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Aims: Finger-prick sampling has emerged as an attractive tool for therapeutic drug monitoring and associated diagnostics. We aimed to validate the clinical performance of using two volumetric devices (Capitainer® qDBS and Mitra®) for monitoring tacrolimus, creatinine and haemoglobin in kidney transplant (KTx) recipients. Secondarily, we evaluated potential differences between finger-prick sampling performed by healthcare professionals vs. self-sampling, and differences between the two devices., Methods: We compared finger-prick and venous sampling in three settings: microsampling performed by healthcare personnel, self-sampling under supervision, unsupervised self-sampling. The finger-prick samples were analysed with adapted methods and results compared to routine method analysis of the venous blood samples., Results: Twenty-five KTx recipients completed the main study and 12 KTx recipients completed a post hoc validation study. For tacrolimus measurements and predicted area under the curve, the proportions within ±20% difference were 79%-96% for Capitainer and 77%-95% for Mitra. For creatinine and haemoglobin, the proportions within ±15% were 92%-100% and 93%-100% for Capitainer and 79%-96% and 67%-92% for Mitra, respectively. Comparing sampling situations, the success rate was consistent for Capitainer (92%-96%), whereas Mitra showed 72%-88% and 52%-72% success rates with samples collected by healthcare personnel and the patients themselves., Conclusions: Capitainer and Mitra are technically feasible for measuring tacrolimus, creatinine and haemoglobin. In the context of self-sampling, Capitainer maintained consistent sampling success and analytical quality. Implementing volumetric finger-prick self-sampling for the monitoring of tacrolimus, creatinine and haemoglobin may simplify and improve the follow-up of KTx recipients., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Therapeutic drug monitoring of tacrolimus (Tac) is mandatory in solid organ transplant (SOT) recipients. Finger-prick microsampling is more flexible and tolerable during the therapeutic drug monitoring of tacrolimus and has been shown to be applicable in adult SOT recipients. In this study, a previously validated method applying volumetric absorptive microsampling (VAMS) to measure Tac in adults was cross-validated in a pediatric population., Methods: Patients with SOT scheduled for standard posttransplant follow-up visits were recruited. Blood samples were obtained by trained phlebotomists using standard venipuncture and capillary microsampling, before the morning dose of Tac as well as 2 and 5 hours after dosing. Tac concentrations were quantified using liquid chromatography-tandem mass spectrometry. Concordance between Tac concentrations obtained with venipuncture and VAMS was evaluated using Passing-Bablok regression, calculation of absolute and relative differences, and percentage of samples within ±20% and ±30% difference., Results: A total of 39 SOT patients aged 4-18 years (22 male) were included. The median (range) predose venous blood concentration was 4.8 (2.6-13.6) mcg/L, with a difference between VAMS and venous blood samples of -0.2 ± 0.7 mcg/L. The relative mean difference was -1.3% [95% confidence interval (CI), -5.9% to 3.4%]. Ninety-two percent and 97% of the sample pairs demonstrated differences within ±20% and ±30%, respectively. Postdose (2 hours and/or 5 hours, n = 17) median concentration in venous blood was 7.9 (4.8-19.2) mcg/L. The difference between VAMS and venous blood samples was 0.1 ± 1.0 mcg/L, with a relative mean difference of -2.5% (95% confidence interval, -8.8% to 3.8%). Eighty-eight percent of the postdose sample pairs were within ±20% difference, and all were within ±30% difference., Conclusions: Tac concentrations can be accurately measured using VAMS technology in pediatric SOT recipients. This makes home-based Tac monitoring feasible in the pediatric population., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

