Clinical Pharmacology And Therapeutics[JOURNAL]
Sun
200 papers
Quantitative Lesion-Level Modeling Reveals Organ-Dependent Therapeutic Response.
Dilley I, Zhou J, Li Q … +1 more , Cao Y
Clin Pharmacol Ther · 2026 Jun · PMID 41820253 · Full text
Conventional RECIST criteria compress heterogeneous metastatic lesions into a single sum-of-diameters endpoint, which can obscure organ-specific pharmacologic effects on response durability and thereby limit the interpre...
Conventional RECIST criteria compress heterogeneous metastatic lesions into a single sum-of-diameters endpoint, which can obscure organ-specific pharmacologic effects on response durability and thereby limit the interpretability of efficacy signals used for model-informed drug development and clinical decision making. We developed a lesion-level modeling framework to quantify compartment-dependent therapeutic effects using routinely collected RECIST diameters. Lesion trajectories were characterized using nonlinear mixed-effects modeling to estimate regression/kill (kkill), regrowth/progression (kge), and a resistance-like fraction (Fx). We then fit pan-cancer multivariable Cox models (adjusted for cancer lineage, treatment class, and clinical covariates) to quantify the independent contribution of metastatic site to response and progression hazards. Organ site emerged as a consistent determinant of response durability across lineages. Liver metastases frequently showed early shrinkage yet higher progression risk, whereas bone metastases, particularly in prostate cancer, tended to regress more slowly but exhibited more durable control once response occurred. Inter-lesion heterogeneity in progression dynamics was greatest in breast and non-small cell lung cancer and lowest in colorectal and pancreatic cancer. To contextualize site effects, we explored literature-derived estimates of Vascular Perfusion and Leakiness Index (VaPLI) for each organ, along with a broad immune surveillance classification. VaPLI correlated with response probability (ρ = 0.44; P < 0.01), and immune-tolerant sites showed higher progression hazards (P < 0.05). With further verification, this analysis can support lesion site-stratified efficacy evaluation by distinguishing true treatment effects from site-driven bias, enabling more balanced interpretation of treatment effects and dose-response relationships.
Patient- and Clinician-Related Factors Associated With the Reduction in Opioid Use Among Adults With Chronic Non-Cancer Pain: A Systematic Review.
Marcelo AC, Hilmer SN, Hunter DJ … +6 more , Mathieson S, Mohamed R, Li L, Fung N, Yue A, Ferreira ML
Clin Pharmacol Ther · 2026 Jul · PMID 41813618 · Full text
Despite known risks, opioids are widely used for chronic non-cancer pain (CNCP). Clinical guidelines now recommend deprescribing, but factors predicting success are poorly understood. This systematic review aimed to iden...
Despite known risks, opioids are widely used for chronic non-cancer pain (CNCP). Clinical guidelines now recommend deprescribing, but factors predicting success are poorly understood. This systematic review aimed to identify clinician and patient factors associated with attaining successful opioid dose reduction or discontinuation in adults with CNCP. We searched major electronic databases on 18 March 2025 for observational studies evaluating factors associated with opioid reduction in deprescribing interventions, excluding studies on cancer/palliative care or primary substance use disorder. The primary outcome was the association between clinician- or patient-related factors and opioid reduction/discontinuation. Two reviewers independently screened studies, extracted data, and assessed bias using the ROBINS-I tool. A narrative synthesis was conducted as there was significant heterogeneity between studies which did not allow for a meta-analysis. Thirty-two studies (n = 26 retrospective cohorts) were included. Evidence on clinician factors was limited, though one study found that a documented deprescribing plan was associated with greater opioid dose reduction (aOR: 3.63, 95% CI: 2.96-4.46). Among patient factors, higher baseline dose and longer duration of opioid use were associated with a lower likelihood of opioid discontinuation in four high-quality studies. Findings for other factors (e.g., age, mental health) were conflicting. Certainty was low due to methodological limitations, with 19 studies having a serious risk of bias. In conclusion, a documented deprescribing plan was the most promising modifiable factor. While long-term opioid use is a consistent barrier, inconsistent evidence for other patient-level factors reinforces the need for individualized care. Future high-quality research should focus on clarifying inconsistent findings and addressing the critical evidence gap regarding clinician and health system-level factors (PROSPERO: CRD42021270488).
Vancomycin-induced acute kidney injury in a type 2 diabetes patient with augmented renal clearance: A case report and dosing strategy implications.
Wang LF, Zhou J, Chen R
Int J Clin Pharmacol Ther · 2026 May · PMID 41793706 · Publisher ↗
Vancomycin-induced acute kidney injury (AKI) is a well-documented adverse effect, particularly in high-risk populations such as patients with type 2 diabetes mellitus (T2DM) and augmented renal clearance (ARC). However,...
