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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.

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.

Background: Everolimus (EVE) is an immunosuppressive drug dosed according to therapeutic drug monitoring in renal transplant recipients. The primary site of action is within activated lymphocytes. EVE is a substrate of the efflux transporter ABCB1 also known as P-glycoprotein. Limited data exist regarding a possible association between whole blood and intralymphocyte concentrations of EVE and the potential influence of ABCB1., Methods: Twelve renal transplant recipients (5 men and 7 women) treated with EVE underwent a pharmacokinetic investigation where EVE concentrations in whole blood and in peripheral blood mononuclear cells (PBMC) were determined within a dosing interval. In addition, the activity of ABCB1 in PBMC was determined using the Rhodamine123 efflux assay and the patients' genotypes of ABCB1 were determined., Results: There was a significant correlation between EVE AUC0-12 in whole blood and in PBMC (r = 0.90, P < 0.01), and no association was demonstrated between the ABCB1 activity and EVE PBMC/whole blood ratio of trough concentrations (r = 0.23, P = 0.76). Furthermore, ABCB1 1236C>T, 3435C>T, and 2677G>T/A polymorphism did not influence EVE AUC0-12 PBMC/whole blood ratio., Conclusions: The results revealed a significant association between EVE whole blood and PBMC concentrations, suggesting that ABCB1-mediated efflux from PBMC to be of minor importance for the distribution of EVE.

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.

Background: Dyslipidemia is a risk factor for premature cardiovascular morbidity and mortality in renal transplant recipients (RTRs). Pharmacotherapy with mTOR inhibitors aggravates dyslipidemia, thus necessitating lipid-lowering therapy with fluvastatin, pravastatin, or atorvastatin. These agents may not sufficiently lower lipid levels, and therefore, a more potent agent like rosuvastatin maybe needed., Methods: We have aimed to assess the lipid-lowering effect of rosuvastatin as compared with fluvastatin in RTR receiving everolimus. Safety was assessed as the pharmacokinetic (PK) interaction potential of a rosuvastatin/everolimus combination in RTR. A 12-hour everolimus PK investigation was performed in 12 stable RTR receiving everolimus and fluvastatin (80 mg/d). Patients were then switched to rosuvastatin (20 mg/d), and a follow-up 12/24-hour PK investigation of everolimus/rosuvastatin was performed after 1 month. All other drugs were kept unchanged., Results: In RTR already receiving fluvastatin, switching to rosuvastatin further decreased LDL cholesterol and total cholesterol by 30.2±12.2% (P<0.01) and 18.2±9.6% (P<0.01), respectively. Everolimus AUC0-12 was not affected by concomitant rosuvastatin treatment, 80.3±21.3 μg*h/L before and 78.5±21.9 μg*h/L after, respectively (P=0.61). Mean rosuvastatin AUC0-24 was 157±61.7 ng*h/mL, approximately threefold higher than reported in the literature for nontransplants. There were no adverse events, and none of the patients had or developed proteinuria., Conclusion: Rosuvastatin showed a superior lipid-lowering effect compared to fluvastatin in stable RTR receiving everolimus. The combination of everolimus/rosuvastatin seems to be as safe as the everolimus/fluvastatin combination.

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]

Background and Objective: Intracellular exposure of everolimus may be a better marker of therapeutic effect than trough whole blood concentrations. We aimed to develop pharmacokinetic population models and Bayesian estimators based on a limited sampling strategy for estimation of dose interval exposures of everolimus in whole blood and peripheral blood mononuclear cells (PBMCs) in renal transplant recipients.Methods: Full whole blood and PBMC concentration-time profiles of everolimus were obtained from 12 stable renal transplant recipients on two different occasions, 4 weeks apart. The dataset was treated as 24 individual profiles and split into a development dataset (n = 20) and a validation dataset (n = 4). The pharmacokinetic model was developed using non-parametric modeling and its performances and those of the derived Bayesian estimator were evaluated in the validation set.Results: A structural two-compartment model with first-order elimination and two absorption phases described by a sum of two gamma distributions were developed. None of the tested covariates (age, sex, albumin, hematocrit, fat-free mass and genetic variants such as CYP3A5*1, ABCB1 haplotype, PPARA*42, PPARA*48, and POR*28) were retained in the final model. A limited sampling schedule of two whole blood samples at 0 and 1.5 h and one PBMC sample at 1.5 h post dose provided accurate estimates of the area under the plasma concentration-time curve (AUC) in comparison with the trapezoidal reference AUC (relative bias ± standard deviation = - 3.9 ± 10.6 and 4.1 ± 12.3% for whole blood and PBMC concentrations, respectively).Conclusion: The developed model allows simultaneous and accurate prediction of everolimus exposure in whole blood and PBMCs, and supplies a base for a feasible exploration of the relationships between intracellular exposure and therapeutic effects in prospective trials. [ABSTRACT FROM AUTHOR]