Penetration of linezolid and tedizolid in cerebrospinal fluid of mouse and impact of blood-brain barrier disruption.

Penetration of antimicrobial treatments into the cerebrospinal fluid is essential to successfully treat infections of the central nervous system. This penetration is hindered by different barriers, including the blood-brain barrier, which is the most impermeable. However, inflammation may lead to structural alterations of these barriers, modifying their permeability.

Development of a dosing-adjustment tool for fluoroquinolones in osteoarticular infections: The Fluo-pop study.

Fluoroquinolones efficacy depend on both the drug exposure and the level of drug resistance of the bacteria responsible for the infection. Specifically for the Staphylococcus species, which is the microorganism mainly involved in osteoarticular infections (OAI), in-vitro data reported that an AUC/MIC ratio above 115 h maximizes drug efficacy. However, data on OAI patients are lacking and a simple approach to access AUCs is still a clinical issue.

Population pharmacokinetics and exposure-response relationship of trastuzumab and bevacizumab in early-stage breast cancer.

Aims: To describe the sources of interindividual variability of bevacizumab and trastuzumab pharmacokinetics in early-stage breast cancer, and to study the relationship between exposure and both early clinical response and specific adverse events.

Patients And Methods: Patients (n = 86) received 6 cycles of docetaxel + trastuzumab. Early tumour response was assessed by determination of the maximum standard uptake value (SUV) variation (ΔSUV) after 1 cycle using [F]-fluorodeoxyglucose (FDG) PET.

Redefining Therapeutic Drug Monitoring of Tacrolimus in Patients Undergoing Liver Transplantation: A Target Trough Concentration of 4-7 ng/mL During the First Month After Liver Transplantation is Safe and Improves Graft and Renal Function.

Background: Currently, the recommended tacrolimus (TAC) trough level (Cmin) after liver transplantation (LT) is 6-10 ng/mL (when associated in triple immunosuppressive therapy). However, few studies have achieved the lower limit of this range, especially below 7 ng/mL. This study evaluated the efficacy of a target TAC Cmin of 4-7 ng/mL after LT.

Cumulative Exposure to Infliximab, But Not Trough Concentrations, Correlates With Rate of Infection.

Background & Aims: Infliximab increases the risk of infection in patients with inflammatory bowel diseases (IBD), but there is controversy over the relationship between drug concentration and infections. We aimed to assess factors associated with infection in infliximab-treated patients, including pharmacokinetic features.

Methods: We collected data from 209 patients with IBD (102 men; mean age, 39 y; 159 with Crohn's disease; 54 received combination therapy) who received an infliximab maintenance regimen from November 2016 through April 2017 in France.

Pharmacogenetic-Whole blood and intracellular pharmacokinetic-Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients.

Tacrolimus (TAC) is the cornerstone of immunosuppressive therapy in liver transplantation. This study aimed at elucidating the interplay between pharmacogenetic determinants of TAC whole blood and intracellular exposures as well as the pharmacokinetic-pharmacodynamic relationship of TAC in both compartments. Complete pharmacokinetic profiles (Predose, and 20 min, 40 min, 1h, 2h, 3h, 4h, 6h, 8h, 12h post drug intake) of twice daily TAC in whole blood and peripheral blood mononuclear cells (PBMC) were collected in 32 liver transplanted patients in the first ten days post transplantation.

Modelling of the Time-Varying Pharmacokinetics of Therapeutic Monoclonal Antibodies: A Literature Review.

Therapeutic monoclonal antibodies (mAbs) are increasingly used to treat a variety of conditions. The sources of their interindividual pharmacokinetic (PK) variability have been extensively studied, but few data on their intraindividual PK variability are available. In this article, we reviewed the published population compartmental models used to describe the time-varying PK of mAbs in clinical settings.

Intra-tracheal amikacin spray delivery in healthy mechanically ventilated piglets.

Background: Nebulization during mechanical ventilation is impeded by large extra-pulmonary drug deposition and long administration durations which currently limit implementation of inhaled antibiotic therapy. Direct intra-tracheal delivery using a sprayer represents an appealing alternative investigated in small animal models, but large animal data are lacking.

Methods: Amikacin was administered through intravenous infusion (20 mg/kg), nebulization (60 mg/kg) and direct intra-tracheal spray (30 mg/kg) to 10 intubated piglets, in a randomized cross-over design.

Pharmacokinetic Parameters of Infliximab Influence the Rate of Relapse After De-Escalation in Adults With Inflammatory Bowel Diseases.

This study aimed at exploring the link among individual concentrations, pharmacokinetic parameters, and the probability of relapse after de-escalation in a real-world prospective cohort of patients with inflammatory bowel disease (IBD) who underwent infliximab treatment de-escalation. Ninety-one patients were included. A time-varying compartment model was used to estimate individual pharmacokinetic parameters and trough concentrations.

Predictors of relapse following infliximab de-escalation in patients with inflammatory bowel disease: the value of a strategy based on therapeutic drug monitoring.

Background: There are limited data concerning infliximab drug monitoring during de-escalation of the treatment of inflammatory bowel disease (IBD).

Aim: To define the rate and the predictors of relapse following infliximab de-escalation in IBD patients in remission.

Methods: All IBD patients at a single referral centre in clinical and biological remission and in whom the dose of infliximab had been de-escalated were included.

Tacrolimus Concentrations Measured in Excreted Bile in Liver Transplant Recipients: The STABILE Study.

