1β-Hydroxydeoxycholic acid as an endogenous biomarker in human plasma for assessment of drug-drug interaction with moderate CYP3A inhibitor.

1β-Hydroxydeoxycholic acid (1β-OH DCA) in plasma has been shown to be a promising biomarker to assess drug-drug interaction (DDI) with a strong CYP3A inducer or a strong CYP3A inhibitor. The changes in total 1β-OH DCA (sum of 1β-OH DCA, 1β-OH glycine deoxycholic acid, and 1β-OH taurine deoxycholic acid equivalents) were more significant than those observed from 4β-hydroxycholesterol, which has been limited to the identification of CYP3A inducers, not CYP3A inhibitors. The significant reduction in total 1β-OH DCA in response to strong CYP3A inhibitors led us to further explore its utility as a biomarker for DDI with moderate CYP3A inhibitors.

Using the grip strength effort task to measure reward processing dysfunction in schizophrenia and major depressive disorder.

The aims of the Reward Task Optimisation Consortium (RTOC) study (Bilderbeck et al., 2020) were to explore the validity, reliability, and feasibility of a battery of reward processing tasks for the development of new treatments for anhedonia. We report our findings from the Grip Strength Effort Task (GSET), an effort-based decision-making task in which participants chose to either perform easy trials that required less physical effort for low monetary reward or hard trials that required more effort for potentially larger rewards.

Differential protein expressions of hepatic drug-metabolizing enzymes between White and Black Americans and the associated genetic polymorphisms.

Although racial differences in drug response have been well documented, the mechanisms underlying these variations remain incompletely understood. The racial differences may be partially attributed to variations in the expression of drug-metabolizing enzymes (DMEs) between racial groups. We conducted a proteomics analysis of selected clinically relevant DMEs, including 12 cytochrome P450s, 10 UDP-glucuronosyltransferases (UGTs), 19 transferases, and 11 hydrolases, in liver samples from White and Black Americans and compared the protein expression levels between the 2 groups.

Functional connectivity alterations of the pregenual anterior cingulate cortex by ketamine and the modulation by lamotrigine.

Background: Neuroimaging studies have linked the beneficial effects of subanaesthetic ketamine doses in psychiatric conditions characterized by chronic stress pathology (CSP) to altered functional connectivity (FC) within the pregenual anterior cingulate cortex (pgACC). Previous research indicates a potential role of glutamate concentration in FC changes; however, the precise relationship between glutamate release and increased FC remains unclear. Lamotrigine, a glutamate-release inhibitor, allows deeper exploration of this relationship.

Exposure-response relationship of fedratinib in patients with intermediate-2 or high-risk myelofibrosis.

Aims: Fedratinib is a potent, oral, Janus kinase inhibitor for the treatment of myelofibrosis (MF). This report describes exposure-response (E-R) analyses of fedratinib based on pooled data from phase 2/3 studies in patients with intermediate-2 or high-risk MF, with or without prior ruxolitinib exposure.

Methods: Pharmacokinetic (PK) exposures were derived from the population PK analysis.

Evaluating the utility of endogenous OCT2 and MATE1/2-K biomarkers for DDI assessment in early clinical settings.

With growing interest in a biomarker-based approach for drug-drug interaction (DDI) predictions, creatinine, N1-methylnicotinamide (NMN), and N1-methyladenosine (mA) have been identified as endogenous substrates of organic cation transporter (OCT) 2 and multidrug and toxin extrusion (MATE) 1/2-K, though clinical validation remains limited. This study builds on recent advancements by evaluating these biomarkers retrospectively using samples from a clinical pharmacology study that assessed DDI via renal cationic transporters between fedratinib (inhibitor) and metformin (substrate) in healthy participants. Fedratinib reduced renal clearance for all endogenous substrates, with mA (38 %) and NMN (36 %) showing reductions comparable to metformin (40 %), while creatinine exhibited slightly lower (29 %), likely reflecting its limited contribution to transporter-mediated renal tubular secretion.

Drug-drug interaction study with itraconazole supplemented with physiologically based pharmacokinetic modelling to characterize the effect of CYP3A inhibitors on venglustat pharmacokinetics.

Aims: Venglustat is an oral glucosylceramide synthase inhibitor under clinical investigation to treat various lysosomal storage diseases. Metabolism is a main pathway for its elimination in humans with CYP3A being the major contributor. This study aims to evaluate effect of CYP3A inhibition (using itraconazole) on venglustat exposure and to develop and validate a physiologically based pharmacokinetic (PBPK) model to assess effects of additional CYP3A inhibitors of varying potencies on venglustat pharmacokinetics.

The quest to define cancer-specific systems parameters for personalized dosing in oncology.

Introduction: Clinical trials in oncology initially recruit heterogeneous populations, without catering for all types of variability. The target cohort is often not representative, leading to variability in pharmacokinetics (PK). To address enrollment challenges in clinical trials, physiologically based pharmacokinetic models (PBPK) models can be used as a guide in the absence of large clinical studies.

Opportunities and Challenges of Hepatic Impairment Physiologically Based Pharmacokinetic Modeling in Drug Development-An IQ Perspective.

PBPK models are gaining special interest as a drug development tool to estimate the effect of intrinsic and extrinsic factors on drug pharmacokinetics. The IQ Consortium Clinical Pharmacology Organ Impairment Working Group conducted a survey across IQ Consortium member pharmaceutical companies to understand current practices on how PBPK is used in understanding the effect of hepatic impairment (HI) on drug disposition and its impact on clinical development. Responses from 21 participants indicated that most organizations (~86%) are already using PBPK models for HI assessment.

