The Journal of Clinical Pharmacology最新文献

{"title":"Pain Severity Trajectories and Patient Profiles in Chronic Pain Patients Treated with Cannabis-Based Medicinal Products: A k-Means Clustering Analysis of the UK Medical Cannabis Registry","authors":"Simon Erridge MBBS, BSc,&nbsp;Aritra Datta MBBS, BSc,&nbsp;Aditya Mukherjee MBBS, BSc,&nbsp;Dhruv Vasooja MBBS, BSc,&nbsp;Ross Coomber BSc, FRCS,&nbsp;Sushil Beri MD, MRCPCH,&nbsp;Shaheen A. Khan MSc, MRCP,&nbsp;Mark W. Weatherall PhD, FRCP,&nbsp;Michael W. Platt MA, FRCA, FFPM, RCA,&nbsp;James J. Rucker PhD, MRCPsych,&nbsp;Pedro A. M. Mediano MSc, PhD,&nbsp;Mikael H. Sodergren PhD, FRCS","doi":"10.1002/jcph.70313","DOIUrl":"10.1002/jcph.70313","url":null,"abstract":"<p>Cannabis-based medicinal products (CBMPs) are increasingly prescribed for chronic pain, yet the supporting evidence remains limited and the extent to which patients differ in their response is poorly understood. This study applied longitudinal k-means clustering to pain-severity trajectories in patients treated with CBMPs for chronic pain to distinguish patterns of response and identify the baseline characteristics predicting them over 24 months. A cohort study was undertaken of UK Medical Cannabis Registry participants whose primary indication was chronic pain. Pain, health-related quality of life, anxiety, and sleep were assessed with patient-reported outcome measures, including the Brief Pain Inventory Short Form (BPI-SF), EuroQol 5-Dimension 5-Level (EQ-5D-5L), Generalised Anxiety Disorder-7, and Single-Item Sleep Quality Scale, at baseline up to 24 months. BPI-SF pain-severity trajectories were grouped by longitudinal k-means clustering. The number of clusters was chosen using the gap statistic and predictors of cluster membership were examined by logistic regression. Of 3744 patients included, every outcome improved from baseline to 24 months, including BPI-SF pain severity (d = 0.57), pain interference (d = 0.59), and the EQ-5D-5L index value (d = −0.76; all <i>P</i> &lt;  .001). More than half of patients achieved a minimal clinically important difference in each pain measure at 24 months. Five distinct trajectory clusters emerged. All ended below their baseline severity, but the magnitude and pattern of change varied markedly. Adverse events were reported by 14.37% (n = 538) of patients, predominantly mild or moderate. Baseline sleep quality, anxiety, and treatment indication were more strongly associated with response than product- or dose-related factors.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70313","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149197232","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":"Concentration-QTc Analysis Supporting Thorough QT Study Waiver for Forvisirvat: Electrocardiogram Assay Sensitivity Demonstrated via Meal Effect","authors":"Yushi Kashihara PhD,&nbsp;Yoshiyuki Igawa PhD,&nbsp;Kei Okita MSc,&nbsp;Masaki Sasaki MSc,&nbsp;Takaki Ohara BSc,&nbsp;Masakatsu Kotsuma PhD,&nbsp;Kazutaka Yoshihara PhD","doi":"10.1002/jcph.70312","DOIUrl":"10.1002/jcph.70312","url":null,"abstract":"<p>Concentration-QTc analysis from Phase 1 studies is increasingly used to evaluate QTc prolongation risk as an alternative to thorough QT (TQT) studies. According to International Conference on Harmonization E14 documents, such analyses should include exposures at twice the highest clinically relevant exposure instead of a positive control to establish electrocardiogram (ECG) assay sensitivity; however, achieving this may be challenging when the highest dose in Phase 1 studies is restricted for various reasons. This study evaluated the QTc prolongation risk of forvisirvat via concentration-QTc analysis and demonstrated ECG assay sensitivity via the well-described meal effect. A double-blind, randomized, placebo-controlled, single ascending dose study evaluated the effect of forvisirvat on ECG parameters following single oral doses up to 80 mg in 32 healthy adults. Time-matched plasma forvisirvat concentrations and 12-lead ECG data were collected. The prespecified linear mixed-effects model assessed the impact of forvisirvat on baseline- and placebo-adjusted QT interval corrected