Laboratory Measurements of Ferric Chloride (FeCl) under Venusian Conditions.

Ferric chloride (FeCl) in sulfuric acid cloud droplets has been proposed to explain the inhomogeneous near-ultraviolet (UV) absorption visible at the Venusian cloud tops. However, the absorption spectrum of FeCl in concentrated sulfuric acid does not appear to have been measured previously; here we report measurements under appropriate conditions of temperature and HSO/HO solution strengths. The choice of solvent has a significant effect on the measured spectrum.

Cross-industry demonstration of the validity of the mixed matrix method for the assessment of cross-species exposure coverage of human circulating drug metabolites.

The mixed matrix method (MmM) is a widely used approach by the pharmaceutical industry for early assessment of whether exposures to major human circulating metabolites, of traditional small-molecule drugs, are adequately covered by the species used for toxicology assessment, which is a key requirement of the safety testing of drug metabolites (metabolites in safety testing guidelines). However, questions remain regarding its accuracy and utility in replacing conventional bioanalytical approaches. Furthermore, the available literature on the topic is not fully consistent in terms of how the assay should be conducted.

Recommendations on the Use of Multiple Labels in Human Mass Balance Studies.

The administration of radiolabeled drug candidates is considered the gold standard in absorption, distribution, metabolism, and excretion studies for small-molecule drugs since it allows facile and accurate quantification of parent drug, metabolites, and total drug-related material independent of the compound structure. The choice of the position of the radiolabel, typically C or H, is critical to obtain relevant information. Sometimes, a biotransformation reaction may lead to cleavage of a part of the molecule.

Non-Labeled, Stable Labeled, or Radiolabelled Approaches for Provision of Intravenous Pharmacokinetics in Humans: A Discussion Piece.

A review of the use of microdoses and isotopic microtracers for clinical intravenous pharmacokinetic (i.v. PK) data provision is presented.

Considerations for Human ADME Strategy and Design Paradigm Shift(s) - An Industry White Paper.

The human absorption, distribution, metabolism, and excretion (hADME) study is the cornerstone of the clinical pharmacology package for small molecule drugs, providing comprehensive information on the rates and routes of disposition and elimination of drug-related material in humans through the use of C-labeled drug. Significant changes have already been made in the design of the hADME study for many companies, but opportunity exists to continue to re-think both the design and timing of the hADME study in light of the potential offered by newer technologies, that enable flexibility in particular to reducing the magnitude of the radioactive dose used. This paper provides considerations on the variety of current strategies that exist across a number of pharmaceutical companies and on some of the ongoing debates around a potential move to the so called "human first/human only" approach, already adopted by at least one company.

Insights into the Chemistry of Iodine New Particle Formation: The Role of Iodine Oxides and the Source of Iodic Acid.

Iodine chemistry is an important driver of new particle formation in the marine and polar boundary layers. There are, however, conflicting views about how iodine gas-to-particle conversion proceeds. Laboratory studies indicate that the photooxidation of iodine produces iodine oxides (IO), which are well-known particle precursors.

An integrated assessment of the ADME properties of the CDK4/6 Inhibitor ribociclib utilizing preclinical in vitro, in vivo, and human ADME data.

Ribociclib (LEE011, Kisqali ®) is a highly selective small molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), which has been approved for the treatment of advanced or metastatic breast cancer. A human ADME study was conducted in healthy male volunteers following a single oral dose of 600 mg [ C]-ribociclib. Mass balance, blood and plasma radioactivity, and plasma ribociclib concentrations were measured.

F-NMR-based determination of the absorption, metabolism and excretion of the oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor leniolisib (CDZ173) in healthy volunteers.

1. Leniolisib is a novel oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor, currently in clinical development for the treatment of inflammatory and autoimmune diseases. 2.

Metabolism and Disposition of Siponimod, a Novel Selective S1P/S1P Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism.

Siponimod, a next-generation selective sphingosine-1-phosphate receptor modulator, is currently being investigated for the treatment of secondary progressive multiple sclerosis. We investigated the absorption, distribution, metabolism, and excretion (ADME) of a single 10-mg oral dose of [C]siponimod in four healthy men. Mass balance, blood and plasma radioactivity, and plasma siponimod concentrations were measured.

A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development under the "Metabolites in Safety Testing" Regulatory Guidance.

Since the introduction of metabolites in safety testing (MIST) guidance by the Food and Drug Administration in 2008, major changes have occurred in the experimental methods for the identification and quantification of metabolites, ways to evaluate coverage of metabolites, and the timing of critical clinical and nonclinical studies to generate this information. In this cross-industry review, we discuss how the increased focus on human drug metabolites and their potential contribution to safety and drug-drug interactions has influenced the approaches taken by industry for the identification and quantitation of human drug metabolites. Before the MIST guidance was issued, the method of choice for generating comprehensive metabolite profile was radio chromatography.

Comparison of F NMR and C Measurements for the Assessment of ADME of BYL719 (Alpelisib) in Humans.

The human mass balance study is the definitive study for the assessment of absorption, distribution, metabolism, and excretion (ADME) properties of a new chemical entity in humans. Traditionally this has been carried out by the administration of radiolabeled drug substances, typically C or occasionally H, as detection methods for these isotopes allow the absolute quantification of drug-related material (DRM) in blood, plasma, and excreta. Coupled with the use of analytical techniques such as liquid chromatography-mass spectrometry, a picture of the metabolic fate of a compound can be elucidated.