Biases affecting injected doses of an experimental drug during clinical trials.

During clinical trials, researchers rarely question nominal doses specified on labels of investigational products, overlooking the potential for inaccuracies that may result when calculating pharmacokinetic and pharmacodynamic parameters. This study evaluated the disparity between nominal doses and the doses actually administered in two Phase I trials of a biosimilar drug. In Trial A, 12 healthy volunteers received various doses of an interferon β-1a biosimilar via either subcutaneous or intravenous injection, prepared by partially emptying 0.53 ml syringes supplied by the manufacturer. In Trial B, 12 volunteers received three different formulations of the drug via intravenous injection (biosimilar with and without albumin and a comparator), followed by multiple subcutaneous injections. In both trials, the dose administered was calculated as D = C × V - losses, where C is the drug concentration assessed using ELISA, V is the volume administered calculated using syringe weighing and losses are deduced from in-vitro experiments. Interferon binding to added albumin and infusion lines was evaluated using a (125)I-interferon tracer with gel-filtration chromatography. In Trial A, measured concentrations were close to the nominal strength indicated by the manufacturer (median bias: -6 %), whereas in Trial B they differed significantly for all three formulations (median biases: +67 %, +73 % and +31 % for the biosimilar with albumin, the biosimilar without albumin and the comparator, respectively). In Trial A, the doses actually administered showed large variability and biases, especially at the lowest doses. Indeed, actually injected volumes differed by as much as 74 % from theoretical volumes - a phenomenon mainly attributed to unnoticed fluid re-aspiration through the syringe needle. This was corrected in Trial B. Interferon was not significantly adsorbed on the infusion lines used for intravenous administration. Its binding to albumin was slow, reaching 50 % after a 16 h incubation. These examples illustrate the importance of assessing the actual doses administered in clinical trials, to ensure accuracy in the determination of clearance, distribution volume, bioavailability and dose-response relationships. Clinicaltrials.gov NCT02515695 (Trial A) and NCT02517788 (Trial B). Registered on 24 July and 5 August 2015, respectively

Médicaments, sexe et genre [Medicines, sex and gender]

Sex-related differences affecting pharmacokinetic and pharmacodynamic processes result mostly from sex dimorphisms in body composition, and liver and kidney function, in addition to hormonal regulation of enzymes, transporters and drug receptors. Gender biases have long compromised the identification of these differences in clinical trials. They also modulate prescription patterns and therapeutic benefits. Men and women would benefit from different standard dosages of some anti-infectives, anticancer agents and other treatments requiring precise dosage adjustment. This would alleviate the well-documented excess of adverse reactions affecting women. However, the variability of pharmacological responses within each sex exceeds the average male-female difference, highlighting the importance of other criteria for therapeutic individualisation

Traitements aggravant une infection par le COVID-19 : vraiment ? [Drugs that aggravate the course of COVID-19 : really ?]

The safety of NSAIDs, corticosteroids and renin-angiotensin inhibitors in COVID-19 is challenged. NSAIDs may interfere with the defense process against viral infection and are best avoided. Systemic corticosteroids have not shown benefit in viral infection, including other coronavirus; thus they should be avoided, unless prescribed for another indication. The benefit-risk ratio is however clearly in favor of continuing inhaled corticosteroids in patients with asthma or COPD. ACE inhibitors and sartans upregulate the expression of angiotensin-converting enzyme 2 (ACE2), the pulmonary receptor for SARS-CoV-2. Any possible clinical impact of these treatments on COVID-19 infection remains to be clarified; in the meantime, they should be continued

Galactic Abundances: Report of Working Group 3

We summarize the various methods and their limitations and strengths to derive galactic abundances from in-situ and remote-sensing measurements, both from ground-based observations and from instruments in space. Because galactic abundances evolve in time and space it is important to obtain information with a variety of different methods covering different regions from the Very Local Insterstellar Medium (VLISM) to the distant galaxy, and different times throughout the evolution of the galaxy. We discuss the study of the present-day VLISM with neutral gas, pickup ions, and Anomalous Cosmic Rays, the study of the local interstellar medium (ISM) at distances <1.5 kpc utilizing absorption line measurements in H I clouds, and the study of galactic cosmic rays, sampling contemporary (~15 Myr) sources in the local ISM within a few kiloparsec of the solar system. Solar system abundances, derived from solar abundances and meteorite studies are discussed in several other chapters of this volume. They provide samples of matter from the ISM from the time of solar system format ion, about 4.5 Gyr ago. The evolution of galactic abundances on longer time scales is discussed in the context of nuclear synthesis in the various contributing stellar objects

Development and validation of a multiplex UHPLC-MS/MS assay with stable isotopic internal standards for the monitoring of the plasma concentrations of the antiretroviral drugs bictegravir, cabotegravir, doravirine, and rilpivirine in people living with HIV

