Early Tacrolimus Concentrations After Lung Transplant Are Predicted by Combined Clinical and Genetic Factors and Associated With Acute Kidney Injury

Miano, Todd A.; Flesch, Judd D.; Feng, Rui; Forker, Caitlin M.; Brown, Melanie; Oyster, Michelle; Kalman, Laurel; Rushefski, Melanie; Cantu, Edward; Porteus, Mary; Yang, Wei; Ar, Localio; Diamond, Joshua M.; Christie, Jason D.; Shashaty, Michael G. S.

doi:10.1002/cpt.1629

Cited by 44 publications

(48 citation statements)

References 33 publications

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“…TAC concentration was associated with post-operative AKI in our study, and a gradient increase with worsening AKI severity was observed ( Table 2 ). The acute nephrotoxicity of TAC may be due to vasoconstriction of glomerular afferent arterioles when concentration is high [ 28 , 29 ]. Till now, only two studies elucidated the relationship between TAC concentration and post-operative AKI in LTx patients [ 10 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Retrospective analysis on incidence and risk factors of early onset acute kidney injury after lung transplantation and its association with mortality

Wang

Zhang

et al. 2021

Renal Failure

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Objectives: Acute kidney injury (AKI) is a common complication after lung transplantation (LTx) which is closely related to the poor prognosis of patients. We aimed to explore potential risk factors and outcomes associated with early post-operative AKI after LTx. Methods: A retrospective study was conducted in 136 patients who underwent LTx at our institution from 2017 to 2019. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline. Univariate and multivariate analyses were conducted to identify risk factors related to AKI. The primary outcome was the incidence of AKI after LTx. Secondary outcomes were associations between AKI and short-term clinical outcomes and mortality. Results: Of the 136 patients analyzed, 110 developed AKI (80.9%). AKI was associated with higher baseline eGFR (odds ratio (OR) 1.01 (95% confidence interval (CI): 1.00-1.03)) and median tacrolimus (TAC) concentration (OR 1.15 (95% CI: 1.02-1.30)). Patients with AKI suffered longer mechanical ventilation days (p ¼ .015) and ICU stay days (p ¼ .011). AKI stage 2-3 patients had higher risk of 1-year mortality (HR 16.98 (95% CI: 2.25-128.45)) compared with no-AKI and stage 1 patients. Conclusions: Our results suggested early post-operative AKI may be associated with higher baseline eGFR and TAC concentrations. AKI stage 1 may have no influence on survival rate, whereas AKI stage 2-3 may be associated with increased mortality at 1-year.

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Section: Discussionmentioning

confidence: 99%

Retrospective analysis on incidence and risk factors of early onset acute kidney injury after lung transplantation and its association with mortality

Wang

Zhang

et al. 2021

Renal Failure

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“…Acute kidney injury often evolves into chronic kidney disease and appears in approximately half of the patients during the first weeks after thoracic organ transplantation [5,6]. The occurrence of acute kidney injury has been associated with supratherapeutic (> 15 ng/mL) whole-blood tacrolimus trough concentrations in the first week after thoracic organ transplantation [7,8], and an increasing tacrolimus concentration has been associated with higher AKI risk and severity [12]. Furthermore, a higher rejection rate has been associated with a high variability in whole-blood concentrations after heart and lung transplantation [13,14].…”

Section: Efficacy and Toxicity Of Tacrolimusmentioning

confidence: 99%

“…In the enterocyte, cytochrome P450 (CYP) 3A4/5 are the main enzymes metabolizing tacrolimus [12,20,21]. Tacrolimus is repeatedly taken up and pumped out of the enterocytes into the gut lumen by the transporter ATP-binding cassette B1 (ABCB1), increasing the probability of tacrolimus being metabolized [20].…”

Section: Key Pointsmentioning

confidence: 99%

“…Miano et al showed that CYP3A5 and CYP3A4*22 are of relevance for the concentration:dose (C/D) ratio in the early phase after lung transplantation. Nevertheless, only a small part of the C/D ratio is determined by CYP enzyme activity in the first week [12]. Initially after lung transplantation, CYP enzyme activity may also be influenced by hypoxemia and drug-drug interactions, which are not dependent on the intrinsic enzyme activity [15].…”

