We review a new methodology for deriving pharmacokinetic clearance equations independent of differential equations or mechanistic models of drug disposition. Nine examples are presented that illustrate the application of this framework to drug dosing decisions based on therapeutic monitoring. Although mass balance is necessary and sufficient in deriving in vitro measures and rate constants relevant to in vivo pharmacokinetics, clinical drug dosing decisions are based on clearance, not rate constants. Mass balance is necessary in deriving pharmacokinetic clearance equations, but in vivo it is not always sufficient in determining which processes drive overall clearance. A key implication of this framework is that pharmaceutical sponsors may possibly formulate a dosage form for high-clearance drugs, where the manufactured delivery clearance from the dosage form becomes the in vivo clearance of drug in the patient, independent of the elimination clearance observed following an intravenous bolus dose and independent of the patient-specific characteristics.
Since the identification of PARP1/2 as synthetic lethal targets in BRCA-deficient breast cancer and the subsequent approval of catalytic domain-targeting PARP inhibitors, the landscape of PARP inhibitors has expanded to encompass a broader chemical tool kit. Beyond PARP1/2's canonical role in DNA repair, PARP inhibitors have revealed context-dependent PARP functions in anticancer immunity, viral infection, neurodegeneration, and cellular organization. These discoveries have motivated new strategies that extend past targeting catalytic domains. In this review, we highlight three emerging directions: (a) biological insights revealed by PARP1/2 inhibitors in oncology and other settings, (b) progress in developing inhibitors against PARP family members beyond PARP1/2, and (c) approaches that target noncatalytic domains or modulate PARP function through mechanisms such as interface disruption and targeted degradation. We conclude by outlining key next steps for advancing PARP pharmacology, including substrate mapping, utilizing rational polypharmacology, targeting ADP-ribose readers and erasers, and expanding structural coverage of PARP family proteins.
Monoaminergic signaling controls many aspects of human physiology, including autonomic responses, movement, and emotion. The vesicular monoamine transporters (VMAT1 and VMAT2) sequester monoamines into synaptic vesicles within the central and peripheral nervous system. Dysregulation of VMAT function contributes to neuropsychiatric and neurodegenerative disorders, including Parkinson's disease, depression, and psychostimulant substance abuse. Clinically, VMATs are targeted by the inhibitors tetrabenazine and reserpine, used to treat hyperkinetic movement disorders and hypertension, respectively, while amphetamines exploit VMAT2-mediated dopamine efflux to treat ADHD. Emerging VMAT2-selective compounds such as lobeline derivatives and GZ-11610 attenuate psychostimulant reinforcement. Tricyclic antidepressants upregulate VMAT2 function and rescue disease-causing variants, highlighting VMAT2 as a promising therapeutic target. Despite their importance, the molecular mechanisms driving proton-coupled transport, inhibition, and psychostimulant action remain poorly understood. This review summarizes current biochemical, structural, and functional insights into VMATs, highlighting proton coupling, transport kinetics, inhibition mechanisms, unresolved questions, and future research directions.
For decades, autoimmune disease treatment depended on long-term immunosuppression, which seldom yields lasting immune tolerance and carries cumulative toxic risks. Recent cell therapies, including chimeric antigen receptor (CAR) T cells, regulatory T cells, and mesenchymal stromal cells, have induced deep remission in refractory diseases, often persisting after treatment withdrawal and indicating benefits beyond short-term inflammation suppression. However, traditional dose-exposure-response pharmacokinetic/pharmacodynamic frameworks are insufficient to account for the in vivo expansion, trafficking, and phenotypic evolution of living cellular products. Here we propose that, in autoimmune diseases, cell-based therapies exemplified by CAR T cells should be reframed from exposure-control pharmacology to state-transition pharmacology. Through endogenous expansion and immune networks, therapeutic cells may shift the immune system from a pathological toward a tolerant steady state. Because toxicities may reflect the amplification or persistence of intended mechanisms, future work requires quantitative metrics of immune state transitions and programmable strategies for precise functional control.
