Tacrolimus exposure early after lung transplantation and exploratory associations with acute cellular rejection

Darley, D.R.; Carlos, Lilibeth; Hennig, Stefanie; Liu, Zhixin; Day, Richard O.; Glanville, Allan R.

doi:10.1007/s00228-019-02658-5

Cited by 8 publications

(4 citation statements)

References 38 publications

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“…David et al reported that tacrolimus CL/F was 21.6 L/h after adjusting for haematocrit in Caucasian patients taking triazole antifungal agents during the early stages of post-lung transplantation, which was higher than that observed in our study 47 . This result cannot be explained by differences in CYP3A5 genetic polymorphisms between Chinese and Caucasian populations, as the frequency of poor metabolizers (CYP3A5*3*3) among Caucasian patients was much higher than among Chinese patients (94% vs. 35.7%); however, it may be explained by a large number of cystic brosis patients in the Caucasian cohort.…”

Section: Discussioncontrasting

confidence: 90%

Pharmacokinetic Evaluation of Tacrolimus in Chinese Adult Patients Receiving Voriconazole During the Early Stage Post-Lung Transplantation

Cui

Zhu

Yan

et al. 2022

Preprint

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Although tacrolimus has been widely used in patients undergoing lung transplantation, few studies have reported the pharmacokinetics of tacrolimus in Chinese patients after lung transplantation. Thus, we aimed to investigate its pharmacokinetics and influential factors in this patient cohort in the early stage after lung transplantation. We enrolled 14 lung transplant recipients who were treated with tacrolimus and voriconazole. We then collected intensive blood samples within a 12-hour dosing interval and analysed them via liquid chromatography-mass spectrometry. The pharmacokinetic parameters of tacrolimus were calculated using non-compartmental analysis, and the influence of physio-pathological characteristics and CYP3A5*3 and CYP3A4*1G genotypes on the pharmacokinetics of tacrolimus was assessed. Using linear regression analysis, we then investigated the correlation between tacrolimus concentration at different sampling points and measured the area under the curve (AUC0 − 12h). Our results showed a mean apparent clearance (CL/F) rate of 14.2 ± 11.0 L/h, with CYP3A5*1 carriers having a CL/F rate five times higher than non-carriers (P < 0.001). Furthermore, tacrolimus concentration 4 h after the administration had the strongest correlation with AUC0 − 12h (R2 = 0.979). In summary, tacrolimus pharmacokinetics varied largely between patients during the early-stage post-lung transplantation, which could be partly explained by CYP3A5 genetic polymorphisms. Therefore, it is crucial to closely monitor tacrolimus blood concentration in the early stages after lung transplantation.

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Section: Discussioncontrasting

confidence: 90%

Pharmacokinetic Evaluation of Tacrolimus in Chinese Adult Patients Receiving Voriconazole During the Early Stage Post-Lung Transplantation

Cui

Zhu

Yan

et al. 2022

Preprint

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“…Darley et al, reported that the CL/F of tacrolimus was 21.6 L/h after adjusting for haematocrit in Caucasian patients taking triazole antifungal agents during the early stages of post-lung transplantation, which was higher than that observed in our study [36]. This discrepancy cannot be explained by differences in CYP3A5 genetic polymorphisms between Chinese and Caucasian populations, as the frequency of poor metabolizers (CYP3A5*3/*3) among Caucasian patients was much higher than among Chinese patients (94% vs. 35.7%, respectively); however, it may be explained by the large number of patients with cystic fibrosis in the Caucasian cohort.…”

Section: Discussioncontrasting

confidence: 87%

“…In our study, the median value of T max was 2 h, which was consistent with previous findings in patients soon after lung transplantation [4] and indicated rapid tacrolimus absorption. However, the geometric mean value of CL/F for tacrolimus was 9.95 L/h, which was larger than those in two previous pharmacokinetic studies in Chinese [34,35] and lower than that in Caucasians [36]. A detailed comparison of pharmacokinetics characteristics and patients' demographics among these studies is presented in Table 4.…”

Section: Discussionmentioning

confidence: 73%

Pharmacokinetic Evaluation of Tacrolimus in Chinese Adult Patients during the Early Stages Post-Lung Transplantation

