Static Versus Dynamic Model Predictions of Competitive Inhibitory Metabolic Drug-Drug Interactions via Cytochromes P450: One Step Forward and Two Steps Backwards.

Background: Predicting metabolic drug-drug interactions (DDIs) via cytochrome P450 enzymes (CYP) is essential in drug development, but controversy has reemerged recently about whether in vitro-in vivo extrapolation (IVIVE) using static models can replace dynamic models for some regulatory filings and label recommendations.

Objective: The aim of this study was to determine if static and dynamic models are equivalent for the quantitative prediction of metabolic DDIs arising from competitive CYP inhibition.

Methods: Drug parameter spaces were varied to simulate 30,000 DDIs between hypothetical substrates and inhibitors of CYP3A4.

Safety, clinical activity, pharmacodynamics, and pharmacokinetics of IMU-856, a SIRT6 modulator, in coeliac disease: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial.

Background: IMU-856 is an orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6), a protein that serves as a transcriptional regulator of bowel epithelium regeneration. We aimed to evaluate the safety, clinical activity, pharmacodynamics, and pharmacokinetics of IMU-856 in healthy participants and in patients with coeliac disease.

Methods: This study reports the results from a completed first-in-human, three-part, double-blind, randomised, placebo-controlled, clinical trial of IMU-856 in healthy participants and patients with coeliac disease done in Australia and New Zealand.

Personality vulnerabilities and adverse event reporting in phase 1 clinical studies.

Background: Phase 1 clinical trials involve rigorous safety monitoring to identify any adverse effects of investigational treatments. There is growing evidence that healthy volunteers recruited in these studies may differ with respect to personality traits from the general population. This, in turn, may have a significant impact on the reporting of adverse events, particularly in trials investigating psychoactive treatments, including the psychedelic substances.

Impact of Food on the Oral Absorption of N-Acetyl-D-Mannosamine in Healthy Men and Women.

N-Acetyl-D-mannosamine (ManNAc) is an endogenous monosaccharide and precursor of N-acetylneuraminic acid (Neu5Ac), a critical sialic acid. ManNAc is currently under clinical development to treat GNE myopathy, a rare muscle-wasting disease. In this randomized, open-label, 2-sequence, crossover study, 16 healthy women and men were administered a single oral dose of ManNAc under fasting and fed conditions.

Phase 1 study of the iodine absorption, safety, and tolerability of a 0.5% povidone-iodine nasal spray (Nasodine).

PVP-I is a widely used antiseptic but only recently proposed for intranasal use. The extent of iodine absorption from available PVP-I nasal products is unknown. Iodine absorption from use of Nasodine (0.

A phase I trial of SON-1010, a tumor-targeted, interleukin-12-linked, albumin-binding cytokine, shows favorable pharmacokinetics, pharmacodynamics, and safety in healthy volunteers.

Background: The benefits of recombinant interleukin-12 (rIL-12) as a multifunctional cytokine and potential immunotherapy for cancer have been sought for decades based on its efficacy in multiple mouse models. Unexpected toxicity in the first phase 2 study required careful attention to revised dosing strategies. Despite some signs of efficacy since then, most rIL-12 clinical trials have encountered hurdles such as short terminal elimination half-life (T), limited tumor microenvironment targeting, and substantial systemic toxicity.

Beyond Population-Level Targets for Drug Concentrations: Precision Dosing Needs Individual-Level Targets that Include Superior Biomarkers of Drug Responses.

The purpose of precision dosing is to increase the chances of therapeutic success in individual patients. This is achieved in practice by adjusting doses to reach precision dosing targets determined previously in relevant populations, ideally with robust supportive evidence showing improved clinical outcomes compared with standard dosing. But is this implicit assumption of translatable population-level precision dosing targets correct and the best for all patients? In this review, the types of precision dosing targets and how they are determined are outlined, problems with the translatability of these targets to individual patients are identified, and ways forward to address these challengers are proposed.