Alcohol-associated liver disease (ALD) is a major driver of morbidity and mortality globally, especially in its most severe phenotypes, including alcohol-associated hepatitis (AH), decompensated cirrhosis, and hepatocellular carcinoma. With no US Food and Drug Administration-approved therapies to improve ALD, there is an unmet clinical need to better define the pathophysiology of early and severe liver disease. Recent improvements in preclinical models have furthered our understanding of the mechanisms of disease in advanced ALD. In this review, our focus is on current progress in identifying therapeutic targets utilizing preclinical models and reporting the rationale for and current status of ongoing clinical trials that aim to develop effective therapies to slow the progression of earlier stages of ALD and especially improve survival in severe AH.
Giving old drugs new uses, a process known as drug repurposing, is an attractive strategy for finding therapeutic candidates for a wide number of diseases. In this context, data-driven approaches have emerged as a suitable framework to target this challenge. From molecular docking and network-based methods to omics data integration, computational techniques give invaluable insights into drug repurposing research. In the present review, we describe these methodologies and knowledge-based resources, also emphasizing the new horizons that artificial intelligence and large language models are revealing. A set of case studies illuminate the practical applications of these computational approaches to the identification of repurposing opportunities. By addressing a set of key challenges and proposing future directions, this review aims to be a resource for researchers navigating the multifaceted landscape of computational drug repurposing.
Pregnant and lactating women have historically been excluded from clinical trials, limiting data on drug pharmacokinetics, safety, and efficacy in these populations. This knowledge gap stems from complex ethical, historical, and cultural factors, which previously categorized these women as vulnerable rather than protected participants. Recent legislative frameworks, including the FDA Pregnancy and Lactation Labeling Rule, have catalyzed efforts to include these populations in structured research. Quantitative pharmacology approaches using innovations such as physiologically based pharmacokinetic models support optimized trial designs, safer dosing regimens, and ethical research frameworks. Emerging technologies, including artificial intelligence, novel drug delivery mechanisms, and organ-on-chip models, further enhance insights into maternal-fetal drug exposure and drug exposures in breastfeeding infants. Integrating in vitro, ex vivo, in vivo, and clinical data and modeling approaches improves understanding of pregnancy-related physiological changes and their impact on drug outcomes, ultimately enabling appropriate and equitable pharmacotherapy for pregnant and breastfeeding women.
Microplastics are emerging as mediators in the interaction between environmental pollutants and cardiovascular health. Micro- and nanoplastics (MNPs) can enter the human body through ingestion, inhalation, or skin exposure, disrupting biological processes such as autophagy, inflammation, oxidative stress, immune activation, and vascular dysfunction. Therefore, MNPs might promote the development of cardiovascular diseases. The link between MNPs and cardiovascular diseases remains unclear, with no consistent data confirming a correlation between their concentration in tissues and disease onset. Continuously evolving analytical techniques to detect MNPs within human organs and tissues will help the design of prospective studies detailing the possible harm provided by different microplastics as well as their effects according to their physical properties and associated chemicals. In this review, we provide an update on the existing techniques for MNP detection and characterization to summarize the mechanisms linking these pollutants to human health, focusing on their effects on the cardiovascular system.
Although HIV treatment and prevention efforts in recent decades have significantly reduced new infections and mortality worldwide, progress has been uneven. Regions with the highest prevalence are those where HIV control programs fail to reach key populations, such as people who inject drugs, men who have sex with men, transgender people, and certain ethnic minorities. More specifically, the rollout of proven HIV prevention tools in these populations, such as antiretroviral therapy and pre-exposure prophylaxis, still presents a challenge. Community-based organizations play a key role in facilitating access to testing and treatment, particularly through rapid testing programs and peer support. These initiatives are crucial for overcoming social and cultural barriers, reducing stigma, and ensuring treatment adherence, especially among key populations.
Environmental pollutants such as heavy metals, pesticides, and plastic nanoparticles pose significant risks to human, animal, and environmental health. New approach methodologies complying with the 3R principles (replace, reduce, refine) are essential for advancing the molecular basis of pollutant-induced toxicity, thus improving risk assessment, disease prevention, and therapies. Thanks to its remarkable features, the multicellular organism Caenorhabditis elegans offers unique opportunities to meet this goal. Mitochondria, central hubs in cellular homeostasis, are particularly vulnerable to pollutants, orchestrating stress responses that progress to toxicity and disease. C. elegans represents a powerful model to study these effects, offering conserved systems with quantifiable end points. While previous studies have mainly focused on environmental stressors inducing DNA damage, this review explores C. elegans ’s end points of relevance for mitotoxicology, highlighting advantages and limitations of the system as an alternative approach for in vivo environmental-induced mitochondrial toxicology and diseases.