by the Fridericia method (ΔΔQTcF). ECG assay sensitivity was established by prospectively evaluating the postprandial QTcF shortening. The two-sided 90% confidence interval (CI) for the model-predicted ΔΔQTcF was below 10 ms up to the maximum observed plasma concentration of 703 ng/mL. Meal-induced QTcF shortening was −6.38 ms (95% CI, −8.51 to −4.26) at 4 h after the standardized lunch, with the two-sided 95% CI below 0. Forvisirvat showed no QTcF prolongation, and ECG assay sensitivity was confirmed via meal-induced QTcF shortening. These results supported regulatory acceptance of a TQT study waiver by the Japanese Pharmaceuticals and Medical Devices Agency.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70312","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149197195","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":"Mechanistic Prediction of Maternal, Fetal, and Amniotic Fluid Betamethasone Concentrations to Support Dosing Optimization in Pregnancy","authors":"Alaa Mahdi MSc,&nbsp;Khaled Abduljalil PhD,&nbsp;Fernanda de Lima Moreira PhD,&nbsp;Hiral Raju Mehta PharmD,&nbsp;Jhohann Richard de Lima Benzi MSc, PhD,&nbsp;Alessandra Cristina Marcolin MD, MSc, PhD,&nbsp;Stephan Schmidt PhD, FCP,&nbsp;Natalia V. de Moraes PhD","doi":"10.1002/jcph.70308","DOIUrl":"10.1002/jcph.70308","url":null,"abstract":"<p>Respiratory distress syndrome (RDS) remains a major cause of neonatal mortality following premature birth. Antenatal betamethasone is the standard of care to accelerate fetal lung maturation and improve neonatal outcomes; however, current dosing recommendations assume uniform maternal and fetal exposure across pregnancies. Gestational age (GA)-dependent physiological changes and maternal obesity may alter betamethasone disposition and fetal exposure. This study developed a maternal–fetal physiologically based pharmacokinetic (m-f-PBPK) model to quantify the effects of GA and maternal obesity on betamethasone exposure and evaluate current dosing recommendations between 24 and 34 gestational weeks. The m-f-PBPK model incorporated maternal CYP3A-mediated metabolism, placental passive diffusion and active efflux via P-glycoprotein (P-gp), placental metabolic clearance, GA-dependent physiology, and formulation-specific release rates of betamethasone phosphate and acetate. Model performance was evaluated using maternal and fetal exposure metrics across gestation. At GA 30 weeks in non-obese pregnancies, placental metabolic clearance contributed approximately 17% of maternal clearance, whereas fetal hepatic metabolism accounted for only 2.4%. Maternal obesity decreased maternal and fetal exposure by approximately 9%, while morbid obesity reduced exposure by 23%. Simulated fetal concentrations remained above the proposed pre-clinical-derived surrogate marker of 2 ng/mL for a median duration of 38-40 h in non-obese, 37.5-39 h in obese, and 30-32 h in morbidly obese populations. This m-f-PBPK model successfully characterized maternal–fetal pharmacokinetics and provides a mechanistic basis for understanding betamethasone fetal exposure across GAs with and without maternal obesity, supporting optimization of antenatal corticosteroid therapy.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149185187","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":"Fostering Clinical Pharmacology and Drug Development in India: A Perspective From SAC-ACCP","authors":"Karthik Venkatakrishnan PhD, FCP,&nbsp;Abhigyan Ravula PhD,&nbsp;Sagar Bachhav PhD,&nbsp;Mohammad Faruq MBBS, PhD,&nbsp;Bratati Kahali PhD,&nbsp;AVS Suresh MD, DM,&nbsp;Sanish Davis MD, DM, FCP,&nbsp;Manish Lavhale M.Pharm, PhD,&nbsp;Amruta Gadade MSc,&nbsp;Gurusharan Dumra MD, ACME,&nbsp;Vikas Dighe M.V.Sc, PhD,&nbsp;Vipin Dhote PhD,&nbsp;Bikash Medhi MBBS, MD, MAMS, FIMSA,&nbsp;Kiran Marthak MD, FACP,&nbsp;Nirmala Rege MD, DNB, PhD,&nbsp;Tushar Garimella PhD,&nbsp;Taruna Madan M.Pharm, PhD,&nbsp;Jagannath Kota PhD,&nbsp;Ravi Shankar P. Singh PhD, FCP,&nbsp;Gangadhar Sunkara PhD,&nbsp;Manoj Jadhav PhD, FCP,&nbsp;Nilima Kshirsagar MD, PhD, FCP,&nbsp;Deven Parmar MD, FCP","doi":"10.1002/jcph.70307","DOIUrl":"10.1002/jcph.70307","url":null,"abstract":"<p>Since its