Vancomycin-induced acute kidney injury (AKI) is a well-documented adverse effect, particularly in high-risk populations such as patients with type 2 diabetes mellitus (T2DM) and augmented renal clearance (ARC). However, optimal dosing strategies for diabetic patients with ARC remain unclear, increasing the risk of nephrotoxicity. A 36-year-old male with newly diagnosed T2DM (HbA1c 11.6%) and ARC (baseline estimation of glomerular filtration rate (eGFR) 270 - 301 mL/min/1.73m) developed AKI following high-dose vancomycin therapy (1.5g q8h) for a methicillin-resistant (MRSA) abscess. Despite initially subtherapeutic trough levels (8.83 μg/mL), the patient experienced AKI (serum creatinine: 195 μmol/L; eGFR 36.1 mL/min) coinciding with a toxic trough level (75.84 μg/mL) on day 7 after vancomycin administration. AKI resolved after vancomycin discontinuation and aggressive hydration. Diabetic patients with ARC are at increased risk of vancomycin-induced AKI, even with subtherapeutic troughs. Close renal function monitoring, individualized dosing, and consideration of AUC-based protocols or alternative antibiotics (e.g., linezolid) are essential for mitigating nephrotoxicity. Further pharmacokinetic studies in this population are warranted to optimize therapeutic outcomes.
Pharmacokinetic Drug-Drug Interaction Potential of Oral Anticancer Drugs.
Alhurayri F, Younis IR, Jalal SI … +8 more , Logan TF, Maniar R, Bray SM, Quinney SK, Desta Z, Skaar TC, Tisdale JE, Shugg T
Clin Pharmacol Ther · 2026 Jun · PMID 41793262 · Full text
Drug-drug interaction (DDI) management is critical for safe and effective use of oral anticancer drugs (OADs). Our study objectives were to (i) compile clinically relevant pharmacokinetic (PK) DDI mechanisms for OADs and...
Drug-drug interaction (DDI) management is critical for safe and effective use of oral anticancer drugs (OADs). Our study objectives were to (i) compile clinically relevant pharmacokinetic (PK) DDI mechanisms for OADs and (ii) assess the prevalence of PK potential DDIs (PDDIs) in patients with advanced solid cancers. OADs approved through January 2023 were assigned DDI mechanisms based on studies obtained from drug labels and primary literature showing ≥ 2-fold exposure change or significant adverse health outcomes during co-administration with interacting drugs. Electronic health records of 3,697 solid cancer patients were reviewed retrospectively to detect PDDIs, defined as overlapping prescriptions of OADs with relevant interacting drugs. FDA labels were reviewed for 99 OADs, and 239 studies were extracted from the primary literature, yielding a total of 748 drug-drug pairs for analysis. Eighty-five OADs (85.9%) had ≥ 1 DDI mechanism. The most common DDI mechanisms were victims with metabolic inducers (71.7%), CYP3A substrates (55.6%), CYP3A perpetrators (29.3%), and victims with acid reducers (17.2%). Our primary literature search detected clinically relevant DDI mechanisms without actionable recommendations in the drug labels for 14 drugs. Among patients prescribed ≥ 1 OADs (46.9%), 17.4% had ≥ 1 PDDI, most commonly involving OADs acting as CYP3A (58.9%) or CYP2D6 (32.5%) perpetrators. Most OADs (~86%) had ≥ 1 DDI mechanism, and ~17% of solid tumor board patients had a clinically relevant PDDI.
Implementation of OMOP and ConcePTION Common Data Models in CPRD GOLD: Risk of Bleeding and Cardiovascular Outcomes From Anticoagulant Use.
Hunt NB, Souverein P, Bazelier M … +6 more , Barclay N, Delmestri A, Sturkenboom M, Prieto-Alhambra D, Gardarsdottir H, Klungel O
Clin Pharmacol Ther · 2026 Jun · PMID 41793101 · Full text
The impact of the choice of common data model (CDM) approach on the study results in a real-world evidence (RWE) study is unknown. We aimed to determine potential differences in the results of an RWE study when data were...