Volume 66 of the Annual Review of Pharmacology and Toxicology includes numerous articles that reveal evolving ideas and insights in pharmacology and toxicology. The major theme is new approaches, technology and techniques. New ideas include the use of systems biology, multiomics, and artificial intelligence to support wellness, prevention, early detection of disease, and precision medicine. Other reviews highlight new ideas and approaches to treat infectious diseases, including the repurposing of drugs approved for other indications and long-acting therapeutics. Related reviews emphasize aspects of global health. One review discusses psychedelics as therapeutics. Several reviews discuss advances in drug discovery modalities. Others relate to a variety of topics in toxicology, including aspects of mitochondrial biology, e-cigarettes, air pollution, microplastics, and nanoplastics. These reviews and others in this volume inform readers about recent advances in pharmacology and toxicology and show how both specialties continue to be vital for improving health and safety globally.
Precision medicine demands a shift from static, single-analyte diagnostics toward dynamic, systems-level understanding of health and disease. This review explores how the convergence of systems biology, multiomics, and artificial intelligence (AI) redefines biomarker discovery to drive early disease detection and personalized intervention. We highlight pioneering efforts that use longitudinal, multimodal data to map individual health trajectories and uncover early disease signals. Advances in AI, including machine learning and contextualization using knowledge graphs and digital twins, are accelerating clinical translation by enabling predictive, context-aware analyses. Real-world applications, including omics-informed diagnostics and digital health monitoring, demonstrate the potential of this approach to transform health care from reactive treatment to proactive wellness. These technologies also inform the development of targeted therapeutics that intervene earlier, personalize treatment, and potentially halt or reverse disease progression. We outline challenges, emerging solutions, and future directions that position AI-driven systems biology at the center of next-generation precision health.
The global rise of antibiotic-resistant bacteria poses a critical threat to healthcare systems, challenging researchers to stay ahead of evolving pathogens. Among the most concerning are invasive infections caused by Staphylococcus aureus (SA), where morbidity and mortality remain high despite advances in care. Resistance in SA has emerged rapidly after the introduction of new antibiotics, limiting treatment options and prompting an urgent need for alternatives. While developing new antimicrobials remains essential, repurposing FDA-approved drugs—originally developed for noninfectious indications—offers a complementary strategy. These agents have known safety and pharmacokinetic profiles and may impact bacterial virulence, antibiotic susceptibility, or host immunity to improve outcomes. This review highlights recent advances in SA drug repurposing, focusing on six mechanistic categories: inhibition of virulence factors, antibiotic resensitization, enhanced susceptibility to innate immunity, host cell protection, augmentation of immune functions, and modulation of pathological inflammation. Together, these strategies offer a multifaceted framework to improve SA infection outcomes using existing therapeutics.
Growing evidence points to mitochondria as not just the “powerhouse of the cell” but as a major cellular hub for signaling. Mitochondria use signaling pathways to communicate with other organelles within the cell or organs within an organism to regulate stress response, metabolic, immune, and longevity pathways. These communication pathways are carried out by mitokine signaling molecules encompassing metabolites, lipids, proteins, and even whole mitochondrial organelles themselves. In this review, we focus on the communication pathways mitochondria use to communicate between different organs in invertebrates, mammalian models, and humans. We cover the molecular events that trigger communication, the signaling mechanisms themselves, and the impact this communication has on organismal health in the context of stress and disease. Further understanding of cross-organ mitochondrial communication pathways will inform the design of therapeutics that take advantage of their protective effects to treat diseases associated with mitochondrial dysfunction.
African populations remain largely underrepresented in genomic studies despite their high genetic diversity. The significant variability in drug efficacy and toxicity across different ancestry populations should trigger more diversified and inclusive pharmacogenomic (PGx) studies. Non-European populations, especially Africans, remain largely underrepresented in GWASs and other genomic studies despite their high genetic diversity, which holds information critical for better understanding drug-related toxicity and enhancing the development of new drugs. Therefore, studies using population genetic clustering, polygenic risk scores, high-throughput organoid models, and multiomics analysis are urgently needed in African populations to enhance pharmacogenomics and drug development globally. For instance, studies of loss-of-function mutations in PCSK9 , commonly found in populations of African descent, have led to the development of PCSK9 inhibitors, which are used globally to reduce hypercholesterolemia and cardiovascular disease risk. More studies on diverse African populations could elevate PGx, drug development, and therapeutics as illustrated by the PCSK9 example.