inception in 2006, the South Asian College, Affiliate of the American College of Clinical Pharmacology (SAC-ACCP), headquartered in Mumbai, India, has fostered the discipline, emphasizing education, training and dialogue across academia, regulators, and industry. The 2026 Annual Conference, themed “Think Global Act Local,” covered topics ranging from Artificial Intelligence in healthcare to the Genome India project and multi‑regional clinical trials, reflecting India's strategic maturation as it moves decisively from participation to co-leadership in global drug development. This Commentary highlights the proceedings of this summit, celebrating India's emergence as a globally visible leader in biomedical research and drug development at a key milestone of the 20th Anniversary of SAC-ACCP.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70307","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149185171","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":"Development and Evaluation of a Population Pharmacokinetic Model for High-Dose Methotrexate in Japanese Pediatric Patients with Acute Lymphoblastic Leukemia","authors":"Takuya Suzuoka MS,&nbsp;Tsubura Noda PhD,&nbsp;Kota Tsuge BPharm,&nbsp;Yasuyoshi Ishiwata PhD,&nbsp;Toshinori Hirai PhD,&nbsp;Takeshi Isoda MDPhD,&nbsp;Masatoshi Takagi MD, PhD,&nbsp;Masashi Nagata PhD","doi":"10.1002/jcph.70310","DOIUrl":"10.1002/jcph.70310","url":null,"abstract":"<p>Methotrexate is a key chemotherapeutic agent for treating pediatric acute lymphoblastic leukemia (ALL); however, its pharmacokinetics exhibit substantial inter-individual variability. Population pharmacokinetic (PPK) models have identified body weight and renal function as major determinants of methotrexate clearance. Nonetheless, the optimal PPK model for Japanese pediatric patients, considering hydration status, has not yet been established. This study aimed to develop a PPK model of high-dose methotrexate specifically for Japanese pediatric patients with ALL. A retrospective PPK analysis was performed in pediatric patients with ALL, who were treated with high-dose methotrexate at the Tokyo Medical and Dental University Hospital. Data from 38 patients (504 methotrexate concentrations; 27 for model development and 11 for validation) were analyzed using a two-compartment model in NONMEM. Predictive performances of the newly developed and previously published models were assessed using the validation dataset. In the final model, clearance was described as a function of body surface area and hydration volume rate per body surface area (HYDR), whereas intercompartmental clearance was associated with age and HYDR. Evaluation using the validation dataset showed that the developed model had the best predictive performance among the evaluated models (median prediction error, 1.79%; median absolute prediction error, 13.3%; percentage of predictions with an absolute prediction error ≤20%, 70.3%; percentage of predictions with an absolute prediction error ≤30%, 82.9%). Simulation revealed modestly improved target-attainment rates at relatively high hydration rates. These findings highlight the importance of fluid management and support the incorporation of hydration parameters into individualized high-dose methotrexate therapy.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171764","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":"ACCP Call to Action—The Need for Vaccine Education","authors":"Kenneth Todd Moore DBE, MS, FAHA, FCP,&nbsp;Sindura Gollamudi MSc, Aman Gupta, MD,&nbsp;Amir S. Youssef PhD, FCP","doi":"10.1002/jcph.70301","DOIUrl":"10.1002/jcph.70301","url":null,"abstract":"&lt;p&gt;The American College of Clinical Pharmacology (ACCP) affirms that vaccine education is essential to safeguarding global health and trust in scientific and medical institutions conducting vaccine programs. Grounded in evidence-based science, transparency, and cultural awareness, effective vaccine education must address misinformation directly while communicating both the benefits and risks of vaccination in an open and accessible manner. The ACCP is recommending a “call to action” in which its members and the broader community of medical research and healthcare professionals and their institutions, work in thoughtful collaboration to promote balanced, scientifically rigorous vaccine education to provide informed decision-making, increase public awareness, and ensure equitable access to these life-saving preventive care treatments.