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Abstract Atezolizumab is an anti‐PDL1 approved for treating lung cancer. A threshold of 6 μg/mL in plasma has been associated with target engagement. The extent to which patients could be overexposed with the standard 1200 mg q3w dosing remains unknown. Here, we monitored atezolizumab peak and trough levels in 27 real‐world patients with lung cancer as part of routine therapeutic drug monitoring. Individual pharmacokinetic (PK) parameters were calculated using a population approach and optimal dosing‐intervals were simulated with respect to the target trough levels. No patient had plasma levels below 6 μg/mL. The results showed that the mean trough level after the first treatment was 78.3 ± 17 μg/mL, that is, 13 times above the target concentration. The overall response rate was 55.5%. Low‐grade immune‐related adverse events was observed in 37% of patients. No relationship was found between exposure metrics of atezolizumab (i.e., minimum plasma concentration, maximum plasma concentration, and area under the curve) and pharmacodynamic end points (i.e., efficacy and toxicity). Further simulations suggest that the dosing interval could be extended from 21 days to 49 up to 136 days (mean: 85.7 days, i.e., q12w), while ensuring plasma levels still above the 6 μg/mL target threshold. This observational, real‐world study suggests that the standard 1200 mg q3w fixed‐dose regimen of atezolizumab results in significant overexposure in all the patients. This was not associated with increased side effects. As plasma levels largely exceed pharmacologically active concentrations, interindividual variability in PK parameters did not impact efficacy. Our data suggest that dosing intervals could be markedly extended with respect to the target threshold associated with efficacy.

The management of brain diseases remains a challenge, particularly because of the difficulty for drugs to cross the blood–brain barrier. Among strategies developed to improve drug delivery, nano-sized emulsions (i.e., nanoemulsions), employed as nanocarriers, have been described. Moreover, focused ultrasound-mediated blood–brain barrier disruption using microbubbles is an attractive method to overcome this barrier, showing promising results in clinical trials. Therefore, nanoemulsions combined with this technology represent a real opportunity to bypass the constraints imposed by the blood–brain barrier and improve the treatment of brain diseases. In this work, a stable freeze-dried emulsion of perfluorooctyl bromide nanodroplets stabilized with home-made fluorinated surfactants able to carry hydrophobic agents is developed. This formulation is biocompatible and droplets composing the emulsion are internalized in multiple cell lines. After intravenous administration in mice, droplets are eliminated from the bloodstream in 24 h (blood half-life (t1/2) = 3.11 h) and no long-term toxicity is expected since they are completely excreted from mice’ bodies after 72 h. In addition, intracerebral accumulation of tagged droplets is safely and significantly increased after focused ultrasound-mediated blood–brain barrier disruption. Thus, the proposed nanoemulsion appears as a promising nanocarrier for a successful focused ultrasound-mediated brain delivery of hydrophobic agents.

This article spot the light on characterization of functioning of Aïn Telout karstic system by hydrodynamic methods (The Tlemcen Mountains, Algeria). The approach adopted in this work is based on the analysis of discharges and rainfalls chronicles of Aïn Telout spring over four hydrological cycles 2010-2014, using the following methods: analysis of the classified discharges, analysis of the recession curves as well as the correlation and spectral analysis. The application of these methods has allowed us to characterize the hydrodynamic functioning of this hydrosystem. It is an inertial system, weakly karstified and poorly drained, with a mediocre dynamic volume estimated at 465,000 m3 and a residence time of water about 405 days. The application of correlation and spectral analysis has permitted extraction of some characteristics. The input signal (rainfall) shows a seasonal trend characteristic of the Mediterranean climate, while the simple correlogram of discharges of the Telout spring display a signal different from that of the input signal, reflecting the regulating character of this system. The simple and cross analysis show a memory effect of 60 days, a regulation time of 35 days and a response time of 15 days. The cross-correlogram indicate a double response of the system following rainfall solicitations, a rapid response of the system, which translates a transmissive character, followed by a second slow and very inertial response reflecting a second capacitive character of this system. [ABSTRACT FROM AUTHOR]