Proper regulation of energy metabolism in the brain is crucial for maintaining brain activity in physiological and different pathophysiological conditions. Ischemic stroke has a complex pathophysiology which includes perturbations in the brain energy metabolism processes which can contribute to worsening of brain injury and stroke outcome. Smoking and diabetes are common risk factors and comorbid conditions for ischemic stroke which have also been associated with disruptions in brain energy metabolism. Simultaneous presence of these conditions may further alter energy metabolism in the brain leading to a poor clinical prognosis after an ischemic stroke event. In this review, we discuss the possible effects of smoking and/or diabetes on brain glucose utilization and mitochondrial energy metabolism which, when present concurrently, may exacerbate energy metabolism in the ischemic brain. More research is needed to investigate brain glucose utilization and mitochondrial oxidative metabolism in ischemic stroke in the presence of smoking and/or diabetes, which would provide further insights on the pathophysiology of these comorbid conditions and facilitate the development of therapeutic interventions.

Quantitative Systems Pharmacology (QSP) is increasingly utilized to support the design and translation of gene therapies. This perspective outlines the application of QSP modeling across three domains of gene therapy: mRNA‐based therapeutics, adeno‐associated virus (AAV) vectors, and genome editing systems. We highlight opportunities for dose optimization, biomarker interpretation, and mechanistic understanding, while addressing current limitations in model generalizability, data sparsity, and translational relevance. Examples include QSP platforms for lipid nanoparticle (LNP)‐delivered mRNA, physiologically based pharmacokinetics (PBPK)‐informed AAV biodistribution models, and CRISPR‐Cas9‐based editing systems. These case studies demonstrate QSP's value in de‐risking development and personalizing therapies for rare and complex diseases.

COVID-19’s main protease (Mpro) unique structure and function, which are conserved among coronaviruses, make it an attractive target for viral inhibition. Limnetrelvir is a novel Mpro inhibitor intended for once-daily administration. The pharmacokinetics, safety, and tolerability results of two phase 1 studies of limnetrelvir are reported herein. These studies consisted of a first-in-human, single-, and multiple-ascending dose study in healthy non-Japanese participants and a single- and multiple-dose study in healthy Japanese participants. Across both studies, a total of 104 participants received limnetrelvir single doses ranging from 200 to 800 mg and multiple doses from 200 to 800 mg QD for 10 days. The harmonic mean half-life of limnetrelvir ranged from 6 to 21 h following a single dose. No clinically significant differences in exposures were observed between Japanese and non-Japanese participants. Limnetrelvir was generally well tolerated in both studies in healthy participants with up to 10 days of dosing, with only mild or moderate adverse events observed. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT05691699 and NCT06009237 .

Limnetrelvir is an oral inhibitor of the SARS-CoV-2 main protease (Mpro) and was developed with the aim of achieving broad-spectrum efficacy against SARS-CoV-2 and emerging variants. The aim of this work was to evaluate potential CYP3A4 drug-drug interactions (DDIs) of limnetrelvir. In two phase 1, open-label studies, limnetrelvir was evaluated for DDIs with midazolam (Study 1), a CYP3A4 substrate, and itraconazole (Study 2), a strong CYP3A4 inhibitor. Study 1 (N = 24) consisted of two parts (Studies 1A and 1B), each with two periods (Periods 1 and 2), and Study 2 (N = 12) consisted of one part with two periods. In Study 1A, 12 healthy adult participants received midazolam (1 mg) on Period 1 Day 1 and Period 2 Day 10 and limnetrelvir 400 mg once daily (QD) on Period 2 Days 1-10. In Study 1B, an additional 12 healthy adult participants received midazolam (1 mg) on Period 1 Day 1 and Period 2 Day 5 and limnetrelvir 200 mg QD on Period 2 Days 1-5. In Study 2, 12 participants received limnetrelvir (50 mg) and itraconazole (200 mg twice daily on Day 1 and QD on Days 2 to 6 in Period 2), with limnetrelvir administered as a single dose on Period 1 Day 1 and Period 2 Day 4. All study drugs were administered orally. Serial blood samples were collected and analyzed for drug concentrations. Pharmacokinetic parameters were determined with noncompartmental methods. Coadministration of limnetrelvir increased the maximum concentration (C_max) and area under the concentration-time curve from time 0 to infinity (AUC_inf) of midazolam by ~ 2.4- to 2.6-fold and ~ 4.6- to 4.3-fold, respectively. The pharmacokinetics of the active metabolite, 1-OH-midazolam, demonstrated a decrease in C_max by ~ 0.66-fold at Day 5 and ~ 0.96-fold at Day 10, while overall AUC remained stable at both time points. No clinically significant differences in CYP3A4 inhibition after 5 days and 10 days of limnetrelvir administration were observed. Limnetrelvir C_max and AUC_inf increased by ~ 1.7- and ~ 3.6-fold, respectively, when coadministered with itraconazole, suggesting that limnetrelvir is a moderately sensitive substrate of CYP3A4. Limnetrelvir was found to be a moderate CYP3A4 inhibitor and substrate, suggesting that dosing adjustment or careful monitoring may be necessary when coadministered with medications highly metabolized by CYP3A4 or with strong CYP3A4 inhibitors to ensure safe and effective treatment. NCT05691699, NCT05895266. Date of registration: 01/09/2023, 05/31/2023.