&lt;/p&gt;&lt;p&gt;The mission of the ACCP is to improve global health by advancing the frontiers of clinical pharmacology. The College follows this guiding principle through its role as an educational institution, not only for its members, but all healthcare professionals and to the communities we serve. As such, when a course of events occurs that creates uncertainty or erodes confidence in established scientific norms, as currently observed in the decreased use of vaccinations, the College has a responsibility to address these issues and educate both its members and the broader community to ensure they are well informed of the scientific and medical facts and are empowered to make decisions based on rigorous evidence rather than fear, pseudoscience, misinformation, or doubt.&lt;/p&gt;&lt;p&gt;Combating fear, pseudoscience, misinformation, and doubt can be a substantial challenge, particularly when false claims regarding vaccine pharmacology, safety, and efficacy, can spread faster via social media than the scientific evidence can be communicated. The rapid and widespread acceptance of false assumptions eventually erodes the trust in our scientific and medical institutions, which can ultimately lead to dangerous outcomes. In this instance, these dangerous outcomes include vaccine hesitancy, refusal, and federal policy changes which can compromise the immunity of our communities and increase the risk for severe outbreaks.&lt;/p&gt;&lt;p&gt;Providing impactful education in this scenario requires both transparency and actively addressing any doubts and fears the recipient may have. An approach in which scientific evidence is the foundation of communication and openly addressing misinformation can lessen these fears and slowly reestablish public trust. Additionally, this type of education must include open and transparent communication about vaccines that were withdrawn, when adverse effects lead to changes in treatment guidelines, or differences in vaccine policies in other peer countries. While rare, vaccine withdrawals do occur, many times due to issues identified during post-marketing surveillance programs, that were not apparent during the conduct of ","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70301","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149117192","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":"A Brief Review of Vaccine History, Hesitancy, and Education Today","authors":"Amir S. Youssef PhD, FCP,&nbsp;Aman Gupta MD,&nbsp;Sindura Gollamudi MSc,&nbsp;Kenneth Todd Moore DBE, MS, FAHA, FCP","doi":"10.1002/jcph.70302","DOIUrl":"10.1002/jcph.70302","url":null,"abstract":"<p>Vaccination remains one of the most effective global health interventions, preventing substantial morbidity and mortality and advancing population health worldwide. However, vaccine hesitancy continues to limit vaccine confidence and uptake in some communities. This brief review summarizes the historical, social, and educational factors shaping vaccine hesitancy and outlines practical strategies to improve confidence and uptake. Key contributors include safety concerns amplified by misinformation, the rapid spread of misleading content through social media, and residual mistrust related to rare past research abuses and manufacturing failures. Additional barriers include socioeconomic disadvantage, limited scientific literacy, religious influences, clustering of vaccine-resistant beliefs, health inequities, and distrust of healthcare institutions. This review emphasizes that effective responses must extend beyond simply providing more information. Evidence supports dialogue-based, tailored communication, transparent discussion of risks and benefits, empathetic parent–provider engagement, stronger vaccinology education for healthcare professionals, and improved access through combination vaccines, mobile clinics, and digital health tools. Addressing vaccine hesitancy requires coordinated, evidence-based strategies centered on trust, communication, professional education, and equitable access to sustain public confidence in vaccination. As outlined in The American College of Clinical Pharmacology “Call to Action,” vaccine education is essential for safeguarding global health and trust in institutions involved in vaccine programs.