The Journal of Clinical Pharmacology最新文献

{"title":"Dose Selection for Ceftibuten Combined with Avibactam Tomilopil, a Potential Oral Alternative to Carbapenems for Patients with Complicated Urinary Tract Infections","authors":"Siddhee A. Sahasrabudhe MS, PhD,&nbsp;Satoshi Shoji PhD,&nbsp;Abhijeet S. Jakate PhD,&nbsp;Bisrat K. Abraham MD, MPH,&nbsp;Sima S. Toussi MD,&nbsp;Benjamin J. Maligalig MPH,&nbsp;Amanda S. Darekar MSc,&nbsp;Sakambari Tripathy MSc, MPhil,&nbsp;Constantino Kantaridis MD, DPM,&nbsp;Josue K. Mfopou MD, PhD, DPM,&nbsp;Oxana Selivanova PhD,&nbsp;Arthur Bergman PhD,&nbsp;Negar Niki Alami MD,&nbsp;Ravi Shankar P. Singh PhD, FCP","doi":"10.1002/jcph.70263","DOIUrl":"https://doi.org/10.1002/jcph.70263","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>There are currently no oral treatment options for infections caused by extended spectrum β‑lactamase-producing Enterobacterales. Avibactam tomilopil, a novel oral prodrug of avibactam, is being developed in combination with the oral cephalosporin, ceftibuten, as a potential treatment for patients with complicated urinary tract infections (cUTIs). The safety, tolerability, and pharmacokinetic profiles of single and multiple doses of avibactam tomilopil (900 to 1350 mg) and ceftibuten (400 to 1600 mg), alone and/or in combination were evaluated in three Phase 1 trials in healthy participants. Avibactam tomilopil was rapidly metabolized to active avibactam and plasma avibactam exposure increased proportionately with dose. Both avibactam and cis-ceftibuten had similar plasma half-lives, and were predominantly renally excreted. While there was negligible food effect on ceftibuten exposures, plasma avibactam exposure in the fed state for a fixed-dose combination ceftibuten-avibactam tomilopil tablet was higher compared with the fasted state. Based on joint probability of target attainment simulations using a simultaneous oral ceftibuten‑avibactam tomilopil population pharmacokinetic model, a tablet formulation ceftibuten 400 mg + avibactam tomilopil 1200 mg dosed every 8 h without regard to food is proposed for Phase 3 evaluation in adult patients with cUTIs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <p>Trial registration: NCT03931876; NCT05554237; NCT06593054.</p>\u0000 </section>\u0000 </div>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70263","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PBPK-Based Prediction of Oliceridine Exposure in Breast Milk and Relative Infant Dose During the First 24 h After Cesarean Delivery","authors":"Yixi Ding BS,&nbsp;Ke Liu BS,&nbsp;Shuaishuai Zhang BS,&nbsp;Yanxu Zhang MS,&nbsp;Xin Tan BS,&nbsp;Weimin Xu MS","doi":"10.1002/jcph.70228","DOIUrl":"https://doi.org/10.1002/jcph.70228","url":null,"abstract":"<p>Oliceridine is an intravenous opioid analgesic for postoperative pain control, but data on transfer into human milk and infant exposure during early breastfeeding remain limited. This study used a postpartum physiologically based pharmacokinetic (PBPK) framework to estimate oliceridine milk exposure and relative infant dose (RID) on postoperative Day 1 (0-24 h) after cesarean delivery under a reconstructed patient-controlled intravenous analgesia regimen. Maternal plasma exposure was simulated in PK-Sim; milk exposure was extrapolated using an externally specified milk-to-plasma ratio (M/P). RID was calculated from mean milk concentration, infant milk intake, and the maternal weight-normalized daily dose. An exposure scaling factor from an independent adult intravenous reference scenario was applied only as a post hoc proportional correction to RID. Morphine benchmarking assessed the physiological plausibility of the M/P extrapolation step, and a 4-24 h temporal sensitivity check examined the influence of the initial accumulation phase. In the base case, maternal plasma AUC over 0-24 h was 120.59 ng·h/mL; mean plasma and milk concentrations were both 5.025 ng/mL. The uncorrected model-predicted RID was 0.375%, and the ESF-corrected RID was 0.307%, both below the empirical 10% reference threshold. In one-way sensitivity analysis, M/P and infant milk intake had greater effects on corrected RID than maternal body weight within the prespecified ranges. The maximum corrected RID was 0.818% in the two-way scan and 1.235% under the prespecified high-exposure scenario. These findings provide a preliminary, assumption-bounded quantitative reference for modeled relative infant exposure under prespecified postoperative Day 1 extrapolation assumptions.