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Background and Objective: Given a high pharmacokinetic inter-individual variability and a low exposure target achievement, ganciclovir (GCV) therapeutic drug monitoring is sometimes used in children. We aimed to develop and validate Bayesian estimators based on limited sampling strategies for the estimation of GCV area under the concentration–time curve from 0 to 24 h in pediatric transplant recipients treated with valganciclovir (VGCV) or GCV. Methods: Solid organ transplant or stem-cell transplant recipients who received GCV or VGCV and had available GCV concentrations per standard of care were retrospectively included in this study for pharmacokinetic modeling and development of Bayesian estimators using the iterative two-stage Bayesian method. Validation datasets included additional child recipients of a solid organ transplant or stem-cell transplant, and child recipients of a kidney or liver transplant enrolled in a previous study. Various combinations of three or two sampling times, applicable in clinical practice, were assessed based on the relative mean bias, standard deviation, and the root mean square error in a development dataset and three independent validation datasets. Results: In the development dataset, the mean bias/standard deviation/root mean square error for the 1 h/2 h/3 h and 1 h/3 h limited sampling strategies were − 1.4%/9.3%/9.1% and − 3.5%/12.2%/12.3%, respectively for GCV, while for VGCV, the mean bias/standard deviation/root mean square error for the 1 h/2 h/6 h and 1 h/6 h limited sampling strategies were 0.7%/13.5%/13.3% and − 0.1%/12.1%/11.8%, respectively. In the independent validation datasets, seven (13%) and five (14%) children would have had misclassifications of their exposure using these Bayesian estimators and limited sampling strategies for VGCV and GCV, respectively. Conclusions: Three plasma samples collected at 1 h/2 h/3 h and 1 h/2 h/6 h post-dose for GCV and VGCV respectively, are sufficient to accurately determine GCV area under the concentration–time curve from 0 to 24 h for pharmacokinetic-enhanced therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Background: Patients with diabetes mellitus treated with successful pancreas transplantation (PTX) normalize hyperglycemia, but are exposed to immunosuppressive drugs that may impair endothelial function. This study aimed to evaluate endothelial function in single PTX recipients. Methods: Flow‐mediated dilatation (FMD) in the brachial artery was measured by ultrasound 8 weeks after transplantation in single PTX (n = 27) and compared with healthy controls (n = 58), simultaneous pancreas and kidney recipients (n = 9), and kidney transplant recipients with (n = 41) and without (n = 95) diabetes mellitus. Adjustments for age, gender, blood pressure, and body mass index were included in a linear regression model. Changes in FMD from before to 1 year after transplantation were assessed in a subgroup of PTX recipients (n = 9). Results: Flow‐mediated dilatation% in PTX recipients was not inferior to healthy controls (8.7 ± 3.6 vs 7.7 ± 3.3, P =.06) and simultaneous pancreas and kidney recipients (6.7 ± 4.5, P =.24) in an adjusted model, and superior to kidney recipients with and without diabetes (3.0 ± 3.0 and 4.8 ± 3.3, respectively, both P <.005). FMD% improved significantly from eight weeks to one year after PTX, mean 7.9 ± 4.2% vs 11.8 ± 4.8% (N = 9; P =.03). Conclusion: Flow‐mediated dilatation is well preserved in patients undergoing pancreas transplantation and is not impaired when immunosuppressive drugs are introduced. [ABSTRACT FROM AUTHOR]