Therapeutic drug monitoring (TDM) is mandatory for the immunosuppressive drug tacrolimus (Tac). For clinical applicability, TDM is performed using morning trough concentrations. With recent developments making tacrolimus concentration determination possible in capillary microsamples and Bayesian estimator predicted area under the concentration curve (AUC), AUC-guided TDM may now be clinically applicable. Tac circadian variation has, however, been reported, with lower systemic exposure following the evening dose. The aim of the present study was to investigate tacrolimus pharmacokinetic (PK) after morning and evening administrations of twice-daily tacrolimus in a real-life setting without restrictions regarding food and concomitant drug timing. Two 12 hour tacrolimus investigations were performed; after the morning dose and the following evening dose, respectively, in 31 renal transplant recipients early after transplantation both in a fasting-state and under real-life nonfasting conditions (14 patients repeated the investigation). We observed circadian variation under fasting-conditions: 45% higher peak-concentration and 20% higher AUC following the morning dose. In the real-life nonfasting setting, the PK-profiles were flat but comparable after the morning and evening doses, showing slower absorption rate and lower AUC compared with the fasting-state. Limited sampling strategies using concentrations at 0, 1, and 3 hours predicted AUC after fasting morning administration, and samples obtained at 1, 3, and 6 hours predicted AUC for the other conditions (evening and real-life nonfasting). In conclusion, circadian variation of tacrolimus is present when performed in patients who are in the fasting-state, whereas flatter PK-profiles and no circadian variation was present in a real-life, nonfasting setting., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Therapeutic drug monitoring (TDM) of tacrolimus (Tac) is mandatory in renal transplant recipients (RTxR). Area under the concentration versus time curve (AUC) is the preferred measure for Tac exposure; however, for practical purposes, most centers use trough concentrations as a clinical surrogate. Limited sampling strategies in combination with population pharmacokinetic model-derived Bayesian estimators (popPK-BE) may accurately predict individual AUC. The use of self-collected capillary microsamples could simplify this strategy. This study aimed to investigate the potential of AUC-targeted Tac TDM using capillary microsamples in combination with popPK-BE., Methods: A single-center prospective pharmacokinetic study was conducted in standard-risk RTxR (n = 27) receiving Tac twice daily. Both venous and capillary microsamples (Mitra; Neoteryx, Torrance, CA) were obtained across 2 separate 12-hour Tac dosing intervals (n = 13 samples/AUC). Using popPK-BE, reference AUC (AUCref) was determined for each patient using all venous samples. Different limited sampling strategies were tested for AUC predictions: (1) the empiric sampling scheme; 0, 1, and 3 hours after dose and (2) 3 sampling times determined by the multiple model optimal sampling time function in Pmetrics. Agreement between the predicted AUCs and AUCref were evaluated using C-statistics. Accepted agreement was defined as a total deviation index ≤±15%., Results: The AUC from capillary microsamples revealed high accuracy and precision compared with venous AUCref, and 85% of the AUCs had an error within ±11.9%. Applying microsamples at 0, 1, and 3 hours after dose predicted venous AUCref with acceptable agreement. Patients performed self-sampling with acceptable accuracy., Conclusions: Capillary microsampling is patient-centered, making AUC-targeted TDM of Tac feasible without extended hospital stays. Samples obtained 0, 1, and 3 hours after dose, combined with popPK-BE, accurately predict venous Tac AUC.

Background: Therapeutic drug monitoring is standard practice for the immunosuppressant tacrolimus (Tac). Venous blood sampling at outpatient clinics is time-consuming and impractical with regard to obtaining trough concentrations on clinical visit days. Home-based blood sampling may be patient friendly and pave the way for limited sampling strategies for the prediction of total drug exposure. The aim was to establish a Tac assay for dried capillary microsamples, ensuring reliable measurements during the full dose interval in renal transplant recipients., Methods: An assay based on volumetric absorptive microsampling and liquid chromatography tandem mass spectrometry was validated. The agreement between capillary microsamples and liquid venous samples was investigated in stable renal recipients on twice-daily Tac dosing. Sampling throughout the 12-hour dose interval was examined at 2 separate days, at least 1 week apart, for each participant. Two sets of samples were obtained at each time point, one delivered directly to the laboratory and one sent through mail., Results: Twenty-seven renal transplant recipients were included, of whom 26 were investigated twice. Tac was efficiently extracted from the dried microsamples (mean recovery 94%-103%). The between-series mean accuracy was 88%-98% with coefficients of variation ≤5.0% (≤11% at the lower limit of quantification), measurement range 0.70-60 mcg/L. The mean difference between parallel microsamples was 5%-7%. Overall, the mean differences between dried microsamples and liquid samples were -3.1% when mailed (n = 679) and -4.2% when directly delivered (n = 682). Less than 8% were outside ±20%. The microsamples were stable for 1 month at ambient temperature., Conclusions: The microsample method demonstrated acceptable performance. Tac concentrations can be reliably quantified throughout the dose interval by using volumetric absorptive microsampling in renal transplant recipients, and the results are not influenced by postal shipment.

Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C0) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration-time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells-regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade. Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients.

Patients with high tacrolimus clearance are more likely to experience transient under-immunosuppression in case of a missed or delayed dose. We wanted to investigate the association between estimated tacrolimus clearance and development of graft interstitial fibrosis and tubular atrophy (IFTA) in kidney transplant recipients. Associations between estimated tacrolimus clearance [daily tacrolimus dose (mg)/trough concentration (μg/l)] and changes in IFTA biopsy scores from week 7 to 1-year post-transplantation were investigated. Data from 504 patients transplanted between 2009 and 2013 with paired protocol biopsies (7 weeks + 1-year post-transplant) were included. There were no differences in baseline biopsy scores (7 weeks) in patients with different estimated tacrolimus clearance. Increasing tacrolimus clearance was significantly associated with increased ci + ct score of ≥2 at 1 year, odds ratio of 1.67 (95% CI; 1.11-2.51). In patients without fibrosis (ci + ct ≤ 1) at 7 weeks (n = 233), increasing tacrolimus clearance was associated with development of de novo IFTA (i + t ≤ 1 and ci + ct ≥ 2) at 1 year, odds ratio of 2.01 (95% CI; 1.18-3.50) after adjusting for confounders. High tacrolimus clearance was significantly associated with development of IFTA the first year following renal transplantation., (© 2018 Steunstichting ESOT.)

Background: Tacrolimus (TAC) is currently the cornerstone of immunosuppressive protocols for renal transplant recipients. Despite therapeutic whole blood monitoring, TAC is associated with nephrotoxicity, and it has been hypothesized that intrarenal accumulation of TAC and/or its metabolites are involved. As TAC is a substrate of P-glycoprotein (P-gp), the expression and activity of this efflux transporter could influence the levels of TAC in renal tissue. The primary aim of this study was to develop and validate a method for quantification of TAC in tissue homogenates from single human renal core biopsies. The secondary aim was to provide measures of P-gp expression and of the demethylated metabolites of TAC in the same renal biopsy., Methods: Human renal tissue, with and without clinical TAC exposure, was used for method development and validation. Homogenates were prepared with bead-beating, and concentrations of TAC and its demethylated metabolites were analyzed with liquid chromatography tandem mass spectrometry after protein precipitation. A Western blot method was used for semiquantification of P-gp expression in the homogenates. The final methods were applied to renal core biopsies from 2 transplant patients., Results: The TAC assay showed within- and between-run mean accuracy between 99.7% and 107% and coefficients of variation ≤6.7%. Matrix effects were nonsignificant, and samples were stable for 3 months preanalytically when stored at -80°C. TAC concentrations in the renal core biopsies were 62.6 and 43.7 pg/mg tissue. The methods for measurement of desmethyl-TAC and P-gp expression were suitable for semiquantification in homogenates from renal core biopsies., Conclusions: These methods may be valuable for the elucidation of the pharmacokinetic mechanisms behind TAC-induced nephrotoxicity in renal transplant recipients.