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simulation-Based Evaluation of Busulfan Sampling Strategies in Adults and Adolescents Undergoing Allogeneic Hematopoietic Stem Cell Transplantation","authors":"Zhiyuan Tan PhD,&nbsp;Federica R. Achini-Gutzwiller MD, PhD,&nbsp;Arjan C. Lankester MDPhD,&nbsp;Joost G. K. van der Hem MD,&nbsp;Peter A. von dem Borne MD, PhD,&nbsp;Dirk Jan. A. R. Moes PharmD, PhD,&nbsp;Tim Preijers PharmD, PhD","doi":"10.1002/jcph.70281","DOIUrl":"https://doi.org/10.1002/jcph.70281","url":null,"abstract":"<p>Busulfan, used in hematopoietic stem cell transplantation, exhibits a narrow therapeutic index and high pharmacokinetic (PK) variability. Therapeutic drug monitoring (TDM) is currently employed to achieve target exposure. However, there is no consensus on an optimal limited sampling strategy (LSS) for busulfan on the once-daily (QD) regimen. A virtual cohort of adult patients (n = 1000) receiving OD intravenous busulfan 3.2 mg/kg as a 3-h infusion was generated by Monte Carlo simulation using three published busulfan population PK models. For each one- and two-sample LSS, individual PK parameters were estimated from Day-1 sample(s) by maximum a posteriori Bayesian estimation and used to estimate the 4-day cumulative AUC. A model-informed precision-dosing (MIPD) analysis quantified the target-attainment benefit of TDM per design. The best-performing designs were validated in an external cohort (n = 37) with adults and adolescents. Across all three models, a two-sample early-plus-late schedule was the most informative, and the recommended two-sample design was 3 and 7 h after the start of infusion. TDM guided by a well-chosen LSS approximately doubled cumulative-target attainment, whereas a single early 3-h sample was markedly weaker. In the external cohort, two-sample designs recovered the cumulative 4-day AUC to ∼5%–8% MAPE versus ∼11%–13% for a single 3-h sample. For OD intravenous busulfan in adults and adolescents, a two-sample schedule at 3 and 7 h after the start of infusion supports the correct dosing decision and, through MIPD-guided dose adjustment, approximately doubles target attainment; a single 6-h sample is a simpler but less robust alternative.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70281","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-Acting Injectable Antiretroviral Therapies for HIV Treatment and Prevention: Clinical Pharmacology, Recent Advances and Future Opportunities","authors":"Alexandra Dunbar MS,&nbsp;Natella Rakhmanina MD, PhD, FAAP, FCP, AAHIVS,&nbsp;Justin Unternaher MPH,&nbsp;Peter L. Anderson PharmD,&nbsp;Kristina M. Brooks PharmD, FCP","doi":"10.1002/jcph.70249","DOIUrl":"10.1002/jcph.70249","url":null,"abstract":"<p>Long-acting (LA) antiretroviral (ARV) medications represent a significant advancement in the HIV treatment and prevention field. LA ARVs help reduce daily pill burden and thus optimize adherence, which has translated into sustained virologic suppression in persons with HIV, prevention of HIV transmission among those at risk, and improved patient satisfaction. This review examines the clinical pharmacology considerations, clinical trials, and real-world use of small molecule LA injectable ARVs, specifically cabotegravir, rilpivirine, and lenacapavir, in adults with or at risk of acquiring HIV, with a particular focus on the pharmacokinetic data and considerations with these agents as implementation expands. Special attention is also paid to understudied populations such as pediatrics and pregnant and breastfeeding women. Discussion of the underlying pharmacokinetics is provided to highlight considerations regarding time to onset of protection, handling residual concentrations and the potential for the development of resistance with treatment discontinuation, factors contributing to variability in drug exposure and relationships between exposure and efficacy. Despite the promise that these LA injectable ARVs hold, there are still opportunities for further investigation to optimize patient care, and these considerations are also covered.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148814658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Neonatal Drug Development Through Industry–Academic Collaboration","authors":"Rangasamy Ramanathan MD,&nbsp;Jacob V. Aranda MD,&nbsp;Daniele De Luca MD,&nbsp;Victoria Niklas MD","doi":"10.1002/jcph.70273","DOIUrl":"10.1002/jcph.70273","url":null,"abstract":"&lt;p&gt;A recent review on the future of neonatology published by &lt;i&gt;The Lancet Child &amp; Adolescent Health Commission&lt;/i&gt; focused on addressing the challenges in advancing health outcomes for infants in their first month of life, which the authors rightly consider a public health problem.