The Journal of Clinical Pharmacology最新文献

{"title":"PBPK Modeling of Esomeprazole to Support Adolescent Pharmacokinetic Extrapolation and Label Extension in Chinese Patients With Gastroesophageal Reflux Disease (GERD)","authors":"Yuwen Jin MS,&nbsp;Junjie Ding PhD,&nbsp;Xiaohan Hua MS,&nbsp;Wei Duan MS,&nbsp;Mo Chen MS,&nbsp;Zhaohui Zhou MD,&nbsp;Ramesh V Pandherpur MBBS,&nbsp;Jin Dong PhD,&nbsp;Sharma Pradeep PhD,&nbsp;Peiming Ma PhD,&nbsp;Weifeng Tang PhD,&nbsp;Diansong Zhou PhD","doi":"10.1002/jcph.70255","DOIUrl":"10.1002/jcph.70255","url":null,"abstract":"<p>Esomeprazole, a proton pump inhibitor (PPI), is widely approved for gastroesophageal reflux disease (GERD) in adults and pediatrics globally, but prior to December 2022, its oral tablets (20 and 40 mg) were approved only for adults in China. To address unmet needs in Chinese adolescents aged 12–17 years, physiologically based pharmacokinetic (PBPK) modeling was employed to extrapolate data and support label extension, leveraging similarities in GERD pathophysiology and PK/PD relationships across ages and ethnicities.</p><p>A PBPK model was developed for esomeprazole to capture the enteric-coated formulation's pharmacokinetics. The model was validated against clinical PK studies in Caucasian, Japanese, and Chinese adults and/or adolescents, demonstrating good predictions of concentration–time profiles and area under the curve (AUC) for CYP2C19-specific genotypes as well as overall populations across these ethnic groups. All predicted-to-observed ratios for AUC fell within 0.5- to 2.0-fold, with 14 out of 18 predictions within the 0.67- to 1.5-fold. This robust validation enabled the model's application to predict PK in Chinese adolescents.</p><p>PBPK predictions for Chinese adolescents indicated that steady-state AUC for 20- and 40-mg doses was comparable to that in Japanese adolescents and slightly higher than in Caucasian adolescents. By integrating an established PK/PD relationship between AUC and the percentage of time with intragastric pH &gt;4, once-daily doses of 20 or 40 mg were justified, achieving adequate acid suppression with a favorable safety profile. This PBPK-informed extrapolation was accepted by China's National Medical Products Administration (NMPA), enabling GERD indication extension to adolescents.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148727296","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":"Bayesian-Estimated Vancomycin AUC24 as a Near-Term Renal Risk Signal after Therapeutic Drug Monitoring: A Multicenter Cohort Study","authors":"Tran Van Anh BPharm, MSc,&nbsp;Bui Thi Tham BPharm, PhD,&nbsp;Tran Thi Ngan BPharm, PhD,&nbsp;Nguyen Duc Long, BPharm,&nbsp;Nguyen Huong Giang BPharm, MSc,&nbsp;Nguyen Hoang Anh BPharm, PhD,&nbsp;Vu Dinh Hoa BPharm, PhD,&nbsp;Hoang Van Dung MD, PhD,&nbsp;Nguyen Thi Thu Phuong MD, PhD","doi":"10.1002/jcph.70265","DOIUrl":"10.1002/jcph.70265","url":null,"abstract":"<p>Vancomycin therapeutic drug monitoring has moved toward area under the concentration–time curve (AUC)-guided dosing, but the clinical meaning of a Bayesian-estimated AUC generated at an individual monitoring episode remains uncertain when renal clearance may already be changing. We conducted a retrospective multicenter cohort study using inpatient dosing, pharmacy, therapeutic drug monitoring, and laboratory data from two hospitals in Hai Phong, Viet Nam, between 2019 and 2025. The analysis included 898 adult index vancomycin monitoring episodes with valid Bayesian-estimated AUC24 and sufficient serum creatinine data to ascertain acute kidney injury (AKI) within 48 h. AUC24 was estimated within the institutional Bayesian monitoring workflow using SmartDoseAI, with BestDose version 2.4.3 used as an independent pharmacokinetic cross-check in selected clinically uncertain episodes. AKI occurred in 84 episodes (9.4%). Higher continuous AUC24 was associated with AKI in the minimally adjusted model (odds ratio, 1.16 per 100 mg·h/L; 95% confidence interval, 1.02–1.33; <i>P</i> = .023), whereas categorical AUC contrasts were imprecise. The association attenuated after exclusion of 23 episodes with possible pre-existing AKI before the index monitoring episode (odds ratio, 1.12; 95% confidence interval, 0.96–1.31; <i>P</i> = .159), and restricted cubic spline modeling did not identify a distinct nonlinear threshold. Bayesian-estimated AUC24 at monitoring may therefore be most useful as a near-term renal risk signal that integrates vancomycin exposure with evolving renal clearance, rather than as a standalone causal toxicity threshold.