Purpose: Tacrolimus (TAC) is the main immunosuppressive drug in liver transplantation. Despite intensive therapeutic drug monitoring (TDM) that relies on whole blood trough concentration (TAC), patients still present with acute cellular rejection or TAC-related toxic effects with concentrations within the therapeutic range. TAC concentration in peripheral blood mononuclear cells (TAC) is considered as an efficient surrogate marker of TAC efficacy.

Tacrolimus overexposure in kidney transplant recipients during the first post-operative week: caution is required in older patients.

In liver transplantation, tacrolimus trough concentrations (Cmin) above 20 ng/mL during the first days led to worse outcome at 1 year but data in the kidney transplant (KT) era are scarce. The aim of this study was to evaluate the impact of tacrolimus overexposure during the first week post-transplantation on the kidney function (KF) of KT recipients. In this retrospective study, 105 KT recipients were attributed to overexposure group (OG) or normal group according to their Cmin during the first week of treatment.

Pharmacogenetics of Membrane Transporters of Tacrolimus in Solid Organ Transplantation.

Membrane transporters play an essential role in the pharmacokinetics of drugs as they mediate exchanges between biological compartments. Tacrolimus is characterized by wide interpatient variability in terms of its pharmacokinetics that may in part be due to genetic factors. The pharmacogenetics of drug transporters is therefore a promising area to explore in the clinical pharmacology of tacrolimus.

Tacrolimus diffusion across the peripheral mononuclear blood cell membrane: impact of drug transporters.

Measuring tacrolimus (TAC) concentration in peripheral blood mononuclear cells (PBMCs) could better reflect the drug effect on its target (calcineurin (CaN) in lymphocytes) than whole blood concentrations. Mechanisms influencing TAC diffusion into PBMC are not well characterized. This work aimed at describing, ex vivo, TAC diffusion kinetics into PBMC and investigating the contribution of membrane transporters to regulate TAC intracellular concentration as well as the impact on CaN activity.

Modeling Immunization To Infliximab in Children With Crohn's Disease Using Population Pharmacokinetics: A Pilot Study.

Background: Antidrug antibodies (ADAs) dramatically increase infliximab clearance and are responsible for underexposure to the drug, leading to treatment failure. This pilot study aimed at developing a population pharmacokinetic model to detect and describe an early increase in infliximab clearance due to ADA.

Methods: Twenty children with Crohn's disease (CD) were followed for 1 year or until treatment failure.

High Intrapatient Variability of Tacrolimus Exposure in the Early Period After Liver Transplantation Is Associated With Poorer Outcomes.

Background: Tacrolimus (TAC) is the cornerstone of immunosuppressive regimen in liver transplantation (LT). Its pharmacokinetics is characterized by a high interpatient and intrapatient variability (IPV) leading to an unpredictable dose-response relationship. The aim of our study was to evaluate the impact of TAC IPV (IPV) on graft and patient outcomes after LT.

Safety study and therapeutic drug monitoring of the oral tablet formulation of posaconazole in patients with haematological malignancies.

Purpose: Posaconazole is a triazole antifungal widely used for prophylaxis of invasive fungal disease (IFI). Posaconazole tablets allow reaching higher plasma levels than the oral suspension, but safety data with this formulation in real life are scarce. This study aimed at evaluating the safety profile, the pharmacokinetic variability, and the concentration-toxicity relationship of posaconazole tablets in patients with haematological malignancies.

Population Pharmacokinetics of Posaconazole Tablets and Monte Carlo Simulations To Determine whether All Patients Should Receive the Same Dose.

Posaconazole is extensively used for prophylaxis for invasive fungal infections. The gastro-resistant tablet formulation has allowed the bioavailability issues encountered with the oral suspension to be overcome. However, overexposure is now frequent.

Ex Vivo Model to Decipher the Impact of Extracorporeal Membrane Oxygenation on Beta-lactam Degradation Kinetics.

Background: As a consequence of drug sequestration, increase in volume of distribution, or alteration of elimination, extracorporeal membrane oxygenation (ECMO) might lead to inadequate plasma concentrations of vital drugs. The aim of this experimental study was to develop an ex vivo model to better characterize the impact of ECMO procedure on beta-lactam antibiotics pharmacokinetics.

Methods: Plasma concentrations of cefotaxime, ceftazidime, cefepime, piperacillin, oxacillin, amoxicillin, and ceftriaxone were measured in an ex vivo ECMO circuit primed with whole human blood and compared with controls stored in glass tubes and polyvinyl chloride tubing.

A high performance liquid chromatography tandem mass spectrometry for the quantification of tacrolimus in human bile in liver transplant recipients.

Tacrolimus whole-blood concentrations imperfectly reflect concentrations at the effect site. Tacrolimus concentrations in the transplanted organ could be more relevant to predict rejection events. Because liver biopsy cannot be repeatedly performed after liver transplantation, we suggested measuring tacrolimus in the bile to have a cost-effective and clinically implementable surrogate marker of intra-hepatic tacrolimus concentration.

Increased inhibition of cytochrome P450 3A4 with the tablet formulation of posaconazole.

Being a substrate of the cytochrome P450 3A4 (CYP3A4) isoenzyme, sirolimus metabolism is decreased when posaconazole is administered concomitantly. However, because of the poor bioavailability of the oral suspension of posaconazole with which low plasma concentrations are obtained, CYP3A4 inhibition is weak and a 50-75% dose reduction of sirolimus is sufficient to avoid sirolimus overdosage. The new tablet formulation allows reaching posaconazole concentrations 3-4 fold higher than those obtained with the oral suspension.