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; To address the inherent challenges in neonatal drug development, the Commission made several key recommendations. This included fostering cross-disciplinary collaborations and engaging key opinion leaders in neonatal clinical pharmacology to leverage preclinical and translational data derived from studies of diseases with comparable biological and pathophysiological characteristics. To strengthen funding support for preclinical and translational research aimed at elucidating the mechanisms underlying neonatal diseases, and thereby improving the evidence base for research and development decision-making. It further recommended that neonatal disorders be recognized as orphan areas to encourage investment and innovation. The prioritization of clinical studies involving repurposed drugs through active collaboration and dialogue with experts in the field was also strongly endorsed.&lt;/p&gt;&lt;p&gt;Importantly, the Commission recognized that a potentially critical factor in realizing these recommendations is industry–academic partnerships to overcome insufficient funding in neonatology drug development and research. More specifically, the Commission proposed that the pharmaceutical industry should revise internal compliance directives in close collaboration with neonatologists to ensure alignment with the unique ethical and clinical considerations of neonatal research and care. It further suggested that strategic priorities be established through structured engagement and dialogue with key opinion leaders in the field of neonatology.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; We strongly endorse these recommendations and advocate that the industry has played a vital, irreplaceable role in drug development in neonatology. Herein, we showcase industry–academic partnerships that have driven major innovations in neonatology and describe how they can be a template for further success to deliver on the Commission's recommendations.&lt;/p&gt;&lt;p&gt;Despite less industry-sponsored drug development in neonatology than in many other fields, such investment has enabled important breakthroughs, including the development and global adoption of surfactant&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; and caffeine.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; Surfactant was the first drug specifically developed for the treatment of neonates and reduced neonatal mortality and pulmonary air leaks by about 50%.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; In the United States alone, the introduction of surfactant was associated with a 6% reduction in infant mortality.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Caffeine can also be considered one of the most cost-beneficial and effective therapies in the newborn. It has been demonstrated that premature infants who receive caf","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148814630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic/Pharmacodynamic Translation and Model-Informed Drug Development for Oligonucleotide Therapeutics","authors":"Paridhi Gupta PhD,&nbsp;Mindy Magee PharmD,&nbsp;Vivaswath S. Ayyar PhD","doi":"10.1002/jcph.70267","DOIUrl":"10.1002/jcph.70267","url":null,"abstract":"<p>Small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) have emerged as clinically validated therapeutic modalities, with approvals and late-stage development programs spanning rare genetic, neurologic, cardiovascular, metabolic, and infectious diseases. Despite these advances, oligonucleotide development presents unique challenges compared with small molecules and biologics, including rapid plasma distributive clearance, nuclease-mediated degradation, limited extrahepatic distribution, and prolonged pharmacodynamic effects driven by tissue retention and intracellular mechanisms such as RNA-induced silencing complex loading or RNase H-mediated activity. Consequently, tissue disposition and intracellular pharmacology most often govern therapeutic response more directly than plasma exposures alone, complicating conventional approaches to dose selection, efficacy prediction, and safety assessment. Model-informed drug development (MIDD) offers a quantitative framework to address these challenges through integration of preclinical, translational, and clinical data into empirical, mechanistic, and systems-level models. This review summarizes current and emerging MIDD applications in oligonucleotide therapeutics, with primary emphasis on siRNAs and complementary insights from ASOs. Approaches discussed include empirical and semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) models, physiologically based pharmacokinetic (PBPK) frameworks describing tissue-selective biodistribution and intracellular disposition, and quantitative systems pharmacology (QSP) models linking molecular target modulation with downstream biologic and clinical responses. Collectively, these approaches have supported cross-species translation; human dose selection; clinical trial optimization; and mechanistic understanding of oligonucleotide absorption, distribution, metabolism, excretion, and pharmacology. Finally, we discuss future opportunities and remaining challenges for MIDD in oligonucleotide therapeutics, including enabling extrahepatic delivery, characterizing interindividual variability, and integrating systems-level and data-driven approaches to improve translational predictability and accelerate development of next-generation oligonucleotide medicines.