Tacrolimus Exposure in Obese Patients: and A Case-Control Study in Kidney Transplantation.

BACKGROUND: Tacrolimus pharmacokinetics in obese (Ob) patients has been poorly studied. In this article, the authors explored the impact of obesity on tacrolimus exposure in kidney transplant recipients (KTRs) and estimated a more suitable initial dosage in this population. METHODS: A retrospective, observational, monocentric case-control study was performed in obese KTRs (BMI > 30 kg/m2) who received tacrolimus between 2013 and 2017 (initial dose: 0.15 mg/kg/d) (actual weight). Nonobese (Nob) controls (BMI <30 kg/m2) were matched for age and sex. Weekly centralized monitoring of tacrolimus trough levels was performed by liquid chromatography/mass spectrometry until the third month (M3). Target trough levels were set between 8 and 10 ng/mL. All patients received antilymphocyte globulin, corticosteroids, and mycophenolate mofetil. RESULTS: Of the 541 KTRs, 28 tacrolimus-treated Ob patients were included and compared with 28 NOb-matched controls. With a mean of 22 assays/patient, tacrolimus trough levels were higher in Ob patients (mean 9.9 versus 8.7 ng/mL; P = 0.008); the weight-related dose of Tac was lower at M3 (mean 0.10 versus 0.13 mg/kg/d, P < 0.0001). The tacrolimus concentration to dose (C0/D) was higher in the Ob cohort [mean 116 versus 76 (ng/mL)/(mg/kg/d); P = 0.001]. In Ob patients, a mean decrease of -4.6 mg/d in the 3 months after tacrolimus initiation was required (versus -1.12 in NOb; P = 0.001) to remain within the therapeutic range. Obesity, high mycophenolate mofetil daily dose at M3, and CYP3A5 expression were independently associated with higher tacrolimus exposure. Four dose-adaptation strategies were simulated and compared with the study results. CONCLUSIONS: An initial dose calculation based on either ideal or lean body weight may allow for faster achievement of tacrolimus trough level targets in Ob KTRs, who are at risk of overexposure when tacrolimus is initiated at 0.15 mg/kg/d. A prospective study is required to validate alternative dose calculation strategies in these patients.

Genetic and Functional Profiling of CD16-Dependent Natural Killer Activation Identifies Patients at Higher Risk of Cardiac Allograft Vasculopathy.

BACKGROUND: Cardiac transplantation is an effective therapy for end-stage heart failure. Because cardiac allograft vasculopathy (CAV) is the major cause of late mortality after heart transplant (HT), there is a need to identify markers that reflect inflammatory or cytotoxic immune mechanisms contributing to its onset. Noninvasive and early stratification of patients at risk remains a challenge for adapting individualized therapy. The CD16 (Fc-gamma receptor 3A [FCGR3A]) receptor was recently identified as a major determinant of antibody-mediated natural killer (NK) cell activation in HT biopsies; however, little is known about the role of CD16 in promoting allograft vasculopathy. This study aimed to investigate whether markers that reflect CD16-dependent circulating NK cell activation may identify patients at higher risk of developing CAV after HT. METHODS: Blood samples were collected from 103 patients undergoing routine coronarography angiography for CAV diagnosis (median 5 years since HT). Genomic and phenotypic analyses of FCGR3A/CD16 Fc-receptor profiles were compared in CAV-positive (n=52) and CAV-free patients (n=51). The levels of CD16 expression and rituximab-dependent cell cytotoxic activity of peripheral NK cells in HT recipients were evaluated using a noninvasive NK-cellular humoral activation test. RESULTS: Enhanced levels of CD16 expression and antibody-dependent NK cell cytotoxic function of HT recipients were associated with the FCGR3A-VV genotype. The frequency of the FCGR3A-VV genotype was significantly higher in the CAV+ group (odds ratio, 3.9; P=0.0317) than in the CAV- group. The FCGR3A-VV genotype was identified as an independent marker correlated with the presence of CAV at the time of coronary angiography by using multivariate logistic regression models. The FCGR3A-VV genotype was also identified as a baseline-independent predictor of CAV risk (odds ratio, 4.7; P=0.023). CONCLUSIONS: This study unravels a prominent role for the CD16-dependent NK cell activation pathway in the complex array of factors that favor the progression of transplant arteriosclerosis. It highlights the clinical potential of a noninvasive evaluation of FCGR3A/CD16 in the early stratification of CAV risk. The recognition of CD16 as a major checkpoint that controls immune surveillance may promote the design of individualized NK cell-targeted therapies to limit vascular damage in highly responsive sensitized patients. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01569334.

Population pharmacokinetics of ceftriaxone and pharmacodynamic considerations in haemodialysed patients.

