Pharmacokinetics and Pharmacodynamics of Once-Daily Tacrolimus Compared With Twice-Daily Tacrolimus in the Early Stage After Living Donor Liver Transplantation

Iwasaki, Mami; Yano, Ikuko; Hashi, Sachiyo; Yamamoto, Yuki; Sugimoto, Mitsuhiro; Fukudo, Masahide; Masuda, Satohiro; Nakagawa, Shoichi; Yonezawa, Atsushi; Kaido, Toshimi; Üemoto, Shinji; Matsubara, Kazuo

doi:10.1097/ftd.0000000000000551

Cited by 10 publications

(24 citation statements)

References 23 publications

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“…In addition, a relatively high inter-patient variability of CaN activities was observed. These results are consistent with previous published work on that topic [27][28][29]. We tried to develop a pharmacokinetic-pharmacodynamic model to describe the relationship between TAC exposure and inhibition of its molecular target but all modeling approaches tested failed.…”

Section: Plos Onesupporting

confidence: 88%

“…acute cellular rejection [24][25][26]. A few studies, conducted in liver transplantation, described the pharmacokinetic-pharmacodynamic relationship of TAC by studying the link between whole blood concentrations and CaN activity in PBMC [27][28][29]. However, the complete relationship between TAC whole blood concentration, TAC intra-PBMC concentration and TAC-induced CaN inhibition, have only been reported in a preliminary work by our team [30], and remains to be widely explored and emphasized with the drug pharmacogenetics.…”

Section: Plos Onementioning

confidence: 99%

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Pharmacogenetic—Whole blood and intracellular pharmacokinetic—Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients

et al. 2020

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Tacrolimus (TAC) is the cornerstone of immunosuppressive therapy in liver transplantation. This study aimed at elucidating the interplay between pharmacogenetic determinants of TAC whole blood and intracellular exposures as well as the pharmacokinetic-pharmacodynamic relationship of TAC in both compartments. Complete pharmacokinetic profiles (Predose, and 20 min, 40 min, 1h, 2h, 3h, 4h, 6h, 8h, 12h post drug intake) of twice daily TAC in whole blood and peripheral blood mononuclear cells (PBMC) were collected in 32 liver transplanted patients in the first ten days post transplantation. A non-parametric population pharmacokinetic model was applied to explore TAC pharmacokinetics in blood and PBMC. Concurrently, calcineurin activity was measured in PBMC. Influence of donor and recipient genetic polymorphisms of ABCB1, CYP3A4 and CYP3A5 on TAC exposure was assessed. Recipient ABCB1 polymorphisms 1199G>A could influence TAC whole blood and intracellular exposure (p<0.05). No association was found between CYP3A4 or CYP3A5 genotypes and TAC whole blood or intracellular concentrations. Finally, intra-PBMC calcineurin activity appeared incompletely inhibited by TAC and less than 50% of patients were expected to achieve intracellular IC 50 concentration (100 pg/millions of cells) at therapeutic whole blood concentration (i.e.: 4-10 ng/mL). Together, these data suggest that personalized medicine regarding TAC therapy might be optimized by ABCB1 pharmacogenetic biomarkers and by monitoring intracellular concentration whereas the relationship between intracellular TAC exposure and pharmacodynamics biomarkers more specific than calcineurin activity should be further investigated.

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Section: Plos Onesupporting

confidence: 88%

Section: Plos Onementioning

confidence: 99%

Pharmacogenetic—Whole blood and intracellular pharmacokinetic—Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients

et al. 2020

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“…3 Monitoring of Cmin is mandatory to minimize the risk of rejection (Cmin below the target range), as well as to reduce the risk of nephrotoxicity, and, to a lesser extent, neurotoxicity (Cmin above the target range). 3,14 In present study, the AUC for twice-daily tacrolimus did not differ significantly from the AUC for once-daily tacrolimus, despite a lower Cmin for the latter. This implies that the same target trough level of tacrolimus cannot be used to predict the efficacy of the drug (AUC) after the conversion, especially among the expressors.…”

Section: Discussioncontrasting

confidence: 57%

“…The safety and efficacy of twice-daily and once-daily tacrolimus in liver transplant recipients were shown to be similar. 3,10,[14][15][16] Several previous studies demonstrated that liver dysfunction is the most common adverse event after converting from twice-daily to once-daily tacrolimus. 11 In our present study, the incidence of liver dysfunction in stable liver transplant recipients converted to once-daily extended-release tacrolimus was higher in the CYP3A5 expressor group than in the non-expressor group.…”

Section: Discussionmentioning

confidence: 99%

“…19 CYP3A5 expression was shown to influence tacrolimus exposure, with the exposure in CYP3A5 expressors receiving either twice-daily tacrolimus or once-daily tacrolimus being lower than in the non-expressors. [6][7][8]14 CYP3A5 expressors carry the *1 variant which encodes the functional enzyme responsible for the metabolism of tacrolimus; therefore, they may require a higher dose of tacrolimus than the non-expressors to achieve the target trough level of the drug. [3][4][5] Our present study demonstrated that CYP3A5 polymorphism influenced both tacrolimus dose and trough level of the drug; the median dose of tacrolimus both before and after switching to the once-daily extended-release formulation was significantly higher in the expressor group than in the non-expressors.…”