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Pharmacology of Eplontersen, the First Approved GalNAc-Conjugated Antisense Oligonucleotide","authors":"Rosie Z. Yu PhD,&nbsp;John K. Diep PharmD,&nbsp;Xiang Gao PhD,&nbsp;Cecilia Arfvidsson PhD,&nbsp;Angelica Quartino PhD","doi":"10.1002/jcph.70276","DOIUrl":"10.1002/jcph.70276","url":null,"abstract":"<p>Eplontersen is a GalNAc-conjugated antisense oligonucleotide (ASO) approved for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN). GalNAc conjugation enables targeted hepatic delivery and improved potency compared with unconjugated ASOs. The clinical pharmacology of eplontersen was characterized by using in vitro studies and data from three Phase 1 studies in healthy participants and one pivotal Phase 3 study in patients with ATTRv-PN. Following subcutaneous administration, eplontersen was rapidly absorbed and exhibited a biphasic pharmacokinetic (PK) profile with a terminal half-life of approximately 3 weeks, supporting once-monthly dosing. Eplontersen is highly plasma protein‑bound, distributes predominantly within the plasma compartment before receptor‑mediated tissue uptake, and is eliminated mainly via nuclease‑mediated metabolism, with minimal renal excretion of intact drug. Across integrated population PK/PKPD and exposure–response analyses at 45 mg Q4W, eplontersen exhibits predictable PK, robust PD, exposure-independent efficacy within the achieved range, and no exposure-dependent safety signals. Albeit some covariates were identified as statistically significant for population PK and population PKPD models, they were not considered clinically meaningful when taking into account the overall variability in PK, their minimal impact on TTR reduction, and the therapeutic window for eplontersen. These findings support that 45 mg Q4W is appropriate for patients with ATTRv-PN without the need for dose modification. In vitro and model-based analyses indicate low potential for clinically relevant plasma protein binding displacement and CYP- or transporter-mediated drug–drug interactions, and demonstrate no clinically meaningful effects on the QT prolongation and a predominantly non-neutralizing anti-drug antibody profile without impact on efficacy or safety.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-In-Human Evaluation of the Pharmacokinetics, Pharmacodynamics, and Safety of Tilpisertib Fosmecarbil (GS-5290), an Oral Prodrug of a Tumor Progression Locus 2 Inhibitor in Healthy Participants","authors":"Priyanka A. Madia PhD,&nbsp;Emily R. Wendt PhD,&nbsp;Ann Ran-Ran Qin MSc, MBA,&nbsp;Xin Qi PhD,&nbsp;Yan Liang PhD,&nbsp;Shital Kalariya MD,&nbsp;Frank Hong MD, PhD,&nbsp;Eda Canales PhD,&nbsp;James G. Taylor PhD,&nbsp;Udayasankar Arulmani MD, Msc, PhD,&nbsp;Tarundeep Kakkar PhD","doi":"10.1002/jcph.70269","DOIUrl":"10.1002/jcph.70269","url":null,"abstract":"<p>Tilpisertib fosmecarbil (TIP; GS-5290) is an intestinally cleaved prodrug of GS-4875, a potent tumor progression locus 2 (TPL2) inhibitor being investigated for ulcerative colitis (UC). The pharmacokinetics, pharmacodynamics, and safety of single or multiple (over 10 days) oral doses of TIP (N = 73; 75-1500 mg) or GS-4875 (N = 82; 15-450 mg) were assessed in two randomized, placebo-controlled studies in healthy participants. A third study (N = 32) assessed the renal effects of GS-4875 (300 mg daily) due to observed serum creatinine increases. TIP was generally undetectable in plasma after administration, indicating rapid conversion to GS-4875. GS-4875 had a half-life of 19-29 h after TIP administration and exposure was greater than with mg-equivalent doses of GS-4875 (population mean [90% CI] AUC_tau slope: 0.72 [0.59-0.85] versus 0.57 [0.47-0.67]). Inhibition of lipopolysaccharide-stimulated phosphorylated extracellular signal-regulated kinase (a TPL2 pathway pharmacodynamic biomarker) 24 h post last dose was greater with TIP versus GS-4875 dosing (&gt;90% [TIP 300-900 mg] versus 75-80% [GS-4875 450 mg]). Investigator-assessed, study drug-related adverse events (AEs) occurred in 9.3% (5/54) of TIP recipients and 5.3% (1/19) of placebo recipients (all grade 1 severity). No serious AEs or deaths occurred. GS-4875 and TIP reduced creatinine-based estimated glomerular filtration rate (GFR; day 10 baseline-adjusted geometric least-squares means ratio [90% CI] for GS-4875/placebo: 83.3% [79.2-87.5%]); this was attributed to renal transporter inhibition rather than GFR impairment as cystatin C- and iohexol-based GFR were unchanged. These data support further development of TIP in an ongoing phase 2 trial in UC (NCT06029972).