Due to a high inter-individual variability in its pharmacokinetics, tacrolimus dose individualization is mandatory. Even though the expert opinion has defined the area under the curve (AUC) as the best marker to use when performing dose adjustment of tacrolimus, most centres only use trough levels. Multiple targets have been proposed for this parameter and physicians rely largely on their personal experience when making a decision about dose adjustment. Several population pharmacokinetics models (POPPK) allowing AUC determination have been developed, but only a few are actually used in routine practice for dose individualization. These POPPK models can also be used to perform Monte Carlo simulations that help to establish different dosing rules or to anticipate the pharmacokinetics of tacrolimus in particular populations, without conducting clinical trials. Various available applications of POPPK models to assist the prescriber in choosing the best tacrolimus dose are discussed in this paper as well as the difficulties in introducing them into routine therapeutic drug monitoring., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Patients with high tacrolimus clearance eliminate more drug within a dose interval compared with those with low clearance. Delays in dosing time will result in transient periods of lower concentrations in high versus low clearance patients. Transient subtherapeutic tacrolimus concentrations may induce acute rejection episodes., Methods: A retrospective study in all renal transplant patients treated with tacrolimus at our center from 2009 to 2013 was conducted. The association between individually estimated tacrolimus clearance (daily tacrolimus dose [mg]/trough concentration [μg/L]) and biopsy-proven acute rejection (BPAR) the first 90 days posttransplantation was investigated., Results: In total, 638 patients treated with oral tacrolimus were included in the analysis. Eighty-five (13.3%) patients experienced BPAR. Patients were stratified into 4 groups per their estimated clearance. The patients in the high clearance group had significantly higher incidence of BPAR (20.6%) with a hazard ratio of 2.39 (95% confidence interval, 1.30-4.40) compared with the low clearance group. Clearance estimate (as a continuous variable) showed a hazard ratio of 2.25 (95% confidence interval, 1.70-2.99) after adjusting for other risk factors. There were no significant differences in neither trough concentrations the first week after transplantation nor time to target trough concentration between patients later experiencing BPAR or not., Conclusions: High estimated clearance is significantly associated with increased risk of BPAR the first 90 days posttransplantation and may predict an increased risk of rejection in the early phase after renal transplantation.

Aims: Tacrolimus is a cornerstone in modern immunosuppressive therapy after kidney transplantation. Tacrolimus dosing is challenged by considerable pharmacokinetic variability, both between patients and over time after transplantation, partly due to variability in cytochrome P450 3A (CYP3A) activity. The aim of this study was to assess the value of the endogenous CYP3A marker 4β-hydroxycholesterol (4βOHC) for tacrolimus dose individualization early after kidney transplantation., Methods: Data were obtained from 79 adult kidney transplant recipients who contributed a total of 625 4βOHC measurements and 1999 tacrolimus whole blood concentrations during the first 2 months after transplantation. The relationships between 4βOHC levels and individual estimates of tacrolimus apparent plasma clearance (CL/F plasma ) at different time points after transplantation were investigated using scatterplots and population pharmacokinetic modelling., Results: There was no significant correlation between pre-transplant 4βOHC levels and tacrolimus CL/F plasma the first week (r = 0.19 [95% CI -0.03-0.40]) or between 4βOHC and tacrolimus CL/F plasma 1 week (r = 0.20 [-0.11-0.47]), 4 weeks (r = 0.21 [-0.07-0.46]) or 2 months (r = 0.24 [-0.03-0.48]) after transplantation (P ≥ 0.06). In the population analysis, time-varying 4βOHC was not a statistically significant covariate on tacrolimus CL/F plasma , neither in terms of absolute values (P = 0.11) nor in terms of changes from baseline (P = 0.17). 4βOHC values increased between 1 week and 2 months after transplantation (median change +57% [IQR +22-83%], P < 0.001), indicating increasing CYP3A activity. Contradictorily, tacrolimus CL/F plasma decreased over the same period (median change -13% [IQR -3 to -26%], P < 0.001)., Conclusions: 4βOHC does not appear to have a clinical potential to improve individualization of tacrolimus doses early after kidney transplantation., (© 2017 The British Pharmacological Society.)

