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Immune checkpoint inhibitors are monoclonal antibodies (mAbs) directed against negative immunologic regulators that are used to restore the immune response against cancer. Approved drugs include anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death-ligand 1 (PD-L1) antibodies exhibiting pharmacokinetic (PK) characteristics typical of mAbs. Most factors such as age, sex, ethnicity, tumour burden, performance status and immunogenicity, but not body weight, do not seem to affect drug clearance clinically. However, an exposure-response relation has been described for both the efficacy and toxicity of anti-CTLA-4 and anti-PD-1 agents. The change in clearance over time is associated with overall response at least for nivolumab and pembrolizumab. Few PK/pharmacodynamic (PD) data are available for anti-PD-L1 mAbs, but time-varying clearance has been described for these drugs, and the high immunogenicity rate observed with atezolizumab may affect PK parameters and should be further studied. These data suggest the need for additional PK/PD studies. In this review, we summarise studies of the PKs of immune checkpoint inhibitors, exploring possible interactions with PD considerations.

The hallmarks of cancer include metabolism with deregulating cellular energetics. Dysfunctions in succinate dehydrogenase (SDH) metabolic enzyme activity, leading to an abnormal accumulation of succinic acid has been described in solid tumors but also in inflammation and ischemia reperfusion injury. Succinic acid is a potential biomarker of SDH related pathologies for diagnostic, evaluation of treatment response and follow-up of the disease. We developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) method allowing a rapid, accurate and precise quantification of succinic acid levels in clinical (serum, urine) and preclinical (cellular pellets, supernatants) samples.

More than 25 therapeutic monoclonal antibodies (mAbs) used in oncology have been approved since 1997. Their nature has been largely modified through the last 20 years, from the chimeric IgG1 rituximab with pharmacokinetic parameters specific of murin or chimeric mAbs to humanized or human mAbs. Doses and administration frequency have been chosen based on this nature. More recently, the developed and registered mAbs are mostly IgG1, IgG2, IgG3 or IgG4 humanized or 100% human. Therefore, their behavior is different from the first mAbs authorized leading to lower systemic clearance and shorter half-life due to higher cellular uptake balanced by FcRn recognition with recirculation. The complexity of the pharmacokinetics and the pharmacokinetics/pharmacodynamics relation are increased for antibody-drug conjugates or bispecific T-cell engagers. However, significant number of studies reported pharmacokinetics/pharmacodynamics relations, with positive exposure-response link justifying the exploration of the pharmacokinetics in routine clinical practice of these therapeutic mAbs to prevent treatment failures and to limit their toxicities.

To assess, in a clinical cohort, the efficacy of switching current ART in virologically suppressed patients to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate as a single-tablet regimen (STR) using the PCR signal of the plasma viral load (pVL) assay and determination of plasma drug concentration ( C 24 ).This was an observational single-centre study enrolling antiretroviral-treated patients with pVL50 copies/mL initiating elvitegravir-based STR. PCRneg was defined as an undetected PCR signal.One hundred and fifty-one patients were enrolled. At STR baseline, the median time since first ART and time of virological suppression were 5 years (IQR 3-9) and 24 months (IQR 9-44), respectively. By week (W) 48, 26 (17%) of the patients had discontinued STR due to adverse events. The proportion of patients maintaining pVL50 copies/mL on treatment was 98%, 96%, 93% and 97% at W12, W24, W36 and W48, respectively. Five patients (3.3%) experienced a virological failure and emergence of resistance was observed in two of them with the selection of M184V and N155H mutations. At baseline, W12, W24, W36 and W48, 70%, 57%, 72%, 61% and 74% of the patients with pVL20 copies/mL had a PCRneg, respectively. The median elvitegravir plasma C 24 value was 648 ng/mL (IQR 348-989; n = 237), with 84% of elvitegravir C 24 values45 ng/mL, the protein-adjusted IC 95 .In this clinical cohort of virologically suppressed patients switching to STR, most subjects had adequate elvitegravir C 24 values with a high proportion maintaining virological suppression with no residual viraemia until W48.

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Blondel Louis. Genève, des origines à l'époque carolingienne. In: Le Globe. Revue genevoise de géographie, tome 79, 1940. pp. 11-12.

Blondel Louis. Genève, des origines de l'époque carolingienne à nos jours. In: Le Globe. Revue genevoise de géographie, tome 79, 1940. pp. 12-13.