Isavuconazole therapeutic drug monitoring associated to a pharmacogenetic exploration is far from being a pharmacologists’ whim

Darnaud, L.; Lamoureux, F.; Godet, C.; Pontier, S.; Debard, A.; Venisse, N.; Martins, P.; Concordet, D.; Gandia, P.

doi:10.1101/316851

Home/Archive/bioRxiv

bioRxiv · 10.1101/316851

Isavuconazole therapeutic drug monitoring associated to a pharmacogenetic exploration is far from being a pharmacologists’ whim

Darnaud, L.·Lamoureux, F.·Godet, C.·Pontier, S.·Debard, A.·Venisse, N.·Martins, P.·Concordet, D.·Gandia, P.

View original source ↗Export metadata ↓

Abstract

Isavuconazole is a new antifungal prodrug to treat invasive aspergillosis and mucormycosis, theoretically not requiring drug monitoring. However, we reported 4 clinical cases with toxic concentrations. Based on Desais population pharmacokinetic model, we estimated patients kinetic profile. Clearance was abnormally low, likely related to CYP3A4/5 polymorphisms. Thus, we recommend to collect blood sample just before the first maintenance dose to estimate pharmacokinetic profile and individualized dose. For patients presenting high concentrations, pharmacogenetics can be done.

Explore related subjects

pharmacology and toxicology Preprint

Keep this discovery

BibTeX RIS

Darnaud, L., Lamoureux, F., Godet, C., Pontier, S., Debard, A., Venisse, N., Martins, P., Concordet, D., Gandia, P.. 2018-05-09. Isavuconazole therapeutic drug monitoring associated to a pharmacogenetic exploration is far from being a pharmacologists’ whim. https://doi.org/10.1101/316851

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Lipid-ASO therapeutics exhibit differential tissue targeted delivery upon systemic or local CNS administration

Antisense oligonucleotides (ASOs) are a powerful therapeutic modality, but their full potential is hindered by pharmacokinetic properties that affect tissue and cellular delivery. Lipid conjugation is increasingly used to modulate ASO's biodistribution and promote extrahepatic activity, yet lipid dependent effects on in vivo functional delivery, particularly in the central nervous system (CNS), remain less explored. Here, we performed a side by side in vivo comparison of cholesterol, palmitic acid (C16:0), docosanoic acid (C22:0), and eicosapentaenoic acid (C20:5) conjugated to a fully phosphorothioated 3 10 3 LNA gapmer ASO targeting the Malat1 long non coding RNA. Lipid-ASO conjugates were administered systemically or locally in the brain of mice and evaluated for tissue level and cellular level distribution by imaging, qPCR and single-cell RNA sequencing, simultaneously annotating cell origin and global transcriptional changes within the cell. Following systemic administration in mice, lipid conjugation improved overall multi organ efficacy compared to unconjugated ASO, but with pronounced tissue specific differences. Single cell sequencing of liver and heart transcriptomes revealed lipid dependent cellular uptake patterns and transcriptional responses distinct from administration of unconjugated ASO. After intracerebroventricular administration, selected fatty acid conjugates enhanced silencing in deep brain regions such as the striatum, whereas cholesterol conjugation impaired functional delivery despite increased CNS retention. Light-sheet microscopy showed restricted parenchymal penetration of cholesterol ASOs compared with broader but heterogeneous distribution of palmitic acid conjugate. Together, these findings demonstrate that lipid identity critically determines ASO efficacy, productive cellular uptake, and regional CNS engagement, emphasizing the need for context specific lipid design in ASO therapeutic development.

pharmacology and toxicology↗

bioRxiv2026

Novel Dissymmetric Ionizable Lipid-Assembled Lipid Nanoparticles for Delivery of Ferroptosis-Related siRNA in Diabetic Treatment

Small interfering RNA (siRNA) enables precise post-transcriptional gene silencing for refractory diseases, yet its clinical translation remains limited by the lack of safe and efficient delivery vectors. Inspired by the dissymmetric alkyl chain architecture of natural membrane phospholipids, we designed and synthesized 34 novel ionizable lipids with dissymmetric hydrophobic tails and formulated them into lipid nanoparticles (LNPs). Through systematic physicochemical and biological assessments, we established clear structure-activity relationships and identified two lead LNPs (O14-LNP, H18a-LNP) with superior endosomal escape capacity, enhanced in vivo gene silencing potency, and favorable biosafety relative to the clinical benchmark MC3-LNP. In both streptozotocin-induced and spontaneous db/db type 2 diabetes (T2D) mouse models, lead LNPs delivering ferroptosis-related siRNAs effectively ameliorated glucose and lipid metabolic disorders, restored islet function, and alleviated hepatic steatosis. This study not only lays a theoretical foundation for the rational design of novel ionizable lipids, but also validates the therapeutic potential of siRNA therapy targeting ferroptosis, providing a versatile delivery platform and targeted therapeutic strategy for the treatment of T2D.

pharmacology and toxicology↗

bioRxiv2018

Characterization of BSN175: A Drug to Treat Prader-Willi Syndrome

The purpose of this research is to choose the best analytical method for determining stability of BSN175. This research uses an accelerated stability study to compare the decomposed and stable drug using IR and 1H NMR spectroscopy. The Bootstrap Error-adjusted Single-sample Technique (BEST) was used to compare the effectiveness of these analytical methods and choose the best option for determining stability.

pharmacology and toxicology↗