Summary: Annual assessment of adherence would strengthen long‐term outcome assessments from registry data. The objective of this study was to evaluate tools suitable for annual routine capture of adherence data in renal transplant recipients. A single‐centre open prospective trial included 295 renal transplant recipients on tacrolimus. Two‐thirds of the patients were included 4 weeks post‐transplant, randomized 1:1 to intensive or single‐point adherence assessment in the early phase and 1‐year post‐transplant. One‐third were included 1‐year post‐transplant during a cross‐sectional investigation. Adherence was assessed using multiple methods: The "Basel Assessment of Adherence to Immunosuppressive Medication Scale" (BAASIS©) questionnaire was used to assess self‐reported adherence. The treating clinician scored patient′s adherence and tacrolimus trough‐concentration variability was calculated. In the analyses, the data from the different tools were dichotomized (adherent/nonadherent). The BAASIS© overall response rate was over 80%. Intensive BAASIS© assessment early after transplantation increased the chance of capturing a nonadherence event, but did not influence the 1‐year adherence prevalence. The adherence tools generally captured different populations. Combining the tools, the nonadherence prevalence at 1 year was 38%. The different tools identified to a large degree different patients as nonadherent. Combining these tools is feasible for annual capture of adherence status. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the leading cause of death in renal transplant recipients. An association between haptoglobin genotype 2-2 and cardiovascular disease has been found in patients with diabetes mellitus and liver transplant recipients. To date, the role of haptoglobin genotype after renal transplantation has not been studied.~Background~Background~In this single-center retrospective cohort study of 1975 adult Norwegian transplant recipients, who underwent transplantation between 1999 and 2011, we estimated the risk of all-cause and cardiovascular mortality and overall and death-censored graft loss for patients with haptoglobin genotype 2-2 compared to genotype 2-1 or 1-1, after adjustment for confounders and competing risks.~Methods~Methods~We found no associations between haptoglobin genotype 2-2 and cardiovascular mortality (subdistributional hazard ratio 1.08, 95% confidence interval 0.78-1.49; P = .63). We also failed to detect any association between haptoglobin 2-2 genotype and all-cause mortality, overall graft loss, and death-censored graft loss. Similar results were found in the subpopulation of transplant recipients with diabetes.~Results~Results~In this large cohort of kidney transplant recipients, we could not demonstrate any association between haptoglobin 2-2 genotype and patient or graft survival after renal transplantation.~Conclusion~Conclusions [ABSTRACT FROM AUTHOR]

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/Fplasma) 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/Fplasma the first week ( r = 0.19 [95% CI −0.03-0.40]) or between 4βOHC and tacrolimus CL/Fplasma 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/Fplasma, 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/Fplasma 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. [ABSTRACT FROM AUTHOR]

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]

Background: While several studies have examined the general inflammatory responses in relation to cytomegalovirus infection, the identification of the various inflammatory mediators as well as their relative importance is far from clear. Patients and Methods: Solid organ recipients enrolled in an international multicenter trial of cytomegalovirus disease treatment (the VICTOR study) were analyzed (n = 289) (ClinicalTrials.gov NCT00431353). Plasma markers of inflammation and endothelial cell activation were assessed at baseline by enzyme immunoassays. Results: The major findings were: (i) Plasma levels of the CXC-chemokine interferon-inducible protein-10 (P<0.001) and C-reactive protein (P = 0.046) were independently associated with the presence of cytomegalovirus DNAemia above lower level of quantification. (ii) High levels of CC-chemokine ligand 21 (P = 0.027) and pentraxin 3 (P = 0.033) were independently associated with tissue invasive cytomegalovirus disease as opposed to cytomegalovirus syndrome. Conclusion: Our findings illustrate the complex interaction between cytomegalovirus and the immune system, involving a wide range of inflammatory mediators that could be associated to disease manifestations in cytomegalovirus related disease. [ABSTRACT FROM AUTHOR]

Background. It is unknown whether specific viral polymorphisms affect in vivo therapeutic response in patients with cytomegalovirus (CMV) disease. Polymorphisms in the CMV glycoprotein B (gB) gene allow discrimination of 4 distinct genotypes (gB1-gB4). We assessed the influence of gB genotypes on the clinical and virologic outcome of CMV disease. Methods. Solid-organ transplant recipients enrolled in a multicenter trial of CMV disease treatment (VICTOR study) were included in this study. CMV gB genotyping was performed using quantitative real-time polymerase chain reaction at day 0 (start of antiviral therapy). Results. Among 239 patients with CMV disease, the prevalence of gB strain types was 26% for gB1, 10% for gB2, 10% for gB3, and 5% for gB4, whereas mixed infections were present in 49%. Donor-seropositive/recipientseropositive patients were more likely to have mixed gB infection than donor-seropositive/recipient-seronegative patients (40% vs. 12%; ). Median baseline viral P < .001 loads were higher and time to viral eradication was longer (P = .005 and Pp.026, respectively) for mixed infection versus infection with a single genotype. In a multivariate model, mixed gB infection was a significant predictor of failure to eradicate virus by day 21 (mixed vs single genotype; odds ratio, 2.66; 95% confidence interval, 1.31-5.38; P = .007) after controlling for baseline viral load, CMV serostatus at baseline, ganciclovir resistance, and antiviral treatment. No effect of gB genotype was seen on virologic or clinical CMV recurrence. Conclusions. No specific gB genotype appears to confer a specific CMV virulence advantage. However, mixed gB genotype infections are associated with higher viral loads and delayed viral clearance. [ABSTRACT FROM AUTHOR]