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70302","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149117113","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":"Physiologically Based Pharmacokinetic Modeling to Characterize the Disposition of Topiramate in Children with and without Obesity","authors":"Patricia D. Maglalang PharmD, PhD,&nbsp;Daniel Gonzalez PharmD, PhD,&nbsp;William J. Muller MD, PhD,&nbsp;Chi D. Hornik PharmD,&nbsp;Stuart L. Goldstein MD,&nbsp;Mobeen Rathore MD,&nbsp;Jennifer L. Ford PhD,&nbsp;Stephen J. Balevic MD, PhD,&nbsp;Jaydeep Sinha PhD,&nbsp;Andrea Edginton PhD,&nbsp;Rachel G. Greenberg MD, MB, MHS,&nbsp;Daniel K. Benjamin Jr., MD, PhD, MPH,&nbsp;Jia-Yuh Chen PhD,&nbsp;Kanecia O. Zimmerman MD, PhD, MPH,&nbsp;the Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee","doi":"10.1002/jcph.70264","DOIUrl":"https://doi.org/10.1002/jcph.70264","url":null,"abstract":"<p>Topiramate (TPM) is used to treat seizures in adults and children ≥2 years. In children, TPM dosing is body weight based. It is unknown whether children with obesity may benefit from an alternative dosing strategy. We developed a novel physiologically based pharmacokinetic (PBPK) model for TPM that accounts for age- and obesity-related changes in disposition. The model was first developed and evaluated in adults before scaling to children then finally evaluated using opportunistic pharmacokinetic data from two multicenter studies where children with and without obesity ages 2–18 years received TPM per standard of care. Simulations were performed to characterize pharmacokinetic parameters and assess the current labeled dosing regimen in a virtual population of children with obesity (≥2 years). The adult PBPK model performed well when evaluated with observed literature data, resulting in an average fold error of 0.989 across the dosing range of 25–1200 mg. The pediatric data used in model evaluation included 43 children (86% with obesity; median [range], 8 [2–18] years); 71% of 134 observed concentrations fell within the 90% prediction interval for the PBPK model. PBPK based dosing simulations revealed comparable exposure (&lt;20% difference) in children with and without obesity receiving the Topamax product label weight-tiered dose for monotherapy (weight tiered for 2 to &lt;10 years and fixed dosing for 10 to ≤18 years) or weight-based adjunctive therapy. Comparable trough concentrations between children with and without obesity suggest the current dosing recommendations, including monotherapy and adjunctive therapy, are appropriate for children with obesity.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70264","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068324","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":"Exposure–Response Analyses of Ropeginterferon Alfa-2b in Essential Thrombocythemia","authors":"Albert Qin MD,PhD,&nbsp;Lucia Masarova MD,&nbsp;Haoqi Chen PhD,&nbsp;Zhijian Xiao MD,PhD,&nbsp;Jie Jin MD,PhD,&nbsp;Harinder Gill MD,&nbsp;Brandi N Reeves MD,&nbsp;Firas El Chaer MD,&nbsp;Keita Kirito MD,PhD,&nbsp;Norio Komatsu MD,PhD,&nbsp;Ghaith Abu-Zeinah MD,&nbsp;Kazuya Shimoda MD,PhD,&nbsp;Oleh Zagrijtschuk MD,&nbsp;Toshiaki Sato MD,PhD,&nbsp;Daoxiang Wu MD,&nbsp;Lei Wu MS,&nbsp;Xia Su PhD,&nbsp;Yucheng Gao MS,&nbsp;Jie Cui MS,&nbsp;Lei Zhang MD,PhD,&nbsp;Ruben A Mesa MD","doi":"10.1002/jcph.70258","DOIUrl":"https://doi.org/10.1002/jcph.70258","url":null,"abstract":"<p>Ropeginterferon alfa-2b is a new-generation interferon therapy for the treatment of myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). This investigation was designed to characterize its population pharmacokinetics–pharmacodynamics (PopPK-PD) and delineate exposure–response (E-R) relationships in ET. A population PK model