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

Abstract

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.

Tacrolimus Therapy in Adult Heart Transplant Recipients: Evaluation of a Bayesian Forecasting Software

“…43 Additionally, in the first week after heart transplant, approximately 95% of transplant recipients in this study received high doses of a proton pump inhibitor, which may reduce the absorption of itraconazole 44 and thereby contribute to a variability in the effect of drugdrug interaction on tacrolimus pharmacokinetics. Consistent with other studies, 1,45 the present study (Table 3) demonstrated that the dynamic physiological changes that occur in heart transplant recipients in the first 1-2 weeks after transplant make predicting tacrolimus drug exposure during this period very difficult. Further work is required to examine whether these temporal changes can be systematically quantified to improve the prediction of tacrolimus concentrations using the Bayesian software during the first 11 days of tacrolimus therapy.…”

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

“…The study by Sikma et al showed further that the majority of C12h, almost 70%, were out of the target range (9-15 ng/mL). Half of the patients displayed subtherapeutic concentrations and approximately 20% of patients displayed supratherapeutic concentrations [28]. Moreover, the interoccasion (dose-to-dose) variability in pharmacokinetics was extreme and exceeded the interpatient variability [29].…”

Clinical Implications of Tacrolimus Time in Therapeutic Range and Intrapatient Variability in Urban Renal Transplant Recipients Undergoing Early Corticosteroid Withdrawal

“…Tacrolimus values from POD21 onward were used to calculate IPV to eliminate initially high variability seen in the postoperative phase of care. 12 , 18 …”

“…Tacrolimus values from POD21 onward were used to calculate IPV to eliminate initially high variability seen in the postoperative phase of care. 12,18 The Rosendaal linear interpolation method was used to calculate TTR, which assumes a linear relationship exists between each measured value and then assigns a specific value for each day between tests. 19 Protocol tacrolimus goals were used to calculate 12-month TTR.…”