Section: Discussionmentioning

confidence: 99%

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Effect of CYP3A5 polymorphism on liver function and tacrolimus pharmacokinetics after conversion to a once-daily tacrolimus formulation in stable liver transplant patients

Kim

Ryu

Lee

et al. 2020

Preprint

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Aim: To analyze the effects of CYP3A5 polymorphism on liver function after LT and to characterize the pharmacokinetics of tacrolimus after conversion from a twice-daily regimen to a once-daily extended-release formulation. Methods: A prospective open-label study included 60 stable liver transplant recipients who underwent 1:1 conversion from twice-daily tacrolimus to oncedaily tacrolimus. All participants were genotyped for CYP3A5 polymorphism. The study was registered at ClinicalTrials.gov (NCT 02882113). Results: Twenty-eight patients were enrolled in the CYP3A5 expressor group and 32 in the non-expressor group. Although there was no statistical difference, incidence of liver dysfunction was higher in the expressor group than in the non-expressor group when converted to once-daily extended-release tacrolimus (P=0.088). No biopsy-proven acute rejection, graft failure, and mortality were observed in either group. The decrease in dose-adjusted trough level (-42.9% vs.-26.1%) and dose/kg-adjusted trough level of tacrolimus (-40.0% vs.-23.7%) was significantly greater in the expressor group than in the non-expressors after the conversion. The absorption of the tacrolimus in the non-expressor group was slower than in the expressors. In line with this observation, the AUC for once-daily tacrolimus correlated with Cmin in the non-expressors and Cmax in the expressors. Conclusions: Determination of CYP3A5 genotype in liver transplant recipients might be helpful in prediction of tacrolimus pharmacokinetics after conversion from a twice-daily regimen to a once-daily formulation.

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Sustained Inhibition of Calcineurin Activity With a Melt‐Dose Once‐daily Tacrolimus Formulation in Renal Transplant Recipients

Fontova

Colom

Rigo-Bonnin

et al. 2021

Clin Pharma and Therapeutics

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Tacrolimus (Tac) is the cornerstone calcineurin inhibitor in transplantation. Extended‐release Meltdose formulation (Tac‐LCP) offers better bioavailability compared with immediate‐release formulation (Tac‐IR). We postulated that the less fluctuating pharmacokinetic (PK) profile of Tac‐LCP might maintain a sustained inhibition of calcineurin activity (CNA) between dose intervals. Higher concentrations (peak plasma concentration (Cmax)) after Tac‐IR may not result in a more potent CNA inhibition due to a capacity‐limited effect. This study was aimed at evaluating the pharmacodynamic (PD)/PK profiles of Tac‐IR compared with Tac‐LCP. An open‐label, prospective, nonrandomized, investigator‐driven study was conducted. Twenty‐five kidney transplant recipients receiving Tac‐IR were switched to Tac‐LCP. Before and 28 days after conversion, intensive CNA‐PD and PK sampling were conducted using ultra‐high‐performance liquid chromatography‐tandem accurate mass spectrometry. PD nonlinear mixed effects model was performed in Phoenix‐WinNonlin. Statistically significant higher Cmax (P < 0.001) after Tac‐IR did not result in lower CNA as compared with after Tac‐LCP (P = 0.860). Tac‐LCP showed a statistically more maintained CNA inhibition between dose intervals (area under the effect‐time curve from 0 to 24 hours (AUE0–24h)) compared with Tac‐IR, in which CNA returned to predose levels after 4 hours of drug intake (373.8 vs. 290.5 pmol RII·h/min·mg prot, Tac‐LCP vs. Tac‐IR; P = 0.039). No correlation was achieved between any PD and PK parameters in any formulations. Moreover, Tac concentration to elicit a 50% of the maximum response (half‐maximal inhibitory concentration) was 9.24 ng/mL. The higher Cmax after Tac‐IR does not result in an additional CNA inhibition compared with Tac‐LCP attributable to a capacity‐limited effect. Tac‐LCP may represent an improvement of the PD of Tac due to the more sustained CNA inhibition during dose intervals.

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Pharmacokinetics and Pharmacodynamics of Once-Daily Tacrolimus Compared With Twice-Daily Tacrolimus in the Early Stage After Living Donor Liver Transplantation

Cited by 10 publications

References 23 publications

Pharmacogenetic—Whole blood and intracellular pharmacokinetic—Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients

Pharmacogenetic—Whole blood and intracellular pharmacokinetic—Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients

Effect of CYP3A5 polymorphism on liver function and tacrolimus pharmacokinetics after conversion to a once-daily tacrolimus formulation in stable liver transplant patients

Sustained Inhibition of Calcineurin Activity With a Melt‐Dose Once‐daily Tacrolimus Formulation in Renal Transplant Recipients

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