was constructed utilizing aggregated data from five clinical trials, encompassing a study population of Asian and Caucasian patients with ET and healthy volunteers. A sequential modeling strategy was employed to evaluate the PK-PD with respect to key hematologic markers including platelet and white blood cell counts. Hematologic changes were effectively modeled using sigmoidal indirect-response models. Individual exposure metrics were subsequently simulated by a target-mediated drug disposition model and then applied in E-R analyses for reductions in the allele burden of MPN driver mutations <i>JAK2</i>V617F and <i>CALR</i>, and safety outcomes. Simulations indicated no significant disparities between ethnicities in ropeginterferon alfa-2b exposure or the extent of hematologic response. A correlation was observed between drug exposure and a decrease in <i>JAK2</i>V617F allele burden at 6 and 12 months of treatment. Exposure–safety assessments identified a risk of exposure-related adverse events, including reversible anemia. Taken together, the data provided a solid PK-PD framework and insights into the E-R relationships for ropeginterferon alfa-2b in the treatment of ET.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70258","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068326","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":"Evaluation and Extrapolation of a Tacrolimus Population Pharmacokinetic Model in Adult Recipients of Allogeneic Hematopoietic Cell Transplantation Receiving Post-Transplant Cyclophosphamide","authors":"Riley M. Randolph MS,&nbsp;Tyler C. Dunlap PharmD,&nbsp;Stephany Gonzalez Tineo BS,&nbsp;Ryan M. Kemper BA,&nbsp;Jing Zhu PharmD, PhD,&nbsp;Kieran Collins PharmD,&nbsp;Yu Fei Wang BS,&nbsp;Pu Ouyang PharmD,&nbsp;Nichole Korpi-Steiner PhD,&nbsp;Eric Weimer PhD,&nbsp;Morgan E. Bizzell PharmD,&nbsp;Jonathan R. Ptachcinski PharmD,&nbsp;Anson E. Snow MD,&nbsp;Paul M. Armistead MD, PhD,&nbsp;J. Ryan Shaw PharmD,&nbsp;Daniel L. Weiner PhD,&nbsp;Daniel J. Crona PharmD, PhD","doi":"10.1002/jcph.70305","DOIUrl":"10.1002/jcph.70305","url":null,"abstract":"<p>Allogeneic hematopoietic cell transplant (allo-HCT) is potentially curative for many hematologic diseases but complicated by acute graft-versus-host disease (aGVHD). While tacrolimus remains the cornerstone of aGVHD prophylaxis, regimens are increasingly including post-transplant cyclophosphamide (PTCy). This single-center study evaluated a previously published tacrolimus population pharmacokinetic (popPK) model developed from allo-HCT recipients administered standard (tacrolimus plus methotrexate) aGVHD prophylaxis for generalizability to PTCy recipients. Adult allo-HCT recipients treated with PTCy for aGVHD prophylaxis were included. Applicability of the established popPK model to the PTCy population was based on an evaluation of simulated to observed concentration ratios, and the distribution was interpreted with respect to a clinical equivalence range (0.8 to 1.25). The model was refit using data from both the standard and PTCy cohorts to describe the PK and support extrapolation to the PTCy population. Individual PK parameters from PTCy recipients were used to simulate steady-state concentrations (C_{trough, ss}) using the current institutional weight-based dosing strategy and the proposed model-informed precision dosing (MIPD) algorithm. The proportion of patients predicted to experience a subtherapeutic C_{trough, ss} (&lt;5 ng/mL) was compared between dosing strategies. Five hundred and ninety-three tacrolimus C_{trough, ss} values from 95 allo-HCT recipients who received PTCy were included. The previous model did not successfully predict tacrolimus C_{trough, ss} values among PTCy patients, but highlighted similarities between clearance in PTCy and standard aGVHD prophylaxis patients who received reduced-intensity conditioning. Dosing simulations suggested a decreased proportion of PTCy patients would experience subtherapeutic tacrolimus C_{trough, ss} with MIPD (3%) compared to conventional weight-based dosing (23%).</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082549","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}