OBJECTIVES: To determine the pharmacokinetic parameters of ceftriaxone following an infusion in haemodialysed outpatients and to use these parameters for an optimisation of dosing based on pharmacodynamic indices. METHODS: Fifty haemodialysed patients were enrolled in a single-centre, prospective, open-label study. They received short intravenous infusions of ceftriaxone 1 or 2 g every 48 hours for bronchopneumonia immediately after the dialysis session. Total plasma concentrations of ceftriaxone were analysed with a population pharmacokinetic approach using nonlinear mixed-effects modelling. Free drug concentrations were derived from published binding parameters in order to estimate the time when they exceed the minimum inhibitory concentration (MIC). RESULTS: The pharmacokinetics were best described by a two-compartment model. None of the covariates tested (age, bodyweight, height, sex, body mass index, albumin) influenced the pharmacokinetic parameters. The estimated population pharmacokinetic parameters (interindividual variability [percentage of coefficient of variation]) were clearance 0.36 L/h (48%), volume of distribution of the central compartment 4.53 L (47%), intercompartmental clearance 10.8 L/h and volume of distribution of the peripheral compartment 9.54 L (63%). The terminal elimination half-life (t(1/2)beta) from plasma was 27.5 hours. The mean (range) times when the free drug concentration exceeded the MIC (T>MIC) following ceftriaxone 1 g infusion were 60.3 (53.0-67.7) hours and 2.5 (1.0-3.9) hours for the breakpoints 1 and 8 mg/L (based on free drug concentration), respectively. After administration of ceftriaxone 2 g, the T>MIC was 88.5 (78.8-98.3) hours and 17.7 (13.3-22.0) hours for the breakpoints 1 and 8 mg/L, respectively. The simulated free drug concentrations (median, first and third quartile) for 48 and 72 hours following the first dose of ceftriaxone 1g were 1.11, 0.63 and 1.89 mg/L, and 0.63, 0.28 and 1.18 mg/L, respectively. For ceftriaxone 2g infusion, the simulated free concentrations (median, first and third quartile) at 48 and 72 hours were 2.50, 1.40 and 4.52 mg/L, and 1.37, 0.60 and 2.70 mg/L, respectively. CONCLUSIONS: On the basis of decreased clearance in haemodialysed patients, it can be argued that the dose of ceftriaxone should be decreased or the delay between doses should be increased. However, taking into account pharmacodynamic considerations, this study showed that following intravenous administration of ceftriaxone 1 g after each dialysis session, some patients were at risk of achieving a concentration below the MIC (1 mg/L), particularly if the second administration occurred 72 hours after the first dosing. Thus, a dose of ceftriaxone 2 g intravenously is recommended immediately following dialysis, particularly in patients with severe infections or when the dosing interval will be higher than 48 hours.

Population pharmacokinetics of moxifloxacin in plasma and bronchial secretions in patients with severe bronchopneumonia.

OBJECTIVE: Our objective was to construct a population pharmacokinetic model for moxifloxacin disposition in plasma and bronchial secretions in patients with severe bronchopneumonia who were mechanically ventilated. METHODS: Seventeen patients receiving 400 mg moxifloxacin intravenously daily were enrolled in this multicenter, prospective, open-label study. Blood and bronchial samples were collected on days 1 and 4. The population pharmacokinetic modeling was performed with NONMEM. RESULTS: Moxifloxacin rapidly appeared in bronchial secretions and reached maximum concentrations within 1 to 2 hours. The concentrations achieved in plasma and bronchial secretions showed parallel profiles versus time on days 1 and 4. The pharmacokinetics was best described by a 2-compartment model with a link to bronchial secretions. The population pharmacokinetic parameters were as follows (given as estimate with percent interindividual variability in parentheses except where otherwise indicated): clearance, 14.3 L/h (25%); central distribution volume, 62.9 L (14%); intercompartmental clearance, 27.2 L/h (36%); peripheral distribution volume; 71 L (32%); fraction of moxifloxacin clearance to bronchial secretions, 0.11 (range, 0.06-0.16); and elimination rate constant for bronchial secretions, 1.7 h(-1) (40%). The plasma terminal half-life was 6.7 hours. The bronchial-to-plasma exposure ratio was 1.0 (range, 0.6-2.0). With a conservative 90% minimum inhibitory concentration (MIC(90)) of 0.25 mg/L, the maximum concentration/MIC(90) ratios were higher than 10 and the area under the curve/MIC(90) ratios were roughly 100 for plasma and bronchial secretions. CONCLUSIONS: This study showed the fast diffusion of moxifloxacin into the lungs in ventilated patients with severe respiratory infection. The bronchial secretions reached bactericidal levels for common germs found in respiratory tract infections.

Increase of CYP1B1 transcription in human keratinocytes and HaCaT cells after UV-B exposure.

Nonmelanoma skin cancers represent the most common malignant neoplasms in humans. UV-B play a major role in the etiology of these tumors, but exposure to environmental procarcinogens is also involved. CYP catalyzes numerous chemical carcinogen bioactivations and effects of UV-B on their expression are poorly understood. The aim of this study was to explore the molecular events involved in the induction of CYP1B1, a major cutaneous CYP, by UV-B. Our results demonstrated that unique UV-B exposure (20 mJ/cm(2)) increases human CYP1B1 transcript in primary keratinocytes and HaCaT cell cultures. Among 20 human samples studied, we observed a large interindividual variability of CYP1B1 mRNA induction (1.1- to 4.5-fold). Pretreatment with an antioxidant, N-acetylcysteine, repressed CYP1B1 increase, suggesting the involvement of UV-B photoproducts. alpha-Amanitin inhibition studies and CAT assays demonstrated that CYP1B1 mRNA induction is associated with a transcriptional activation of its expression. alpha-Naphthoflavone inhibition studies and CAT assays performed after directed mutagenesis of xenobiotic responsive element sites showed the involvement of Ah receptor. Taken together, these data demonstrated that UV-B induces CYP1B1 gene expression after an activation of its transcription, which involves Ah receptor.