The impact of the choice of common data model (CDM) approach on the study results in a real-world evidence (RWE) study is unknown. We aimed to determine potential differences in the results of an RWE study when data were mapped to two different CDMs, ConcePTION and OMOP. With the same instance of CPRD GOLD, data were mapped to both CDMs. Using the same programming steps, we estimated the risk of direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs) on bleeding and cardiovascular (CVD) outcomes in patients with non-valvular atrial fibrillation. Baseline characteristics, incidence rates, and Cox proportional hazards ratios were compared between the analyses. OMOP and ConcePTION mapped study populations included 80,701 (93,350 person-years) and 76,726 exposed persons (100,135 person-years), respectively. DOACs showed no differential risk of CVD compared to VKAs in ConcePTION mapped data (HR 0.99, 95% CI [0.91; 1.08]), but protective effects in OMOP (HR 0.82, 95% CI [0.74; 0.90]). DOACs had a similar increase in risk of stroke (ConcePTION HR 1.19, 95% CI [1.02; 1.37]; OMOP HR 1.10, 95% CI [0.96; 1.26]). No increased risk of major bleeding was identified (ConcePTION HR 0.97, 95% CI [0.84; 1.13]; OMOP HR 0.90, 95% CI [0.78; 1.04]). OMOP gave lower effect estimates for CVD and equivalent risks of stroke and bleeding associated with DOACs use. This study highlights the challenges in repeating the same analysis across the two data CDMs. Differences potentially stem from the cohort construction, the identification of phenotypes in the different CDMs, and the use of imputed variables defined during mapping processes, such as drug exposure duration.
Advancing Pharmacometrics in Africa: Insights and Perspectives From the 2025 Pharmacometrics Africa Conference.
Adeagbo BA, Asiimwe IG, Chaba L … +10 more , Kawuma AN, Ojara FW, Orherhe OM, Asiimwe SP, Pillay-Fuentes Lorente V, Sawe S, Phogole CM, Waitt C, Mouksassi S, Pillai GC
Clin Pharmacol Ther · 2026 May · PMID 41787065 · Full text
Pharmacometrics (PMX) in Africa has transitioned from foundational capacity-building to job creation, scientific leadership, regulatory influence, and health innovation. To accelerate this progress, the 2025 Pharmacometr...
Pharmacometrics (PMX) in Africa has transitioned from foundational capacity-building to job creation, scientific leadership, regulatory influence, and health innovation. To accelerate this progress, the 2025 Pharmacometrics Africa Conference (PMXAC-2025) convened key stakeholders to consolidate the continental PMX community, review progress in local capacity, and define priorities for African-led quantitative pharmacology and regulation. Held as a hybrid event in Kampala, Uganda, PMXAC-2025 featured plenary sessions, technical workshops, and poster presentations. A pre-conference nlmixr2 workshop strengthened open-source modeling expertise, while eight presentations and 32 posters facilitated discussions on capacity development, regulatory integration, and methodological innovation. The conference brought together 108 delegates, including 40 online participants from 14 countries (six African), reflecting strong global engagement. Regulatory representation (4.6%) demonstrated growing interdisciplinary collaboration. Sessions highlighted PMX as central to evidence-based healthcare, with applications in regulatory harmonization, patient-centered dosing, and equitable access. Presentations on model-based bioequivalence (MBBE), physiologically based pharmacokinetic (PBPK) modeling for safely extrapolating drug exposure in complex, understudied populations such as pregnant women and children, and model-based meta-analysis (MBMA) illustrated data-driven solutions for resource-limited settings. Emphasis on open-source tools reinforced technical equity, while career discussions promoted mentorship and cross-border collaboration. A closing panel outlined eight priorities for sustained progress, including funding, leadership, and integrated multi-sector partnerships. PMXAC-2025 signaled Africa's transition toward PMX self-reliance and innovation, uniting continental and diaspora experts, advancing open science, and setting a roadmap for sustainable, model-informed drug development across the continent. To sustain this momentum, establishing PMXAC-2025 as a regular annual event was strongly recommended.
Concomitant 5-Aminosalicylic Acid Does Not Affect the Efficacy of Janus Kinase Inhibitors in Ulcerative Colitis.
Tursi A, Pasta A, Elisei W … +9 more , Barberio B, Mocci G, Maconi G, Gravina AG, Pellegrino R, Bodini G, Savarino EV, Papa A, Italian Network for Inflammatory Bowel Diseases (IN‐IBD)
Clin Pharmacol Ther · 2026 Jul · PMID 41786642 · Full text
We evaluated whether concomitant 5-aminosalicylic acid (5-ASA) influences clinical remission in patients with ulcerative colitis (UC) receiving Janus kinase inhibitors (JAKi). In this retrospective, multicenter cohort st...