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148727363","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":"Safety, Tolerability, and Pharmacokinetics of Oral Camlipixant: A Randomized First-In-Human Study Using Single and Multiple Ascending Doses","authors":"Nathalie Chauret MSc,&nbsp;Denis Garceau PhD,&nbsp;Laurent Harvey MSc,&nbsp;Zelie Bailes MSc,&nbsp;Elizabeth A. Duncan MD, PhD,&nbsp;Rhian McNaughton PhD,&nbsp;Miren Zamacona PhD","doi":"10.1002/jcph.70253","DOIUrl":"10.1002/jcph.70253","url":null,"abstract":"<p>Camlipixant is a highly selective P2X3 receptor antagonist with demonstrated efficacy in pre-clinical models of evoked cough. We report the safety, tolerability, and pharmacokinetics of camlipixant in healthy participants. This Phase 1, double-blind, randomized study evaluated single ascending doses (SAD; 50/100/200/400/800/1200 mg) and multiple ascending doses (MAD; 100/200/400 mg, twice daily [BID]) of oral camlipixant versus placebo. Ninety participants were included (SAD n =  60; MAD n =  30). Treatment-emergent adverse event (TEAE) incidence was similar between camlipixant (32/72) and placebo (9/18). TEAEs were mostly mild (83%), and the most common with camlipixant was dysgeusia, primarily at doses ≥400 mg (n =  13), versus 50–200 mg (n =  1). Camlipixant was rapidly absorbed (time to maximum plasma concentration SAD: 0.77–2.29 h; MAD: 0.50–2.00 h), with a short half-life (SAD 4.28–6.71 h; MAD 7.60–8.39 h). In both cohorts, maximum plasma concentration (C_max) increased proportionally with dose. The area under the curve extrapolated to infinity (AUC_0–∞) increased proportionally with dose in the SAD cohort; the increase was slightly supra-proportional in the MAD cohort (steady state reached on Day 2). The geometric mean apparent volume of distribution ranged from 44.9 to 70.2 L and clearance from 5.7 to 10.4 L/h in the SAD cohort. Pharmacokinetics were unaffected by food (geometric mean fed/fasted ratio C_max 91.4% [90% confidence interval, CI, 69.8–119.6]; AUC_0–∞ 105.5% [90% CI, 89.8–124.0]). In summary, camlipixant was well tolerated, with pharmacokinetics supporting BID dosing and further clinical development for refractory chronic cough.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70253","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148708182","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":"FDA's Approval Summary of the First Biosimilar to Natalizumab for the Treatment of Multiple Sclerosis and Crohn's Disease","authors":"Poonam R. Delvadia PhD,&nbsp;Anantha Ram Nookala PhD,&nbsp;Gopichand Gottipati PhD,&nbsp;Sreedharan Sabarinath PhD,&nbsp;Ramana S. Uppoor PhD,&nbsp;Mehul U. Mehta PhD,&nbsp;Xiulian Du PhD,&nbsp;Yow-Ming C. Wang PhD,&nbsp;Milos Dokmanovic PhD,&nbsp;Riley Myers PhD,&nbsp;Jessica Stevens MD,&nbsp;Laura Baldassari MD, MHS,&nbsp;Paul Lee MD, PhD,&nbsp;Laura Jawidzik MD, FAAN,&nbsp;Sandhya Apparaju PhD,&nbsp;Suna Seo MD, MSc,&nbsp;Nina N. Brahme PhD, MPH,&nbsp;Sarah J. Schrieber PharmD","doi":"10.1002/jcph.70257","DOIUrl":"10.1002/jcph.70257","url":null,"abstract":"<p>The development and approval of biosimilars are imperative for improving patient access to safe and effective treatments. This article summarizes the regulatory approval for Tyruko, the first FDA-approved biosimilar for natalizumab for the treatment of multiple sclerosis and Crohn's disease. Biosimilarity between the proposed biosimilar