Background and Objective: The pharmacokinetic disposition of ciclosporin shows great intra- and interpatient variability, and that combined with a narrow therapeutic window makes therapeutic drug monitoring of ciclosporin necessary. The nonlinear mixed-effects population pharmacokinetic program NONMEM® predicts individual pharmacokinetic parameters based not only on individual patient observations but also on population characteristics and the patient's covariates. The aim of this model development is to potentially use it in the clinical setting to optimize ciclosporin dosing in renal transplant recipients. Methods: A population pharmacokinetic model of ciclosporin has been developed with NONMEM® using full 12-hour pharmacokinetic profiles from 29 renal transplant recipients, 3 months of daily follow-up data from an additional 11 recipients, and both 3 months of follow-up data and full 12-hour pharmacokinetic profiles from nine patients. The internal validation of the model was based on data splitting and jack-knife methods. In addition, the model was validated for its clinical applicability on standard trough and 2-hour post-dose concentration data from 12 additional patients with 3 months of follow-up. Results: The model that best described the ciclosporin data was a two-compartment model with first-order absorption process with lagged time. The population pharmacokinetic parameters were oral clearance (CL/F) = 26.9L/h; central volume of distribution after oral administration (V1/F) = 24.4 L; absorption rate constant (ka) = 0.544 h-1; lag time = 0.460 h; peripheral volume of distribution = 1119L and intercompartmental clearance after oral administration (Q/F) = 19.6L/h. Three covariates had significant effect on a total of six pharmacokinetic parameters. These were bodyweight onV1/Fand ka, time after transplantation on ka, and age on CL/F, ka and V1/F. Cytochrome P450 3A5 genotype was also a significant covariate but was not included in the final model since such information is not available in clinical practice. The external validation showed that the model was able to predict ciclosporin concentrations in the 12 new patients with an average predictive error of 17.4 ± 14% when the standard sample concentrations from the previous week were given. Conclusion: A NONMEM® pharmacokinetic model for ciclosporin in renal transplant recipients was successfully developed and validated for the first 3 months post-transplantation. The model showed good predictability in a new patient cohort. After further clinical validation, the model may be applicable as a clinical tool for optimizing ciclosporin dosing in renal transplant recipients in the early post-transplant period. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present study was to develop a time-efficient chromatographic method for the analysis of therapeutic concentrations of ganciclovir (GCV) in plasma, urine as well as dialysate (from continuous renal replacement therapy) from solid organ transplant recipient treated with either GCV or its prodrug valganciclovir (VGCV) in combination with a wide variety of other concomitant drugs. Sample preparation was performed by reversed phase solid phase extraction and was followed by separation of the analytes on a reversed phase column using isocratic elution with a mobile phase consisting of acetonitrile—a counter ion (50mM 1-heptanesulfonic acid) in an aqueous sodium dihydrogen phosphate buffer (pH 2.1; 10mM) (10:90 v/v) and a fluorescence detector. Validation of the method showed linearity within the concentration range of 0.1–40μg/mL for plasma and 0.1–120μg/mL for urine and dialysate (R 2 >0.99, n ≥5). Accuracy and precision (evaluated at 0.1, 5 and 40μg/mL) were both satisfactory. The LLOQ was determined to be 0.1μg/mL. The method was successfully applied on clinical samples from renal transplant recipients treated with VGCV in combination with a variety of usually used concomitant drugs for solid organ transplant recipients. [Copyright &y& Elsevier]