We evaluated whether concomitant 5-aminosalicylic acid (5-ASA) influences clinical remission in patients with ulcerative colitis (UC) receiving Janus kinase inhibitors (JAKi). In this retrospective, multicenter cohort study, UC patients receiving tofacitinib (n = 181), upadacitinib (n = 313), or filgotinib (n = 139) were included. Time to clinical remission was analyzed using interval-censored Cox models. Among the 633 patients treated with JAKi, 476 patients received 5-ASA, and 151 did not. Cumulative probability of remission at week 48 was similar with and without 5-ASA, at 81.3% and 77.0%, respectively. The adjusted hazard ratio for 5-ASA vs. no 5-ASA was 1.12 (95% CI 0.91-1.37, P = 0.519). We therefore found that concomitant 5-ASA did not significantly affect the time to clinical remission in UC patients treated with JAKi.
Unveiling Hepatic Protein Alterations in Neonatal and Infant Biliary Atresia.
Al-Majdoub ZM, Howard M, Achour B … +3 more , Barber J, Alizai N, Rostami-Hodjegan A
Clin Pharmacol Ther · 2026 Jun · PMID 41781340 · Full text
Pediatric populations differ from adults in drug elimination capacity. While current scaling methods account for enzyme and transporter maturation, they overlook comorbidities, such as biliary atresia (BA), a liver disea...
Pediatric populations differ from adults in drug elimination capacity. While current scaling methods account for enzyme and transporter maturation, they overlook comorbidities, such as biliary atresia (BA), a liver disease appearing within the first 2-8 weeks of life that can progress to cirrhosis. Such conditions may impair hepatic drug clearance, requiring dose adjustments. Physiologically based pharmacokinetic (PBPK) tools aim to address such cases and have been advocated to fill gaps in clinical data instead of less formalized and evidence-based guesswork. However, the paucity of systems data in rare disease populations has hindered the development of robust PBPK models. This study used global liquid chromatography and tandem mass spectrometry (LC-MS/MS) proteomics to quantify drug-metabolizing enzymes and transporters in diseased neonatal (n = 13) and infant (n = 12) liver samples, revealing significant expression changes in biliary atresia (BA) livers vs. controls (n = 19). Based on cohort means, CYP2A6, CYP2B6, and CYP2E1 levels were 6-17-fold higher in BA livers compared to controls, while CYP4F11 and CYP20A1 were reduced. UGT1A1, UGT2B4, and UGT2B7 showed up to 16-fold higher abundance in neonates with BA. Among transporters, ABCF1 abundance increased dramatically (46-fold), whereas B3AT/SLC4A1, ADT1/SLC25A4, and S27A5/SLC27A5 were decreased. The observed alterations suggest that assuming similar liver function in BA and non-BA patients has implications, with impact varying by drug clearance pathway. While in silico models can explore this, clinical pharmacokinetic studies in BA are essential for verification. To our knowledge, such studies are absent. Our observations underscore the urgent need for dedicated pharmacokinetic studies in BA patients to improve precision dosing.
Clinical Pharmacology Quality Assurance Program for Global HIV and Co-Infection Drug Development.
DiFrancesco R, Wood TD, Cha R … +15 more , Hochreiter JS, Rosenkranz SL, Farhad M, Whitson KR, Gould CE, Hill LE, Hale LL, Lindhorst PH, Ghazal D, Taylor CR, Quraishi M, Siminski SM, Cramer Y, Sprenger HL, Morse GD
Clin Pharmacol Ther · 2026 May · PMID 41771782 · Full text
When the acquired immunodeficiency syndrome emerged in the 1980s, the United States National Institutes of Health established research networks to conduct clinical trials with the pharmaceutical industry to identify effe...
When the acquired immunodeficiency syndrome emerged in the 1980s, the United States National Institutes of Health established research networks to conduct clinical trials with the pharmaceutical industry to identify effective antiretroviral therapeutics. The clinical trials networks included laboratory centers with academic pharmacology laboratories measuring drug concentrations to allow for the estimation of pharmacokinetic parameters and correlation with pharmacodynamic outcomes. Adoption of comprehensive quality assurance initiatives was key to ensuring the integrity of pharmacology sampling and laboratory data provided by clinical sites and laboratories. Subsequently, this infrastructure facilitated rapid responses to co-infection pathogens such as hepatitis C virus, Mycobacterium tuberculosis, and severe acute respiratory syndrome coronavirus 2. In 2008, the Center for Integrated Global Biomedical Sciences at the University at Buffalo was awarded the initial National Institute of Allergy and Infectious Diseases contract for the Clinical Pharmacology Quality Assurance Program. Since 2015, over 4,500 tutorial certificates for research staff and laboratories have been awarded on topics including the conduct of clinical pharmacology research protocols and bioanalytical method validation for antiretroviral assays. A bioanalytical peer review program for ensuring the quality of the assay methods has approved over 350 assays for > 100 analytes in 21 human biological matrices. An ISO-17043 accredited external proficiency testing program has completed 35 rounds for 15 analytes. Also, a laboratory assessment program was established that utilizes international laboratory and regulatory standards, and multiple mechanisms for training, assistance and guidance to participants. This report summarizes the development of the CPQA program over the last decade.