Aim: Optimal tacrolimus exposure in transplant recipients is not well established. The results from the Symphony study indicated that low-target tacrolimus (trough concentrations 3-7 µg/L) in de novo standard risk renal transplant recipients should be appropriate. The aim of this study was to evaluate real-life outcomes when applying a similar strategy in a clinical setting., Methods: A single-centre analysis was conducted in standard risk renal transplant recipients receiving low-target tacrolimus, mycophenolate mofetil, glucocorticoids and basiliximab induction. One-year estimated glomerular filtration rate (eGFR, Cockcroft-Gault), one-year biopsy-proven acute rejection rate and graft- and patient survival up to 3 years post-transplant were compared with the outcomes in the Symphony study., Results: From 1 January 2009 to 31 March 2013, we included 406 patients. One year after transplantation, the mean ± SD eGFR was 76.8 ± 28.3 mL/min (Symphony: 65.4 ± 27.0 mL/min, P < 0.001). Biopsy-proven acute rejections were seen in 14.5% of the patients (Symphony: 12.3%, P = 0.35). Kaplan-Meier estimates [95% confidence interval] of three-year death-censored graft- and patient survival were 96.6% [94.2-99.0%] (Symphony: 93%) and 95.0% [92.6-97.3%] (Symphony: 95%), respectively., Conclusion: Low-target tacrolimus-based immunosuppression is safe and effective also in a standard clinical setting in de novo standard risk renal transplant recipients., (© 2016 Asian Pacific Society of Nephrology.)

Background: Early after renal transplantation, it is often challenging to achieve and maintain tacrolimus concentrations within the target range. Computerized dose individualization using population pharmacokinetic models may be helpful. The objective of this study was to prospectively evaluate the target concentration achievement of tacrolimus using computerized dosing compared with conventional dosing performed by experienced transplant physicians., Methods: A single-center, prospective study was conducted. Renal transplant recipients were randomized to receive either computerized or conventional tacrolimus dosing during the first 8 weeks after transplantation. The median proportion of tacrolimus trough concentrations within the target range was compared between the groups. Standard risk (target, 3-7 μg/L) and high-risk (8-12 μg/L) recipients were analyzed separately., Results: Eighty renal transplant recipients were randomized, and 78 were included in the analysis (computerized dosing (n = 39): 32 standard risk/7 high-risk, conventional dosing (n = 39): 35 standard risk/4 high-risk). A total of 1711 tacrolimus whole blood concentrations were evaluated. The proportion of concentrations per patient within the target range was significantly higher with computerized dosing than with conventional dosing, both in standard risk patients (medians, 90% [95% confidence interval {95% CI}, 84-95%] vs 78% [95% CI, 76-82%], respectively, P < 0.001) and in high-risk patients (medians, 77% [95% CI, 71-80%] vs 59% [95% CI, 40-74%], respectively, P = 0.04)., Conclusions: Computerized dose individualization improves target concentration achievement of tacrolimus after renal transplantation. The computer software is applicable as a clinical dosing tool to optimize tacrolimus exposure and may potentially improve long-term outcome.

Background: Proper bioequivalence studies comparing original with generic immunosuppressive drugs in patients are limited, especially in the increasing population of elderly renal transplant recipients. We performed an open-label, single-center, prospective, randomized, cross-over study and compared steady-state pharmacokinetics (PK) of a generic tacrolimus (Tacni) formulation with the original (Prograf) in renal transplant recipients older than 60 years., Methods: Twenty-eight patients, with a median age of 69 years (range, 60 to 78), were randomized at time of transplantation to receive original or generic tacrolimus, and 25 (21 men, 4 women) provided two evaluable 12-hr PK profiles. The PK investigations were performed in a stable phase approximately 6 and 8 weeks postengraftment. After the first PK investigation, tacrolimus formulations were switched (1:1 dose ratio)., Results: Generic tacrolimus did not meet the bioequivalence criteria; the area under the curve(0-12) ratio of generic-original tacrolimus formulation was 1.17 (90% confidence interval, 1.10-1.23) and the Cmax ratio was 1.49 (90% confidence interval, 1.35-1.65). The generic formulation also showed a shorter time to C(max) (T(max)) (P=0.04). Importantly, the lack of bioequivalence was not reflected in the standard monitoring parameter, trough concentrations (P=0.80)., Conclusion: Generic tacrolimus (Tacni) was not found to be bioequivalent to the original formulation in elderly renal transplant recipients. The significantly higher systemic exposure of tacrolimus, despite similar trough concentrations, may in the long run increase the risk of adverse effects.

