Risk Factors for the Adverse Events after Conversion from Twice-Daily to Once-Daily Tacrolimus in Stable Liver Transplantation Patients

et al. 2020

Preprint

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.

Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 42%

Section: Introductionmentioning

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

et al. 2020

Preprint

“…Patient selection and post‐LT immunosuppressive details have been previously described . Usage of mammalian target of rapamycin inhibitor (mTORi) was considered for patients with far advanced HCC, defined as HCC larger than 10 cm or more than 10 in number, or with macrovascular invasion, 1 month after LT .…”

Section: Methodsmentioning

confidence: 99%

Different prognostic factors and strategies for early and late recurrence after adult living donor liver transplantation for hepatocellular carcinoma

Hong

Clinical Transplantation

Yoon

et al. 2019

Self Cite

Liver transplantation (LT) is a well-established treatment optionfor hepatocellular carcinoma (HCC) patients. 1 Theoretically, LT has the advantage of both eliminating the tumor and curing the underlying diseased liver. However, post-transplant HCC recurrence occurs in 5%-30% of cases. 1,2 Once post-transplant HCC recurrence occurs, it is more frequently found in the first 1 or 2 years following LT, with the majority (67%) involving extrahepatic recurrence, lung, bone, adrenal gland, peritoneal lymph nodes, and brain. 3 The high incidence of extrahepatic HCC recurrence and the inevitable usage of immunosuppressants after LT may be associated with poor survival after recurrence, with a median survival of less than 1 year. 4 Abstract Background: Some patients with hepatocellular carcinoma (HCC) recurrence after LT show good long-term survival. We aimed to determine the prognostic factors affecting survival after recurrence and to suggest treatment strategies. Methods: Between January 2000 and December 2015, 532 patients underwent adult living donor liver transplantation (LDLT) for HCC. Among these, 92 (17.3%) who experienced recurrence were retrospectively reviewed.Results: The 1-, 3-, and 5-year survival rates after recurrence were 59.5%, 23.0%, and 11.9%, respectively. In multivariate analysis, time to recurrence >6 months and surgical resection after recurrence were related to longer survival after recurrence, while multi-organ involvement at the time of primary recurrence was related to poorer survival. We classified patients into early (≤6 months) and late (>6 months) recurrence groups. In the early recurrence group, tumor size >5 cm in the explant liver, liver as the first detected site of recurrence, and multiple organ involvement at primary recurrence were related to survival on multivariate analysis. In the late recurrence group, mammalian target of rapamycin inhibitor (mTORi) usage and multi-organ involvement were significantly associated with the prognosis on multivariate analysis. Conclusions:Various therapeutic approaches are needed depending on the period of recurrence after LT and multiplicity of involved organs. K E Y W O R D Shepatectomy, living donor, local neoplasm recurrence, metastasis, mTOR serine-threonine kinases

“…Several studies have demonstrated that in stable patients after LT, conversion from twice-daily to once-daily tacrolimus was well-tolerated, safe, and convenient [ 10 , 11 ]. However, despite the similar pharmacokinetics of the twice-daily and once-daily tacrolimus, some patients experienced adverse events, including liver dysfunction, after the conversion [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of CYP3A5 on the Once-Daily Tacrolimus Conversion in Stable Liver Transplant Patients

Kim

Ryu

et al. 2020

JCM

Self Cite

Cytochrome P450 (CYP) 3A5 polymorphism influences tacrolimus metabolism, but its effect on the drug pharmacokinetics in liver transplant recipients switched to once-daily extended-release formulation remains unknown. The aim of this study is to analyze the effect of CYP3A5 polymorphism on liver function after once-daily tacrolimus conversion in liver transplant patients. A prospective open-label study included 60 stable liver transplant recipients who underwent 1:1 conversion from twice-daily tacrolimus to once-daily tacrolimus. All participants were genotyped for CYP3A5 polymorphism. The study was registered at ClinicalTrials.gov (NCT 02882113). 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. A pharmacokinetic analysis was performed in 10 patients and tacrolimus absorption in the non-expressor group was slower than in the expressor group. In line with this observation, the area under the curve for once-daily tacrolimus correlated with trough level (Cmin) in the non-expressors and peak concentration (Cmax) in the expressors. CYP3A5 genotyping in liver transplant recipients leads to prediction of pharmacokinetics after switching from a twice-daily regimen to a once-daily dosage form, which makes it possible to establish an appropriate dose of tacrolimus.