Comparing the Efficacy of Various Treatment Strategies for Patients With Advanced Triple-Negative Breast Cancer: An Umbrella Review.
Ma X, Jia S, Gao T … +7 more , Liu J, Xin T, Liu Z, Yang Y, Xiang R, Gao M, Zhao M
Clin Pharmacol Ther · 2026 Jun · PMID 41771765 · Publisher ↗
Chemotherapy (CT) remains the standard first-line treatment for advanced triple-negative breast cancer (aTNBC), despite the emergence of innovative therapies, including targeted therapies (TT) and immune checkpoint inhib...
Chemotherapy (CT) remains the standard first-line treatment for advanced triple-negative breast cancer (aTNBC), despite the emergence of innovative therapies, including targeted therapies (TT) and immune checkpoint inhibitors (ICI). Studies have shown that the treatment strategies for aTNBC vary widely, with inconsistent efficacy across different treatment modalities. A comprehensive search was carried out in electronic databases, such as PubMed and Embase, for systematic reviews and randomized clinical trials (RCTs) that investigated the efficacy of TT, ICI, and CT to treat aTNBC until June 2025. Seventeen published meta-analyses and 52 RCTs reporting the prognosis of the disease treated with TT, ICI, and CT in aTNBC patients were analyzed. It showed that in terms of prolonging PFS, both the TT group and the ICI group were superior to the CT group [ICI: HR = 0.81 (0.69, 0.94); TT: HR = 0.68 (0.62, 0.74)]. In terms of OS, the TT group was superior to the CT group [HR = 0.77 (0.68, 0.88)]. In the subgroup analysis of TT, compared with CT alone, both sacituzumab govitecan (SG) monotherapy and trilaciclib combined with chemotherapy (TRI_CT) significantly improved the time of PFS [SG: HR = 0.41 (0.30, 0.56); TRI_CT: HR = 0.62 (0.46, 0.86)] and OS [SG: HR = 0.48 (0.33, 0.70); TRI_CT: HR = 0.41 (0.28, 0.59)]. This umbrella review supports SG monotherapy and TRI_CT as the first choice for patients with aTNBC. Additionally, the review was rated as high-quality evidence using AMSTAR 2, the credibility classification standard, and GRADE rating. The study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline and is registered with PROSPERO: CRD420251034666.
Safety and Efficacy of Colchicine across the Spectrum of Coronary Artery Disease: A Systematic Review and Meta-Analysis of 20 Randomized Trials.
Laudani C, Bujak K, Occhipinti G … +8 more , Rinaldi R, Imbesi A, Sanchez JS, Galli M, Abbate A, Ortega-Paz L, Capodanno D, Angiolillo DJ
Clin Pharmacol Ther · 2026 Jun · PMID 41760558 · Publisher ↗
Recent evidence questioned the overall safety and efficacy of colchicine in patients with coronary artery disease (CAD), as novel evidence focusing on acute coronary syndromes (ACSs) gave neutral results, while trials fo...
Recent evidence questioned the overall safety and efficacy of colchicine in patients with coronary artery disease (CAD), as novel evidence focusing on acute coronary syndromes (ACSs) gave neutral results, while trials focusing on chronic coronary syndrome supported colchicine administration to improve long-term outcomes. However, no study has ever explored whether there is a true therapeutic difference across the populations or these discrepancies are due to additional confounders. Against this background, we performed a systematic review and meta-analysis of randomized trials of colchicine in patients with CAD. The primary endpoints were trial-defined major adverse cardiovascular events (MACE) and serious adverse events (SAEs). Secondary endpoints included all-cause death, measures of ischemia (cardiovascular death, myocardial infarction [MI], any revascularization, stroke) and measures of safety (serious infections or sepsis and gastrointestinal adverse events). All analyses included an interaction term for the clinical presentation. Sensitivity analyses were performed to explore sources of heterogeneity. After literature search, 20 trials encompassing a total of 21,486 patients (65.4% ACS) were included. Colchicine significantly reduced MACE (incidence rate ratio [IRR]: 0.70; 95% CI 0.55-0.87) without increasing risk for SAEs. Colchicine also reduced MI (IRR 0.81; 95% CI 0.70-0.94) and any revascularization (IRR 0.71; 95% CI 0.51-0.99), while increasing the risk of gastrointestinal adverse events (IRR 1.68; 95% CI 1.23-2.28). No statistically significant interaction was noted for clinical presentation for any endpoint, but a significant interaction for the drug dosage administered and the relationship with the COVID-19 pandemic was noted. In conclusion, the use of colchicine in patients with CAD reduces MACE without significantly increasing SAEs compared to control, although increasing gastrointestinal adverse events, without interaction by clinical presentation.