Aims: The aim was to develop a theory-based population pharmacokinetic model of tacrolimus in adult kidney transplant recipients and to externally evaluate this model and two previous empirical models., Methods: Data were obtained from 242 patients with 3100 tacrolimus whole blood concentrations. External evaluation was performed by examining model predictive performance using Bayesian forecasting., Results: Pharmacokinetic disposition parameters were estimated based on tacrolimus plasma concentrations, predicted from whole blood concentrations, haematocrit and literature values for tacrolimus binding to red blood cells. Disposition parameters were allometrically scaled to fat free mass. Tacrolimus whole blood clearance/bioavailability standardized to haematocrit of 45% and fat free mass of 60 kg was estimated to be 16.1 l h−1 [95% CI 12.6, 18.0 l h−1]. Tacrolimus clearance was 30% higher (95% CI 13, 46%) and bioavailability 18% lower (95% CI 2, 29%) in CYP3A5 expressers compared with non-expressers. An Emax model described decreasing tacrolimus bioavailability with increasing prednisolone dose. The theory-based model was superior to the empirical models during external evaluation displaying a median prediction error of −1.2% (95% CI −3.0, 0.1%). Based on simulation, Bayesian forecasting led to 65% (95% CI 62, 68%) of patients achieving a tacrolimus average steady-state concentration within a suggested acceptable range., Conclusion: A theory-based population pharmacokinetic model was superior to two empirical models for prediction of tacrolimus concentrations and seemed suitable for Bayesian prediction of tacrolimus doses early after kidney transplantation.

Purpose: Tacrolimus (Tac) and cyclosporine (CsA) are mainly metabolized by CYP3A4 and CYP3A5. Several studies have demonstrated an association between the CYP3A5 genotype and Tac dose requirements. Recently, CYP3A4, PPARA, and POR gene variants have been shown to influence CYP3A metabolism. The present study investigated potential associations between CYP3A5*3, CYP3A4*22, PPARA c.209- 1003G>A and c.208+3819A>G, and POR*28 alleles and dose-adjusted concentrations (C/D) of Tac and CsA in 177 renal transplant patients early post-transplant., Methods: All patients (n=177) were genotyped for CYP3A4*22, CYP3A5*3, POR*28, PPARA c.209-1003G>A, and PPARA c.208+3819A>G using real-time polymerase chain reaction (PCR) and melting curve analysis with allelespecific hybridization probes or PCR restriction fragment length polymorphisms (RFLP) methods. Drug concentrations and administered doses were retrospectively collected from patient charts at Oslo University Hospital, Rikshospitalet, Norway. One steady-state concentration was collected for each patient., Results: We confirmed a significant impact of the CYP3A5*3 allele on Tac exposure. Patients with POR*28 and PPARA variant alleles demonstrated 15 % lower (P=0.04) and 19 % higher (P=0.01) Tac C0/D respectively. CsA C2/D was 53 % higher among CYP3A4*22 carriers (P=0.03)., Conclusion: The results support the use of pre-transplant CYP3A5 genotyping to improve initial dosing of Tac, and suggest that Tac dosing may be further individualized by additional POR and PPARA genotyping. Furthermore, initial CsA dosing may be improved by pre-transplant CYP3A4*22 determination.

Purpose: To identify patient characteristics that influence tacrolimus individual dose requirement in kidney transplant recipients., Methods: Data on forty-four 12-h pharmacokinetic profiles from 29 patients and trough concentrations in 44 patients measured during the first 70 days after transplantation (1,546 tacrolimus whole blood concentrations) were analyzed. Population pharmacokinetic modeling was performed using NONMEM 7.2®., Results: Standardization of tacrolimus whole blood concentrations to a hematocrit value of 45 % improved the model fit significantly (p<0.001). Fat-free mass was the best body size metric to predict tacrolimus clearance and volume of distribution. Bioavailability was 49 % lower in expressers of cytochrome P450 3A5 (CYP3A5) than in CYP3A5 nonexpressers. Younger females (<40 years) showed a 35 % lower bioavailability than younger males. Bioavailability increased with age for both males and females towards a common value at age >55 years that was 47 % higher than the male value at age <40 years. Bioavailability was highest immediately after transplantation, decreasing steeply thereafter to reach its nadir at day 5, following which it increased during the next 55 days towards an asymptotic value that was 28 % higher than that on day 5., Conclusions: Hematocrit predicts variability in tacrolimus whole blood concentrations but is not expected to influence unbound (therapeutically active) concentrations. Fat-free mass, CYP3A5 genotype, sex, age and time after transplant influence the tacrolimus individual dose requirement. Because hematocrit is highly variable in kidney transplant patients and increases substantially after kidney transplantation, hematocrit is a key factor in the interpretation of tacrolimus whole blood concentrations.

