adult kidney transplantation

Associations of ABCB1 3435C>T and IL-10-1082G>A Polymorphisms With Long-Term Sirolimus Dose Requirements in Renal Transplant Patients

Overweight Kidney Transplant Recipients Are at Risk of Being Overdosed Following Standard Bodyweight-Based Tacrolimus Starting Dose

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