Avenciguat: a novel soluble guanylate cyclase activator that affects multiple cell types to inhibit IFN-1 signalling and fibrosis.

Objectives: The soluble guanylate cyclase (sGC) stimulator riociguat is approved for the treatment of pulmonary arterial hypertension and may have antifibrotic effects. However, in fibrotic tissues, oxidative stress and hypoxia can render sGC insensitive to sGC stimulators. sGC activators overcome this limitation.

Evaluation of Solubility-Limited Absorption as a Surrogate to Predicting Positive Food Effect of BCS II/IV Drugs.

Introduction And Objective: Physiologically based pharmacokinetic (PBPK) models are increasingly used to predict food effect (FE) but model parameterization is challenged by in vitro-in vivo (IVIV) disconnect and/or parameter nonidentifiability. To overcome these issues, we propose a simplified PBPK model, in which all solubility-driven processes are lumped into a single parameter, solubility, which is optimized against observed concentration-time data.

Methods: A set of commercially available biopharmaceutical classification system (BCS) II/IV compounds was selected to measure the solubility in a fasted state simulated intestinal fluid (FaSSIF) medium.

Population Pharmacokinetics of Orvacabtagene Autoleucel, an Autologous BCMA-Directed Chimeric Antigen Receptor T-cell Product, in Patients with Relapsed/Refractory Multiple Myeloma.

Purpose: Orvacabtagene autoleucel (orva-cel; JCARH125), a chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen, was evaluated in patients with relapsed/refractory multiple myeloma in the EVOLVE phase I/II study (NCT03430011). We applied a modified piecewise model to characterize orva-cel transgene kinetics and assessed the impact of various covariates on its pharmacokinetics (PK).

Experimental Design: The population PK analysis included 159 patients from the EVOLVE study.

A non-interventional biomarker study in patients with adenocarcinoma of the lung treated with nintedanib plus docetaxel following progression on chemotherapy and/or immunotherapy: LUME-BioNIS.

Background: Anti-angiogenic agents, such as nintedanib and ramucirumab, when combined with docetaxel, are subsequent treatment options in patients with non-small cell lung cancer (NSCLC) who have failed on first-line chemotherapy or immunochemotherapy. However, to date, there are no validated predictive biomarkers for efficacy of anti-angiogenic therapies in this setting. The aim of this study was to explore whether genetic or genomic markers, alone or combined with clinical covariates, could be used to predict overall survival (OS) in patients with NSCLC who are eligible for treatment with nintedanib plus docetaxel.

New Insights Into Hepatic Impairment (HI) Trials.

Hepatic impairment (HI) trials are traditionally part of the clinical pharmacology development to assess the need for dose adaptation in people with impaired metabolic capacity due to their diseased liver. This review aimed at looking into the data from dedicated HI studies, cluster these data into various categories and connect the effect by HI with reported pharmacokinetics (PK) properties in order to identify patterns that may allow waiver, extrapolations, or adapted HI study designs. Based on a ratio ≥ 2 or ≤ 0.

A Model-Based Evaluation of Noninvasive Biomarkers to Reflect Histological Nonalcoholic Fatty Liver Disease Scores.

Background: Nonalcoholic fatty liver disease (NAFLD) comprises multiple heterogeneous pathophysiological conditions commonly evaluated by suboptimal liver biopsies. This study aimed to elucidate the role of 13 diverse histological liver scores in assessing NAFLD disease activity using an in silico pharmacometric model-based approach. We further sought to investigate various noninvasive patient characteristics for their ability to reflect all 13 histological scores and the NAFLD activity score (NAS).

Impact of Chronic Inflammatory Diseases on Clinical Pharmacokinetics of Antibody-Based Therapeutic Proteins.

Antibody-based therapeutic proteins (TPs) emerged as a promising therapeutic modality for chronic inflammatory diseases. During clinical development, the impact of disease on pharmacokinetics (PK) should be carefully considered to reliably extrapolate PK from healthy volunteers (HVs) in early-phase studies to patients in later-phase studies. This paper aimed to provide an overview of the impact of chronic inflammatory diseases on the PK of antibody-based TPs.

Semi-mechanistic population pharmacokinetic modeling of DZIF-10c, a neutralizing antibody against SARS-Cov-2: predicting systemic and lung exposure following inhaled and intravenous administration.

DZIF-10c (BI 767551) is a recombinant human monoclonal antibody of the IgG1 kappa isotype. It acts as a SARS-CoV-2 neutralizing antibody. DZIF-10c has been developed for both systemic exposure by intravenous infusion as well as for specific exposure to the respiratory tract by application as an inhaled aerosol generated by a nebulizer.

Beyond CL and V: A comprehensive approach to human pharmacokinetic predictions.

This article presents a comprehensive examination of processes related to the prediction of human pharmacokinetics (PK), a crucial task of clinical drug candidate selection. By systematically incorporating in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo PK data with expert judgement, the study achieves high-quality human PK predictions for 40 orally administered compounds from Boehringer Ingelheim's new chemical entity (NCE) portfolio. Overall, the article provides a detailed evaluation of and guidance for a structured process to predict full concentration-time profiles beyond single-parameter predictions, using state-of-the-art methodologies.

Subclassification of obesity for precision prediction of cardiometabolic diseases.

Obesity and cardiometabolic disease often, but not always, coincide. Distinguishing subpopulations within which cardiometabolic risk diverges from the risk expected for a given body mass index (BMI) may facilitate precision prevention of cardiometabolic diseases. Accordingly, we performed unsupervised clustering in four European population-based cohorts (N ≈ 173,000).