Following organ engraftment, initial dosing of tacrolimus is based on recipient weight and adjusted by measured C(0) concentrations. The bioavailability and elimination of tacrolimus are affected by the patients CYP3A5 genotype. Prospective data of the clinical advantage of knowing patient's CYP3A5 genotype prior to transplantation are lacking. A nonparametric population model was developed for tacrolimus in renal transplant recipients. Data from 99 patients were used for model development and validation. A three-compartment model with first-order absorption and lag time from the dosing compartment described the data well. Clearances and volumes of distribution were allometrically scaled to body size. The final model included fat-free mass, body mass index, hematocrit, time after transplantation, and CYP3A5 genotype as covariates. The bias and imprecision were 0.35 and 1.38, respectively, in the external data set. Patients with functional CYP3A5 had 26% higher clearance and 37% lower bioavailability. Knowledge of CYP3A5 genotype provided an initial advantage, but only until 3-4 tacrolimus concentrations were known. After this, a model without CYP3A5 genotype predicted just as well. The present models seem applicable for clinical individual dose predictions but need a prospective evaluation., (© 2013 The Authors Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs used in the majority of patients with solid organ transplants, generally in combination with a wide range of drugs. CsA and Tac seem not only to be substrates of CYP3A but have also been described as inhibitors of CYP3A. For CsA, in particular, inhibition of CYP3A has been suggested as the main mechanism of interactions seen clinically with various drugs. The aim of this study was to investigate the inhibitory effect and inhibition characteristics of CsA and Tac on CYP3A4 and CYP3A5 in vitro and to evaluate its clinical relevance. Inhibition by CsA and Tac was studied using midazolam as the probe substrate in coincubation and preincubation investigations using human liver microsomes (HLMs) as well as specific CYP3A4- and CYP3A5-expressing insect microsomes (Supersomes). In vitro-in vivo extrapolations (IVIVEs) were performed to evaluate the clinical relevance of the inhibition. Both CsA and Tac competitively inhibited CYP3A in HLMs, showing inhibition constants (K(i)) of 0.98 and 0.61 μM, respectively. Experiments in Supersomes revealed that Tac inhibited both CYP3A4 and CYP3A5, whereas CsA only inhibited CYP3A4. In contrast to the HLM experiments, studies in Supersomes showed inhibition by Tac to be NADPH- and time-dependent, with a 5-fold reduction in IC(50) after preincubation, supporting a time-dependent inhibition mechanism in recombinant microsomes. By application of HLM data, IVIVE estimated the area under the concentration versus time curve of midazolam to increase by 73 and 27% with CsA and Tac, respectively. The inhibitory effect was predominantly on the intestinal level, whereas hepatic intrinsic clearance seemed unaffected.

Background: New-onset diabetes after transplantation may be associated with the use of tacrolimus (Tac) causing impaired insulin release or reduced insulin sensitivity. Such effects have not been studied in renal transplant recipients receiving traditional twice-daily tacrolimus (TacBID) and then compared to the new once-daily prolonged release formulation of tacrolimus (TacOD)., Methods: We performed a prospective crossover study of 20 stable non-diabetic renal transplant recipients. All patients underwent one hyperglycaemic clamp on TacBID (3.8 ± 2.2 mg/day) and a new clamp 4-6 weeks after a 1:1 mg/day switch to TacOD (4.0 ± 2.8 mg/day)., Results: Tac trough concentrations decreased from 6.6 ± 2.9 to 5.4 ± 1.4 μg/mL (P = 0.037) and Tac max from 21.3 ± 8.4 to 15.2 ± 3.5 μg/L (P = 0.001). Tac AUC(0-24) was reduced from 265 ± 112 to 218 ± 47 μg × h/L (P = 0.12). The hyperglycaemic clamp did not detect any change in insulin sensitivity index after conversion [0.26 ± 0.21 versus 0.26 ± 0.25 μmol/min/kg/(pmol/L insulin), P = 0.99] nor any change in first (334 ± 274 versus 353 ± 248 μIU × min/mL, P = 0.41) or second phase insulin secretion (224 ± 155 versus 263 ± 210 μIU × min/mL/mmol glucose, P = 0.60) on TacBID versus TacOD., Conclusions: Conversion from standard TacBID to TacOD on a 1:1 mg basis is safe. In spite of a reduced Tac exposure, there was no change in insulin release or sensitivity in renal transplant recipients.