Here I highlight personal and professional experiences that shaped my career and defined my scientific journey, with my longtime colleague, Ermelinda Porpiglia. I hope that sharing my life's adventures will inspire others to enjoy both a fulfilling scientific career and the fruits of parenthood. I have always enjoyed addressing big questions and challenging dogma. In my early career I probed cell plasticity, challenging the dogma that a cell's specialized state is fixed and irreversible. I then sought to understand stem cells, crucial to tissue repair. Most recently, my lab discovered a gerozyme, 15-prostaglandin dehydrogenase (15-PGDH), a master regulator of muscle aging, and showed that muscle tissue is rejuvenated and strengthened when the gerozyme is inhibited with a small-molecule drug. It would be a dream come true if this discovery in my lab becomes a treatment for the debilitating muscle wasting arising from disuse, disease, or aging.
We explore three emerging molecular pathways driving neuroinflammation in chronic and acute brain diseases: the EP2 receptor for prostaglandin E2, the CCR2 receptor for chemokine CCL2, and JAK/STAT signaling. Inflammation is now recognized as a causative factor in neurodegenerative disorders, with neuroinflammation preceding symptom onset in Alzheimer's disease and likely heralding the onset of epilepsy and Parkinson's disease. The EP2 receptor modulates immune cell activation and exacerbates inflammatory responses, while CCR2 regulates peripheral immune cell recruitment to sites of brain inflammation. JAK/STAT pathways regulate neuronal and glial function across brain regions and can both amplify and resolve neuroinflammatory processes. These three signaling pathways converge at multiple nodes—immune cell recruitment, cytokine amplification, and transcriptional regulation—establishing feedforward loops that sustain pathology in chronic diseases. Understanding these mechanisms and their complex interactions provides opportunities for novel therapeutic interventions in neurological conditions characterized by inflammation, potentially leading to disease-modifying treatments.
Long-acting (LA) therapeutics have emerged as a key component of infectious disease treatment and prevention strategies, their uptake fueled by the need to bridge notable gaps with short-acting drug formulations. In this review, we present the key drivers and summarize the enabling technologies. Focusing on infections with significant global disease burden (HIV, hepatitis B and C, tuberculosis, malaria, and COVID-19), the current state of knowledge on approved LA therapeutics and promising innovations currently in development are summarized. The potential role of LA therapeutics as countermeasures for diseases of pandemic potential and new approaches using computational modeling to accelerate their development for pediatric and perinatal health are discussed. Due to complexities in manufacturing, and the diversity of patent-protected technologies, barriers exist for global access to LA products and in upscaling intricate LA formulations. A multipronged strategic framework, including acceleration of equitable access through generic product manufacture, is proposed to realize the full potential of LA therapeutics for global health.
Atrial fibrillation (AF) is a common arrhythmia with a tremendous impact on quality of life and mortality. Its prevalence continues to rise alongside the increasing obesity and type 2 diabetes epidemics, raising a need for improved therapeutic strategies and a better understanding of the factors and mechanisms that drive metabolic disease-associated AF. To this end, the link between AF and metabolic disease is being increasingly explored in observational, clinical, and experimental studies. Chronic inflammation is a hallmark of metabolic disease, and multiple studies have also demonstrated a strong relationship between AF and inflammation. In this review, we discuss recent advances in our understanding of the mechanisms governing the development of AF in the context of metabolism and inflammation, related concepts in therapeutic development, and a novel role for calcitonin in AF.
In light of the success of blockbuster drugs for type 2 diabetes and obesity based on the GLP-1 hormone, drugmakers have concentrated their efforts on developing new and improved variations that address the route of administration, dosing, pathway selectivity, or polypharmacology. While some of these modifications have demonstrated improved efficacy in clinical studies and offered exciting opportunities for treating other diseases, drug-induced shifts to the conformational landscape of target receptors may have consequences for side effects. Our review summarizes advances in the understanding of the biochemistry, pharmacogenomics, and molecular pharmacology of incretins and their cognate receptors. We further highlight the current landscape of incretin mimetics and discuss how differences in compartmentalized pathway selectivity affect drug action and outcomes.