NLP in Support of Pharmacovigilance: QUality Adverse Drug Reaction AcTIve Control (QUADRATIC).
Franchini A, Noseda R, Cornelius J … +6 more , Colombo A, Mitrovic S, Bertoli R, Ceschi A, Ruinelli L, Rinaldi F
Clin Pharmacol Ther · 2026 Jun · PMID 41757758 · Publisher ↗
Adverse drug reactions (ADRs) are a major cause of morbidity, hospital admissions, and in-hospital mortality, yet remain incompletely captured by post-marketing pharmacovigilance, which suffers from underreporting. Elect...
Adverse drug reactions (ADRs) are a major cause of morbidity, hospital admissions, and in-hospital mortality, yet remain incompletely captured by post-marketing pharmacovigilance, which suffers from underreporting. Electronic health records (EHRs) contain clinical narratives that can reveal otherwise unreported ADRs. Natural language processing (NLP) offers a scalable means to extract structured information from clinical narratives, supporting ADR detection and assessment. We conducted a retrospective cross-sectional study within a multisite hospital network in Southern Switzerland to develop and evaluate NLP systems for ADR detection and information extraction from electronic discharge summaries. ADR classification models were trained on 400 discharge summaries and compared across multiple machine learning and vectorization strategies against a regular expression (regex) system. Drug and clinical event extraction were evaluated using 100 manually annotated summaries, benchmarking a dictionary-based approach against a two-step deep learning (DL) pipeline integrating transformer-based named entity recognition (NER) with a pharmacovigilance-oriented contextual relevance classifier. Performance was evaluated using standard metrics and a custom top-k ranking metric aligned with pharmacovigilance experts' daily capacity for reviewing positive cases to confirm the presence of ADRs. Logistic regression with Bag-of-Words achieved the best overall performance, combining high precision and effective case ranking. In a simulated deployment, this model identified nearly twice as many discharge summaries containing confirmed ADRs than as regex system. The two-step DL pipeline outperformed the dictionary-based approach for drug and clinical event recognition and accurately classified them according to pharmacovigilance purposes. These results demonstrate that NLP-based analysis of real-world clinical narratives can enhance pharmacovigilance while maintaining a manageable expert workload.
Population Pharmacokinetics of Dupilumab in Adults, Adolescents, and Children With Eosinophilic Esophagitis.
Nguyen JH, Chehade M, Dellon ES … +6 more , Radin A, Chittenden J, Kamal MA, Louisias M, Xu C, Kosloski MP
Clin Pharmacol Ther · 2026 Jun · PMID 41749054 · Full text
Dupilumab, a fully human monoclonal antibody that blocks key drivers of type 2 inflammation, is approved across 8 diseases, including eosinophilic esophagitis. Subcutaneous dupilumab 300 mg weekly improved outcomes vs. p...
Dupilumab, a fully human monoclonal antibody that blocks key drivers of type 2 inflammation, is approved across 8 diseases, including eosinophilic esophagitis. Subcutaneous dupilumab 300 mg weekly improved outcomes vs. placebo in adults (aged ≥ 18 years) and adolescents (aged ≥ 12 to < 18 years) during the phase III LIBERTY EoE TREET study (NCT03633617). The phase III EoE KIDS study (NCT04394351) demonstrated efficacy of a weight-tiered, higher exposure dupilumab dose approximating 300 mg weekly exposure in TREET vs. placebo in children aged ≥ 1 to < 12 years. To characterize dupilumab pharmacokinetics, inform clinical trial design, and optimize posology, a population pharmacokinetic model was developed using dupilumab concentration data from 6 single-dose studies in healthy adults and 3 eosinophilic esophagitis clinical trials. Healthy volunteer data were used to construct a stable base model; incorporation of patient data allowed estimation covariate effects for the disease population. Observational data from up to 52 weeks of treatment in eosinophilic esophagitis trials validated model performance. Significant effects were identified for body weight on clearance and volume of distribution, including time-varying weight in children and adolescents, and of albumin on clearance; age was not a significant covariate. Simulations identified alternative dupilumab regimens for patients weighing ≥ 5 to <15 kg (200 mg every 3 weeks) and ≥ 40 to <60 kg (300 mg weekly) with improved exposure matching to the 300 mg weekly dose in TREET. The final model was used to inform regulatory approval and potential future clinical trial design.