</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of Model-Informed Approaches in Neuroscience Drug Development and Regulatory Decision-Making","authors":"Michael Bewernitz PhD,&nbsp;Anantha Ram Nookala PhD,&nbsp;Gopichand Gottipati PhD FCP,&nbsp;Praveen Balimane PhD,&nbsp;Venkateswaran C. Pillai PhD,&nbsp;Jeffry Florian PhD,&nbsp;Adarsh Gandhi PhD,&nbsp;Kevin Krudys PhD,&nbsp;David Lee PhD,&nbsp;Dawei Li PhD,&nbsp;Min Li PhD,&nbsp;Zhihua Li PhD,&nbsp;Jie Liu PhD,&nbsp;Rajanikanth Madabushi PhD,&nbsp;Grimstein Manuela PhD,&nbsp;Mehul Mehta PhD,&nbsp;Srikanth C. Nallani PhD,&nbsp;Nimishraj Panse PhD,&nbsp;Wei Qiu PhD,&nbsp;Sreedharan Sabarinath PhD FCP,&nbsp;Vishnu Sharma PhD,&nbsp;Li Tan PhD,&nbsp;Ramana Uppoor PhD,&nbsp;Yun Xu PhD,&nbsp;Hao Zhu PhD,&nbsp;Venkatesh Atul Bhattaram PhD","doi":"10.1002/jcph.70272","DOIUrl":"10.1002/jcph.70272","url":null,"abstract":"<p>Model-informed drug development (MIDD) approaches are being increasingly used in neuroscience drug development programs and regulatory decision-making. In this work, the authors summarize a select set of cases in neurology, psychiatry, addiction, anesthesia, and analgesia, where MIDD approaches were utilized to address critical drug development questions or fill knowledge gaps. These examples include efficacy considerations such as biomarker-clinical endpoint relationships, surrogate endpoints for accelerated approval, extrapolation of efficacy, and safety aspects such as informing driving studies. Additionally, the examples also inform optimal dosing regimen selection, dose adjustments in drug interactions, life cycle management decisions such as indication expansion, formulation switching, and informing patient population selection. Together, these examples offer insights into the utility of MIDD approaches to streamline drug development and opportunities to save costs and resources.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Review of Semi-Mechanistic HbA1c Models in People with Type 2 Diabetes: Strengths, Limitations, and Applications","authors":"Austin Yue Feng Tan BSc,&nbsp;Parag Garhyan PhD,&nbsp;Lai San Tham PharmD","doi":"10.1002/jcph.70274","DOIUrl":"https://doi.org/10.1002/jcph.70274","url":null,"abstract":"<p>Type 2 diabetes (T2D) is a chronic metabolic disorder associated with high morbidity and mortality, necessitating the urgent need for the research of novel antidiabetic compounds. Population pharmacokinetic/pharmacodynamic (PK/PD) models have been used in T2D drug development to inform dose selection for antidiabetic compounds. However, most population PK/PD models are empirical, and physiological processes (e.g., glucose-mediated hemoglobin glycation) are not routinely incorporated. Conversely, semi-mechanistic models in people with T2D incorporate some relevant physiological processes, enabling prediction of long-term glycated hemoglobin (HbA1c) using only short-term glucose and HbA1c data. Semi-mechanistic T2D models may also have improved ability for extrapolation to multiple antidiabetic drug classes. This narrative review summarizes six published semi-mechanistic models commonly used or discussed for HbA1c prediction in people with T2D: A Dynamic HbA1c EndpOint Prediction Tool (ADOPT), FPG-FSI-HbA1c (FFH), FPG-Hb-HbA1c (FHH), Integrated Glucose-RBC-HbA1c (IGRH), Weight-HbA1c-Insulin-Glucose (WHIG), and Body Weight-Directed Disease Trial (BWDDT) models. An overview of the HbA1c predictive performance is presented for four of these models (ADOPT, FFH, FHH, and IGRH models). Strengths and limitations of the six semi-mechanistic T2D models are evaluated based on model assumptions, HbA1c model predictive performance, predictive accuracy for collected biomarker data, model complexity, and computational considerations. A decision tree framework is provided for model selection. Practical strategies for model development are discussed, including approaches for incorporating different drug effects into the models. Future directions include model validation with early-phase data from various antidiabetic drug classes, and exploration of alternative implementation of disease progression models.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148785161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}