Section: Variability In Tacrolimus Pharmacokinetics Early After Heartmentioning

confidence: 99%

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Clinical Pharmacokinetics and Impact of Hematocrit on Monitoring and Dosing of Tacrolimus Early After Heart and Lung Transplantation

et al. 2019

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The calcineurin inhibitor tacrolimus is an effective immunosuppressant and is extensively used in solid organ transplantation. In the first week after heart and lung transplantation, tacrolimus dosing is difficult due to considerable physiological changes because of clinical instability, and toxicity often occurs, even when tacrolimus concentrations are within the therapeutic range. The physiological and pharmacokinetic changes are outlined. Excessive variability in bioavailability may lead to higher interoccasion (dose-to-dose) variability than interindividual variability of pharmacokinetic parameters. Intravenous tacrolimus dosing may circumvent this high variability in bioavailability. Moreover, the interpretation of whole-blood concentrations is discussed. The unbound concentration is related to hematocrit, and changes in hematocrit may increase toxicity, even within the therapeutic range of whole-blood concentrations. Therefore, in clinically unstable patients with varying hematocrit, aiming at the lower therapeutic level is recommended and tacrolimus personalized dosing based on hematocrit-corrected whole-blood concentrations may be used to control the unbound tacrolimus plasma concentrations and subsequently reduce toxicity. Invited proposal CPKA-D-18-00212.

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“…Also, a low clearance rate has been observed in heart transplant recipients early post-transplantation [18]. The interoccasion (dose-to-dose) variability (IOV) of oral tacrolimus pharmacokinetics early post-transplantation was studied by Miano et al Their study showed that CYP3A5 combined with CYP3A4*22 expression along with clinical factors such as the use of CYP450 inhibitors (azole antifungals, amiodarone), the transplant type, a diagnosis of cystic fibrosis and haematocrit accounted for 42% of the variance in the dose-corrected concentration during the first 2 weeks after lung transplantation [19]. Organ dysfunction (such as gut dysmotility and liver dysfunction) and the use of extended extracorporeal life support were not taken into account.…”

Section: Introductionmentioning

confidence: 99%

High Variability of Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation

Sikma

Hunault

Maarseveen

et al. 2019

Eur J Drug Metab Pharmacokinet

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Background and Objective Oral tacrolimus is initiated perioperatively in heart and lung transplantation patients. There have been few studies on oral tacrolimus pharmacokinetics early post-transplantation, even though tacrolimus-related toxicity may occur early, potentially leading to morbidity and mortality. Therefore, we aimed to study the pharmacokinetics of oral tacrolimus in thoracic organ recipients during the first days after transplantation. Methods We conducted a pharmacokinetic study in 30 thoracic organ transplants at intensive care at the University Medical Center Utrecht in the first week post-transplantation. Twelve-hour whole-blood tacrolimus profiles were examined using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) and analysed via population pharmacokinetic modelling. Results The concentration-time profiles showed high variability. Concentrations at 12 h were outside the target range in 69% of the cases. A two-compartment model with mixed first-order and zero-order absorption adequately described tacrolimus concentrations. The typical value of the apparent clearance was 19.6 L/h (95% CI 16.2-22.9), and the apparent distribution volumes of central and peripheral compartments, V1 and V2, were 231 L (95% CI 199-267) and 521 L (95% CI 441-634), respectively. Inter-occasion (dose-to-dose) variability far exceeded the interindividual variability (IIV), with an estimated variability in relative bioavailability of 55% (95% CI 48.5-64.4). Conclusions The high variability of tacrolimus pharmacokinetics early after thoracic organ transplantation is largely due to excessive variability in bioavailability, making individualised dosing based on measured concentrations futile. To bypass this bioavailability issue, we suggest administering tacrolimus intravenously and aiming below the upper therapeutic range early post-transplantation. Clinical Trial Registraion: NTR 3912/EudraCT 2012-001909-24.

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Early Tacrolimus Concentrations After Lung Transplant Are Predicted by Combined Clinical and Genetic Factors and Associated With Acute Kidney Injury

Cited by 44 publications

References 33 publications

Retrospective analysis on incidence and risk factors of early onset acute kidney injury after lung transplantation and its association with mortality

Retrospective analysis on incidence and risk factors of early onset acute kidney injury after lung transplantation and its association with mortality

Clinical Pharmacokinetics and Impact of Hematocrit on Monitoring and Dosing of Tacrolimus Early After Heart and Lung Transplantation

High Variability of Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation

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