Integrating Patient Engagement into Clinical Pharmacology and Pharmacometrics: Bringing the Patient Voice into Data-Driven Science.
Zhou J, Frank SC, Spears PA … +3 more , Musante CJ, Wheeler SB, Muluneh B
Clin Pharmacol Ther · 2026 Jun · PMID 41748862 · Publisher ↗
Patient engagement (PE) refers to the active partnership between researchers and patients throughout the research process. Here, we introduce a novel framework that embeds PE directly into quantitative modeling workflows...
Patient engagement (PE) refers to the active partnership between researchers and patients throughout the research process. Here, we introduce a novel framework that embeds PE directly into quantitative modeling workflows, including model scoping and question framing, covariate selection, dose and regimen optimization, and interpretation of model outputs. Practical approaches such as feedback sessions and "data parties" demonstrate how integrating PE can systematically inform modeling decisions and ensure analyses remain patient-centered.
Reframing the "Rescue Window": From Physiological Upper Bounds to Actionable Thresholds.
Sun M, Zang D, Chen J
Clin Pharmacol Ther · 2026 Jul · PMID 41745689 · Publisher ↗
Abstract loading — click title to view on PubMed.
ASCPT Annual Meeting Abstracts: Advancing Pharmacoequity.
Clin Pharmacol Ther · 2026 Mar · PMID 41733569 · Publisher ↗
Abstract loading — click title to view on PubMed.
Post hoc Population Standardization of Trial Emulation Studies in Claims Data: An RCT-DUPLICATE Analysis.
Htoo PT, Patorno E, Schneeweiss S … +1 more , Wang SV
Clin Pharmacol Ther · 2026 May · PMID 41733244 · Publisher ↗
Benchmarking evidence from nonrandomized healthcare database studies against randomized clinical trials could strengthen confidence that database studies can reproduce known trial results and extend analyses to questions...
Benchmarking evidence from nonrandomized healthcare database studies against randomized clinical trials could strengthen confidence that database studies can reproduce known trial results and extend analyses to questions not directly addressed in trials. However, the process can be challenging if differences in effect modifier distributions persist despite the same eligibility criteria between trials and their emulations. Post hoc population standardization can address this by aligning observable population distributions. Across four cardiovascular outcome trials previously emulated in claims data by the RCT-DUPLICATE initiative, we implemented post hoc population standardization by potential effect modifiers to study whether effect estimates meaningfully move closer to the trial findings. Exposures and comparators were 1:1 propensity score-matched on > 100 baseline characteristics. In all trials, we standardized age and sex distributions to match those of the emulated RCTs and, additionally, some cardiovascular risk factors, data permitting. Standardization resulted in close alignment of the select baseline characteristics, yet produced minimal changes in hazard ratios (HRs) and 1-year risk differences. Variance increased in some analyses, reflecting large population differences in certain trial-database comparisons. The benefits of population standardization must be weighed against challenges such as weight variability, bias-variance tradeoff, and limited overlap in covariate distributions. Importantly, differences in effect modifier distributions may not alter effect estimates if modifiers do not change the exposure-outcome relationship on the multiplicative scale, underscoring the distinction between statistical and biological interactions. In our four example trials, post hoc population standardization equalized populations but did not result in closer alignment of treatment effect estimates and expanded 95% confidence intervals.
Antihypertensive drug-induced adverse events in patients aged 80 years and older: A retrospective analysis using the Japanese Adverse Drug Event Report Database.
Matsushima R, Hashiguchi M, Shiga T
Int J Clin Pharmacol Ther · 2026 Jun · PMID 41723747 · Publisher ↗
BACKGROUND: This study aimed to evaluate major antihypertensive drugs associated with adverse events (AEs) in patients aged ≥ 80 years using the Japanese Adverse Drug Event Report (JADER) database. MATERIALS AND METHODS:...