Pharmacogenomics - a minor rather than major force in clinical medicine.

Introduction: Pharmacogenomics (PGx) is touted as essential for the future of precision medicine. But the opportunity cost of PGx from the prescribers' perspective is rarely considered. The aim of this article is to critique PGx-guided prescribing using clinical pharmacology principles so that important cases for PGx testing are not missed by doctors responsible for therapeutic decision making.

Virtual twins for model-informed precision dosing of clozapine in patients with treatment-resistant schizophrenia.

Model-informed precision dosing using virtual twins (MIPD-VTs) is an emerging strategy to predict target drug concentrations in clinical practice. Using a high virtualization MIPD-VT approach (Simcyp version 21), we predicted the steady-state clozapine concentration and clozapine dosage range to achieve a target concentration of 350 to 600 ng/mL in hospitalized patients with treatment-resistant schizophrenia (N = 11). We confirmed that high virtualization MIPD-VT can reasonably predict clozapine concentrations in individual patients with a coefficient of determination (R ) ranging between 0.

First-in-human single-dose study of nizubaglustat, a dual inhibitor of ceramide glucosyltransferase and non-lysosomal glucosylceramidase: Safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending and multiple doses in healthy adults.

Nizubaglustat is a novel, orally available, brain penetrant, potent, and selective dual inhibitor of ceramide glucosyltranferase and non-lysosomal neutral glucosylceramidase (NLGase), which is currently under development for the treatment of subjects with neurological manifestations in primary and secondary gangliosidoses. The objectives of this first-in-human study were to evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics (PD) of single oral doses of nizubaglustat after single (1, 3, and 9 mg) and multiple oral doses (9 mg once per day (QD) over 14 days) in healthy adults. Nizubaglustat was rapidly absorbed and systemic exposure was dose-proportional.

Virtual twin for healthcare management.

Healthcare is increasingly fragmented, resulting in escalating costs, patient dissatisfaction, and sometimes adverse clinical outcomes. Strategies to decrease healthcare fragmentation are therefore attractive from payer and patient perspectives. In this commentary, a patient-centered smart phone application called Virtual Twin for Healthcare Management (VTHM) is proposed, including its organizational layout, basic functionality, and potential clinical applications.

Drug-drug interactions that alter the exposure of glucuronidated drugs: Scope, UDP-glucuronosyltransferase (UGT) enzyme selectivity, mechanisms (inhibition and induction), and clinical significance.

Drug-drug interactions (DDIs) arising from the perturbation of drug metabolising enzyme activities represent both a clinical problem and a potential economic loss for the pharmaceutical industry. DDIs involving glucuronidated drugs have historically attracted little attention and there is a perception that interactions are of minor clinical relevance. This review critically examines the scope and aetiology of DDIs that result in altered exposure of glucuronidated drugs.

Calculation of the pharmacogenomics benefit score for patients with medication-related problems.

Unexpected poor efficacy and intolerable adverse effects are medication-related problems that may result from genetic variation in genes encoding key proteins involved in pharmacokinetics or pharmacodynamics. Pharmacogenomic (PGx) testing can be used in medical practice "pre-emptively" to avoid future patient harm from medications and "reactively" to diagnose medication-related problems following their occurrence. A structured approach to PGx consulting is proposed to calculate the pharmacogenomics benefit score (PGxBS), a patient-centered objective measure of congruency between medication-related problems and patient genotypes.

The PRESIDE (PhaRmacogEnomicS In DEpression) Trial: a double-blind randomised controlled trial of pharmacogenomic-informed prescribing of antidepressants on depression outcomes in patients with major depressive disorder in primary care.

Background: The evidence for the clinical utility of pharmacogenomic (PGx) testing is growing, and guidelines exist for the use of PGx testing to inform prescribing of 13 antidepressants. Although previous randomised controlled trials of PGx testing for antidepressant prescribing have shown an association with remission of depression in clinical psychiatric settings, few trials have focused on the primary care setting, where most antidepressant prescribing occurs.