Therapeutic drug monitoring (TDM) is mandatory for the immunosuppressive drug tacrolimus (Tac). For clinical applicability, TDM is performed using morning trough concentrations. With recent developments making tacrolimus concentration determination possible in capillary microsamples and Bayesian estimator predicted area under the concentration curve (AUC), AUC‐guided TDM may now be clinically applicable. Tac circadian variation has, however, been reported, with lower systemic exposure following the evening dose. The aim of the present study was to investigate tacrolimus pharmacokinetic (PK) after morning and evening administrations of twice‐daily tacrolimus in a real‐life setting without restrictions regarding food and concomitant drug timing. Two 12 hour tacrolimus investigations were performed; after the morning dose and the following evening dose, respectively, in 31 renal transplant recipients early after transplantation both in a fasting‐state and under real‐life nonfasting conditions (14 patients repeated the investigation). We observed circadian variation under fasting‐conditions: 45% higher peak‐concentration and 20% higher AUC following the morning dose. In the real‐life nonfasting setting, the PK‐profiles were flat but comparable after the morning and evening doses, showing slower absorption rate and lower AUC compared with the fasting‐state. Limited sampling strategies using concentrations at 0, 1, and 3 hours predicted AUC after fasting morning administration, and samples obtained at 1, 3, and 6 hours predicted AUC for the other conditions (evening and real‐life nonfasting). In conclusion, circadian variation of tacrolimus is present when performed in patients who are in the fasting‐state, whereas flatter PK‐profiles and no circadian variation was present in a real‐life, nonfasting setting. [ABSTRACT FROM AUTHOR]

In some parts of the world, high intake of marine omega-3 FAs is recommended for the general population and it is likely that RTRs use omega-3 FA supplements without consulting a transplant physician [2]. Doses were kept unchanged between the two sub-study pharmacokinetic investigations. gl The main finding in the present study was that the systemic exposure of once-daily tacrolimus was increased on average by 25% after daily high-dose marine omega-3 FA supplementation. Physicians should be aware that this clinically relevant increase in the systemic exposure of tacrolimus may not necessarily induce a similar increase in trough concentrations [10], which make it difficult to monitor tacrolimus levels following the initiation and discontinuation of marine omega-3 FA supplementation. [Extracted from the article]

Following organ engraftment, initial dosing of tacrolimus is based on recipient weight and adjusted by measured C0 concentrations. The bioavailability and elimination of tacrolimus are affected by the patients CYP3A5 genotype. Prospective data of the clinical advantage of knowing patient's CYP3A5 genotype prior to transplantation are lacking. A nonparametric population model was developed for tacrolimus in renal transplant recipients. Data from 99 patients were used for model development and validation. A three-compartment model with first-order absorption and lag time from the dosing compartment described the data well. Clearances and volumes of distribution were allometrically scaled to body size. The final model included fat-free mass, body mass index, hematocrit, time after transplantation, and CYP3A5 genotype as covariates. The bias and imprecision were 0.35 and 1.38, respectively, in the external data set. Patients with functional CYP3A5 had 26% higher clearance and 37% lower bioavailability. Knowledge of CYP3A5 genotype provided an initial advantage, but only until 3-4 tacrolimus concentrations were known. After this, a model without CYP3 A5 genotype predicted just as well. The present models seem applicable for clinical individual dose predictions but need a prospective evaluation. [ABSTRACT FROM AUTHOR]