Endothelial dysfunction is a common finding in renal transplant recipients (RTR) and is related to impaired local regulation of vasodilative and vasoconstrictive substances, such as nitric monoxide (NO) and endothelin-1 (ET-1). In non-transplanted patients, an association between impaired endothelial function and insulin resistance has been shown. Whether such an association also exists in RTR is unknown. Objective: The aim of the present study was to examine whether insulin resistance is associated with endothelial dysfunction in RTR. Material and methods: A total of 47 RTR in a stable phase six yr post-transplant were included in the statistical analysis. The immunosuppressive therapy was based on cyclosporine and prednisolone. Non-invasive assessment of endothelial function was performed with laser Doppler flowmetry of the forearm skin vasculature after local acetylcholine stimulation. Oral glucose tolerance tests comprising both glucose and insulin measurements were used to calculate insulin sensitivity (IS) indices. NO, ET-1 and von Willebrand factor were measured in fasting plasma samples. Results: Normal glucose tolerance was found in 31 RTR. In these subjects, both IS (r2=0.164, p=0.044) and plasma NO (r2=0.326, p=0.002) were significantly correlated with endothelial function. Patients with glucose intolerance (n=16) had higher plasma ET-1 and lower NO levels, but the association between IS and endothelial function was not significant in these subjects. In the total patient cohort, IS and endothelial function tended to be correlated (p=0.127). Conclusions: Endothelial dysfunction is significantly associated with insulin resistance in normoglycemic RTR but explains a rather small part of the variation. In glucose-intolerant recipients, IS appears to be more critically dependent on other factors not revealed in the present study. [ABSTRACT FROM AUTHOR]

Abstract: Background: Cardiovascular risk is greatly increased in renal transplant recipients. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy may reduce cardiovascular risk by improving both dyslipidemia and endothelial function. We therefore performed this study to assess the effect of fluvastatin on endothelial function in renal transplant recipients. Methods: This randomized, placebo-controlled, double-blind designed study investigated the effect of fluvastatin on endothelial function. Thirty-seven recipients received fluvastatin 40 mg/d and 35 received placebo during the first 12 wk following transplantation. All patients initially received cyclosporin A, prednisolone and azathioprine. At the end of treatment, endothelial function was assessed in the forearm skin microvasculature by laser Doppler flowmetry following acetylcholine stimulation. Samples were taken for measurements of serum lipids and vasoactive markers. Results: There were no differences in endothelial function between fluvastatin recipients and controls, AUCACh was 656 ± 479 and 627 ± 518 AU min, respectively (fluv vs. control, p > 0.65). In the placebo limb, total cholesterol and LDL cholesterol increased 22 ± 12% and 22 ± 18%, respectively in the first 12 wk following transplantation. The respective values were 18 ± 13% (p = 0.010) and 34 ± 19% (p = 0.0013) lower at 12 wk in the fluvastatin treated patients. Plasma ET-1, BigET-1 and urinary excretion of cGMP were not significantly different between treatment groups (p > 0.55). Conclusion: Although fluvastatin 40 mg/d significantly lowers cholesterol it does not affect endothelial function the first 3 months after renal transplantation. The lack of effect on endothelial function is consistent with a lack of effect on vasoactive substances. [ABSTRACT FROM AUTHOR]

Why dose adjust systemic exposure when looking for associations with adverse events in tacrolimus-treated transplant recipients? Keywords: adverse drug reactions; drug metabolism; other; pharmacokinetics; transplantation EN adverse drug reactions drug metabolism other pharmacokinetics transplantation 2535 2535 1 11/28/20 20201201 NES 201201 The article by Campagne et al1 highlights a timely issue in modern immunosuppressive therapy of transplanted patients; what is the impact of tacrolimus (Tac) exposure on extrarenal adverse effects? Adverse drug reactions, drug metabolism, other, pharmacokinetics, transplantation. [Extracted from the article]

We appreciate the input of Drs Yildiz and Yildiz.[1] They suggest an addition to our review on the bioavailability of immunosuppressive drugs after bariatric surgery,[2] specifically in relation to transplantation surgery. Our general recommendation would therefore be to use standard TDM procedure in patients transplanted after bariatric surgery and to intensify TDM in case of bariatric surgery in transplanted patients. [Extracted from the article]