and the reference product was demonstrated through a comprehensive comparative assessment that included structural and functional characterization, pharmacokinetics (PK)/pharmacodynamics (PD) data, immunogenicity, and safety. The PD assessment incorporated a panel of biomarkers indicative of target engagement and downstream biological responses. The current case underscores the importance of the 351(k) pathway and highlights how the PD-based approach, in conjunction with comparative analytical assessments and PK data, supported the approval of the biosimilar through a study design relying on fewer subjects and a shorter duration compared to an efficacy study.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148702216","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":"Population Pharmacokinetics and Exposure–Response Analyses of Vepdegestrant, a First-in-Class PROteolysis-TArgeting Chimera Estrogen Receptor Degrader","authors":"Derek Z. Yang PharmD,&nbsp;Joanna C. Masters PharmD, FCP,&nbsp;Hechuan Wang PhD,&nbsp;Lana Tran PharmD,&nbsp;Yuanyuan Zhang PhD,&nbsp;Kimberly C. Lee MBA,&nbsp;Weiwei Tan PhD,&nbsp;Brian Jermain PharmD","doi":"10.1002/jcph.70252","DOIUrl":"10.1002/jcph.70252","url":null,"abstract":"<p>Population pharmacokinetic (PK) and exposure–response analyses were performed to characterize the PK and exposure–response relationships of vepdegestrant, a first-in-class, oral PROteolysis-TArgeting Chimera estrogen receptor degrader. Population PK and exposure–response analyses for safety utilized data from the first-in-human study (ARV-471-mBC-101, NCT04072952) and the registrational VERITAC-2 study (NCT05654623), which included patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Safety endpoints of clinical interest were evaluated using logistic regression and included grade ≥3 treatment-emergent adverse events (TEAEs) and TEAEs of any grade (arthralgia, fatigue, nausea, aspartate aminotransferase or alanine aminotransferase elevations, anemia, and neutrophil count decreased). Exposure–efficacy analysis included patients with estrogen receptor-1 (ESR1)-mutated, ER-positive, HER2-negative advanced breast cancer from the VERITAC-2 vepdegestrant arm only. Progression-free survival (PFS) as assessed by blinded independent central review, the primary efficacy endpoint in VERITAC-2, was assessed via Cox proportional hazards modeling. Vepdegestrant PK was described by a two-compartment model with linear elimination and sequential zero-, first-order absorption. None of the evaluated covariates significantly influenced the disposition of vepdegestrant. There was no statistically significant relationship between vepdegestrant exposure and any of the evaluated safety endpoints across 30-500 mg total daily doses. In patients with ESR1-mutated, ER-positive, HER2-negative advanced breast cancer treated with vepdegestrant 200 mg once daily in the VERITAC-2 study, exposure was not a statistically significant predictor of PFS. Overall, integrated analyses adequately characterized the PK of vepdegestrant, with no clinically meaningful covariate effects. No exposure–response relationships were identified between vepdegestrant exposure and efficacy or safety outcomes.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148702345","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":"From Small Data to Big Decisions: How Clinical Pharmacology Shapes Rare Disease Development","authors":"Yan Xu MD, PhD, FCP,&nbsp;Alissa Verone-Boyle PhD,&nbsp;Natalie Schmitz PharmD, PhD,&nbsp;Hamim Zahir PhD,&nbsp;Brian A. Willis PhD","doi":"10.1002/jcph.70250","DOIUrl":"https://doi.org/10.1002/jcph.70250","url":null,"abstract":"<p>Rare‑disease drug development is constrained by small and heterogeneous patient populations, limited natural‑history data, and the impracticality of large, randomized trials. Despite increasing regulatory acceptance of totality-of-evidence and mechanism-based development pathways, generating reliable, decision-ready evidence under