Cui

Yan

Zhu

et al. 2023

JPM

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Background: Although tacrolimus has been widely used in patients undergoing lung transplantation, few studies have reported the pharmacokinetics of tacrolimus in Chinese patients after lung transplantation. Thus, we aimed to investigate the pharmacokinetics and influential factors in this patient cohort in the early stage after lung transplantation. Methods: We enrolled 14 adult lung transplant recipients who were treated with tacrolimus and then intensively collected blood samples within a 12-h dosing interval. The pharmacokinetic parameters of tacrolimus were calculated using non-compartmental analysis, and the influence of pathophysiological characteristics and CYP3A5*3 and CYP3A4*1G genotypes on the pharmacokinetics of tacrolimus was assessed. Using linear regression analysis, we investigated the correlation between tacrolimus concentration at different sampling points and measured the area under the time-concentration curve (AUC0–12h). Results: Geometric mean of apparent clearance (CL/F) was 18.13 ± 1.65 L/h in non-CYP3A5*3/*3 carriers, five times higher than that in CYP3A5*3/*3 carriers (p < 0.001). Furthermore, the tacrolimus concentration 4 h after administration had the strongest correlation with AUC0–12h (R2 = 0.979). Conclusion: The pharmacokinetics of tacrolimus varied largely between patients during the early stage post-transplantation, which could be partially explained by CYP3A5*3 genetic polymorphisms.

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“…7 Darley et al reported a significantly higher proportion of rejection biopsies (85.7% versus 31.9%) with C 0 fell below their target range of 12-15 ng/mL within the first three months after transplantation. 21 The discrepancies in lower limits of TAC C 0 may be attributed to variations in target ranges employed across different studies. In our center, where a substantial number of elderly patients undergo transplantation and face high risk of infection resulting in mortality, we have observed a significant association between C 0 < 8 ng/mL and inferior outcomes, thereby suggesting this lower limit remains acceptable.…”

Section: Discussionmentioning

confidence: 99%

Exploratory associations of tacrolimus exposure and clinical outcomes after lung transplantation: a retrospective, single center experience

Du,

Wang,

Zhang

et al. 2023

Preprint

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Aims: This study aimed to investigate the potential impact of tacrolimus (TAC) exposure on clinical outcomes after lung transplantation. Methods: This retrospective observational study enrolled a total of 234 lung transplant recipients. TAC trough levels (C) were collected for 3 intervals: 0–3 months, 3–12 months, and 12–24 months. The intra-patient variability (IPV) was calculated using coefficient of variation. Genotyping of CYP3A5*3 (rs776746) was performed. Patients were further divided into groups based on the C cut-off value of 8 ng/mL and IPV cut-off value of 30%. Cox proportional hazards regression models were used to explore the potential impact of C and IPV on outcomes of interests, including donor-specific antibodies (DSA), chronic lung allograft dysfunction (CLAD) and mortality. Results: The influence of CYP3A5*3 polymorphism was only significant for C and IPV during the first 3 months. Low C (< 8 ng/mL) at 3–12 months increased the risk of DSA (hazard ratio [HR] 2.820, 95% confidence interval [CI] 1.093–7.276) and mortality (HR 2.220, 95% CI 1.162–4.243), while High IPV (>=30%) during this period was associated with an increased risk of mortality (HR 2.100, 95% CI 1.120–3.937). Patients with Low C/High IPV combination had significantly higher risks for DSA (HR 4.534, 95% CI 1.326–15.507) and survival (HR 4.205, 95% CI 1.739–10.168), surpassing the predictive power provided by C or IPV alone. Conclusion: A combination of Low C/High IPV might be considered in categorizing patients towards risk of adverse clinical outcomes following lung transplantation.

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Tacrolimus exposure early after lung transplantation and exploratory associations with acute cellular rejection

Cited by 8 publications

References 38 publications

Pharmacokinetic Evaluation of Tacrolimus in Chinese Adult Patients Receiving Voriconazole During the Early Stage Post-Lung Transplantation

Pharmacokinetic Evaluation of Tacrolimus in Chinese Adult Patients Receiving Voriconazole During the Early Stage Post-Lung Transplantation

Pharmacokinetic Evaluation of Tacrolimus in Chinese Adult Patients during the Early Stages Post-Lung Transplantation

Exploratory associations of tacrolimus exposure and clinical outcomes after lung transplantation: a retrospective, single center experience

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