The widespread use of highly active antiretroviral treatments has dramatically changed the prognosis of people living with HIV (PLWH). However, such treatments have to be taken lifelong raising issues regarding the maintenance of both therapeutic effectiveness and long-term tolerability. Recently approved or investigational antiretroviral drugs present considerable advantages, allowing once daily oral dosage along with activity against resistant variants (eg, bictegravir and doravirine) and also parenteral intramuscular administration that facilitates treatment adherence (eg, long-acting injectable formulations such as cabotegravir and rilpivirine). Still, there remains a risk of insufficient or exaggerated circulating exposure due to absorption issues, abnormal elimination, drug-drug interactions, and others. In this context, a multiplex ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) bioassay has been developed for the monitoring of plasma levels of bictegravir, cabotegravir, doravirine, and rilpivirine in PLWH. A simple and convenient protein precipitation was performed followed by direct injection of the supernatant into the UHPLC-MS/MS system. The four analytes were eluted in less than 3 minutes using a reversed-phase chromatography method coupled with triple quadrupole mass spectrometry detection. This bioassay was fully validated following international guidelines and achieved good performances in terms of trueness (94.7%-107.5%), repeatability (2.6%-11%), and intermediate precision (3.0%-11.2%) over the clinically relevant concentration ranges (from 30 to 9000 ng/mL for bictegravir, cabotegravir, and doravirine and from 10 to 1800 ng/mL for rilpivirine). This sensitive, accurate, and rapid UHPLC-MS/MS assay is currently applied in our laboratory for routine therapeutic drug monitoring of the oral drugs bictegravir and doravirine and is also intended to be applied for the monitoring of cabotegravir/rilpivirine levels in plasma from PLWH receiving once monthly or every 2-month intramuscular injection of these long-acting antiretroviral drugs

Pharmacovigilance - Vaccins à ARNm contre le Covid-19 : le point sur les effets indésirables [Pharmacovigilance - mRNA COVID-19 vaccines : current state of knowledge on their adverse effects]

The COVID-19 pandemic has stimulated the rapid development and large-scale use of technologically innovative vaccines, such as the mRNA vaccines Spikevax (Moderna) and Comirnaty (Pfizer-BioNTech). This unprecedented deployment has challenged pharmacovigilance, requiring combined skills in safety monitoring, prompt data analysis and continuous dissemination of knowledge. Main recognised adverse events of these vaccines are moderate and transient, linked to their significant reactogenicity. Active post-marketing surveillance has identified rare adverse events such as myopericarditis and a variety of skin reactions. A number of potential rare adverse events are being evaluated and could be retained at the individual level, but do not question the overall safety of these vaccines

An innovative ethosuximide granule formulation designed for pediatric use: Comparative pharmacokinetics, safety, tolerability, and palatability profile versus reference syrup.

Ethosuximide, the first-line therapy for childhood absence epilepsy, is currently formulated as a syrup (Zarontin®, Pfizer) with a bitter taste and high sugar content, poorly adapted to children, and a ketogenic diet. The collaborative European FP7 project KIEKIDS aimed at developing an innovative sugar-free, tasteless formulation convenient for pediatric use. This dual Phase-I study evaluated two granule formulations based on lipid multiparticulate (LMP) technology. Two panels of 6 healthy adult volunteers underwent a randomized, placebo-controlled, partly blinded, 3-way cross-over trial, comparing ethosuximide granules A or B with placebo granules and syrup at single 10 mg/kg doses. Corresponding plasma pharmacokinetic profiles of ethosuximide were compared, along with palatability, safety, and tolerability. The LMP granule A proved suboptimal due to bitterness and adherence to beaker walls, while the optimized granule B revealed excellent palatability, similar to placebo granules, and low adherence to glass. The relative bioavailability of granules A versus syrup, based on dose-normalized C &lt;sub&gt;max&lt;/sub&gt; and AUC &lt;sub&gt;0-∞&lt;/sub&gt; was 93.7% [90% CI: 76.3-115.1] and 96.1% [91.0-101.5], respectively. For granules B it was 87.6% [81.6-94.0] and 92.5% [88.5-96.6], respectively, with slightly delayed t &lt;sub&gt;max&lt;/sub&gt; of 0.75 h [0.5-4.05] compared to syrup 0.5 h [0.3-0.8]. Tolerability visual analog scales revealed a trend for statistically non-significant improvement versus syrup at peak (30 min) for transient dizziness (both granules), fatigue (granules A), and anxiety (granules B). The innovative ethosuximide granule formulation B achieves a suitable profile for pediatric use, being sugar-free, tasteless, bioequivalent, and well-tolerated while enabling precise adjustment to body weight