Methods: The PRESIDE Trial is a stratified double-blinded randomised controlled superiority trial that aims to evaluate the impact of a PGx-informed antidepressant prescribing report (compared with standard prescribing using the Australian Therapeutic Guidelines) on depressive symptoms after 12 weeks, when delivered in primary care.

Safety, Tolerability, and Pharmacokinetics of IMU-935, a Novel Inverse Agonist of Retinoic Acid Receptor-Related Orphan Nuclear Receptor γt: Results From a Double-Blind, Placebo-Controlled, First-in-Human Phase 1 Study.

Retinoic acid receptor-related orphan nuclear receptor (ROR)γt regulates the transcription of interleukin-17 and other cytokines implicated in inflammatory and autoimmune diseases. We assessed the safety, tolerability, and pharmacokinetics (PK) of IMU-935, an inverse agonist of RORγt, in a first-in-human phase 1 study. This was a double-blind, placebo-controlled trial that randomly assigned healthy subjects single ascending doses (25-400 mg) or multiple ascending doses (150 mg once or twice daily for 14 days) of IMU-935 or placebo.

Delineating gene-environment effects using virtual twins of patients treated with clozapine.

Studies that focus on individual covariates, while ignoring their interactions, may not be adequate for model-informed precision dosing (MIPD) in any given patient. Genetic variations that influence protein synthesis should be studied in conjunction with environmental covariates, such as cigarette smoking. The aim of this study was to build virtual twins (VTs) of real patients receiving clozapine with interacting covariates related to genetics and environment and to delineate the impact of interacting covariates on predicted clozapine plasma concentrations.

Pharmacogenomics in psychiatry - the challenge of cytochrome P450 enzyme phenoconversion and solutions to assist precision dosing.

Pharmacogenomic (PGx) testing of cytochrome P450 (CYP) enzymes may improve the efficacy and/or safety of some medications. This is facilitated by increased availability and affordability of genotyping, the development of clinical practice PGx guidelines and regulatory support. However, the common occurrence of CYP phenoconversion, a mismatch between genotype-predicted CYP phenotype and the actual CYP phenotype, currently limits the application of PGx testing for precision dosing in psychiatry.

Liquid Biopsy for Patient Characterization in Cardiovascular Disease: Verification against Markers of Cytochrome P450 and P-Glycoprotein Activities.

Precision dosing strategies require accounting for between-patient variability in pharmacokinetics together with subsequent pharmacodynamic differences. Liquid biopsy is a valuable new approach to diagnose disease prior to the appearance of clinical signs and symptoms, potentially circumventing invasive tissue biopsies. However, the possibility of quantitative grading of biomarkers, as opposed to simply confirming their presence or absence, is relatively new.

Attitudes of healthy volunteers to genetic testing in phase 1 clinical trials.

Genetic testing in clinical trials introduces several ethical and logistical issues to discuss with potential participants when taking informed consent. The aim of this study was to explore the attitudes of healthy volunteers in phase 1 studies to the topics of genetic security, genetic privacy and incidental genetic findings. Healthy volunteers presenting for screening appointments at a phase 1 clinical trial unit (CMAX Clinical Research, Adelaide, Australia) took an anonymous paper survey about genetic testing.

Combining Therapeutic Drug Monitoring and Pharmacokinetic Modelling Deconvolutes Physiological and Environmental Sources of Variability in Clozapine Exposure.

Clozapine is a key antipsychotic drug for treatment-resistant schizophrenia but exhibits highly variable pharmacokinetics and a propensity for serious adverse effects. Currently, these challenges are addressed using therapeutic drug monitoring (TDM). This study primarily sought to (i) verify the importance of covariates identified in a prior clozapine population pharmacokinetic (popPK) model in the absence of environmental covariates using physiologically based pharmacokinetic (PBPK) modelling, and then to (ii) evaluate the performance of the popPK model as an adjunct or alternative to TDM-guided dosing in an active TDM population.