BACKGROUND: This study aimed to evaluate major antihypertensive drugs associated with adverse events (AEs) in patients aged ≥ 80 years using the Japanese Adverse Drug Event Report (JADER) database. MATERIALS AND METHODS: We utilized the JADER database (April 2004 - September 2023). Patients aged ≥ 80 years who were taking angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), dihydropyridine calcium channel blockers (CCBs), β-blockers, and thiazide/thiazide-like diuretics as "suspected agents" were included. Eight AEs were extracted for analysis. Adjusted reporting odds ratios (aRORs) and 95% confidence intervals (CIs) were calculated using sex as a covariate. RESULTS: The highest aROR for syncope/loss of consciousness was associated with β-blockers (2.57 (95% CI 1.84 - 3.58)), followed by CCBs (2.56 (95% CI 1.95 - 3.36)). Only CCBs showed a significant associated with falls (1.58 (95% CI 1.10 - 2.27)). The highest aROR for bradycardia was associated with β-blockers (18.20 (95% CI 15.64 - 21.18)). The highest aROR for renal failure was for diuretics (2.71 (95% CI 1.83 - 4.02)), followed by ACEIs/ARBs (2.26 (95% CI 1.97 - 2.58)). Electrolyte abnormalities had the greatest aROR for hyperkalemia with ACEIs/ARBs (15.34 (95% CI 13.70 - 17.18)) and for hypokalemia and hyponatremia with diuretics (15.72 (95% CI 11.30 - 21.87), 27.40 (20.27 - 37.0)). Only CCBs showed a significant associated with edema (4.00 (95% CI 2.32 - 6.91)). CONCLUSION: This study, which employed the JADER database, identified specific AEs associated with drug use in patients aged ≥ 80 years. These AEs included syncope/loss of consciousness associated with β-blockers or CCBs as well as falls and edema associated with CCBs.
Iodixanol-induced acute kidney injury and multi-organ complications via alternative excretion: A case report and mechanism exploration.
Li L, Yang L, Wu H … +2 more , Chen L, Jiang Z
Int J Clin Pharmacol Ther · 2026 Jun · PMID 41723746 · Publisher ↗
OBJECTIVE: To report a rare case of vicarious contrast material excretion (VCME) following iodixanol administration, leading to acute kidney injury (AKI) and multi-organ complications, and to explore the underlying mecha...
OBJECTIVE: To report a rare case of vicarious contrast material excretion (VCME) following iodixanol administration, leading to acute kidney injury (AKI) and multi-organ complications, and to explore the underlying mechanisms. CASE PRESENTATION: A 71-year-old female underwent lower limb venography with intravenous iodixanol. Post-procedure, she developed AKI, followed by acute pancreatitis, hepatic hemorrhage, and hemoperitoneum. Imaging revealed contrast accumulation in the gallbladder and biliary tract, consistent with VCME. INTERVENTION AND OUTCOME: The patient was managed with hemodialysis, octreotide, transfusion, and supportive care. Laboratory and imaging improvements were observed by day 22, with successful discharge. CONCLUSION: This case highlights the potential for iodixanol to induce VCME and subsequent multi-organ injury in the setting of AKI. Enhanced preoperative risk assessment, postoperative monitoring, and multidisciplinary management are essential for mitigating such rare but severe complications.
A randomized, open-label, single-dose study to evaluate the safety and pharmacokinetics of two formulations containing 40 mg of fexuprazan in healthy Korean subjects.
Hur J, Lee JA, Park H … +5 more , Choi Y, Chae J, Kwak YG, Moon SJ, Kim MG
Int J Clin Pharmacol Ther · 2026 May · PMID 41723745 · Publisher ↗
OBJECTIVE: To evaluate the pharmacokinetics and safety of two 40-mg fexuprazan formulations. MATERIALS AND METHODS: This study was an open-label, randomized, single-dose, crossover bioequivalence trial in healthy subject...
OBJECTIVE: To evaluate the pharmacokinetics and safety of two 40-mg fexuprazan formulations. MATERIALS AND METHODS: This study was an open-label, randomized, single-dose, crossover bioequivalence trial in healthy subjects. 24 subjects were randomized to receive either the test formulation, tablet A (40 mg fexuprazan), or the reference formulation, tablet B (40 mg fexuprazan), with crossover administration. Plasma samples were collected up to 48 hours post-dose and analysed for fexuprazan using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Individual pharmacokinetic parameters were derived by noncompartmental analysis. Safety was evaluated throughout the study. RESULTS: 22 subjects completed the study and were included in the pharmacokinetic analysis. Geometric mean values of area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC) was 380.17 and 390.33 ng×h/mL for the test and reference formulations, respectively. Geometric mean values of maximum plasma concentration (C) were 29.36 and 31.65 ng/mL for the test and reference formulations, respectively. The 90% confidence intervals (CIs) for the test/reference geometric mean ratios of AUC and C were 0.9098 - 1.0427 and 0.8665 - 0.9931, respectively. All adverse events were mild, and no serious adverse events occurred. CONCLUSION: The novel 40-mg fexuprazan formulation (tablet A) was demonstrated to be bioequivalent to the initially developed formulation (tablet B), with comparable systemic exposure (AUC) and peak concentration (C). Both formulations were well tolerated, with no clinically meaningful differences in adverse event profiles.
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