these constraints remains challenging. This review describes how clinical pharmacology contributes within an evidence‑integration and decision‑support framework through quantitative, model‑informed approaches to address this gap. By integrating nonclinical data, pharmacokinetics, pharmacodynamics, biomarkers, natural‑history information, and clinical efficacy and safety outcomes, and through close collaboration with clinical, statistical, and translational experts, clinical pharmacology supports interpretation of treatment effects and quantitative characterization of uncertainty when conventional evidence is limited. In practice, these approaches inform key development decisions, including dose selection, innovative trial designs, extrapolation and bridging across populations, use of external controls, and evaluation of biomarkers and surrogate endpoints. Importantly, such practices help align regulatory expectations with patient needs, particularly in pediatric and ultra‑rare settings, by enabling appropriate dosing, reduced trial and patient burden, and quantitative assessment of benefit/risk. Examples from rare‑disease programs illustrate how integrated quantitative evidence has supported regulatory decisions, including label expansion and accelerated approval when data may be sparse, heterogeneous, or evolving. Looking ahead, emerging technologies such as artificial intelligence, digital biomarkers, and individualized approaches are expected to further advance rare‑disease drug development. With this evolving landscape, clinical pharmacology is expected to continue playing an important role in evaluating mechanistic plausibility, ensuring analytic rigor, and translating small datasets into meaningful evidence to inform development and regulatory decisions in rare diseases.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148617315","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":"Concentrated Magnesium Sulfate and Pharmacokinetics-Guided Neuroprotection in Pregnant Patients with Cardiac Disease","authors":"Gregory W. Kirschen MD, PhD,&nbsp;Huda Eldabbas PharmD,&nbsp;Tyler Nichols PharmD,&nbsp;Reeba John PharmD,&nbsp;Madeline F. Perry MD,&nbsp;Laura Smith MD","doi":"10.1002/jcph.70254","DOIUrl":"https://doi.org/10.1002/jcph.70254","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Magnesium sulfate (MgSO&lt;sub&gt;4&lt;/sub&gt;) is a commonly employed medication in the obstetrics space for fetal neuroprotection and maternal eclampsia prophylaxis. While the therapeutic window of MgSO&lt;sub&gt;4&lt;/sub&gt; in severe preeclampsia is established at 4.8–8.4 mg/dL, target levels for fetal neuroprotection remain poorly defined.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Another common issue related to MgSO&lt;sub&gt;4&lt;/sub&gt; is the high volume of intravenous (IV) fluid administration required to achieve/maintain therapeutic targets. In our institution, MgSO&lt;sub&gt;4&lt;/sub&gt; for obstetric patients comes as a premix of 20 g in 500 mL of carrier fluid (40 mg/mL), which is run at a rate of 6 g (150 mL) bolus + 2 g (50 mL)/h infusion (assuming normal renal function) at least until delivery and up to 24 h thereafter, depending on indication. This becomes clinically problematic for patients who cannot handle the large volume of IV fluid required for administration. In such cases, magnesium may be withheld or subtherapeutically dosed, potentially leading to suboptimal maternal/neonatal neurological outcomes.&lt;/p&gt;&lt;p&gt;We therefore compounded a novel concentrated formulation of MgSO&lt;sub&gt;4&lt;/sub&gt; for IV administration in two pregnant patients with maternal cardiac disease (Patient 1: heart failure with reduced ejection fraction; Patient 2: dilated cardiomyopathy and pulmonary hypertension) both with normal renal function who required magnesium for neuroprotection. Based on the elegant modeling study by Brookfield and colleagues, a secondary analysis of pharmacokinetics (PK) data from the BEAM Trial, we were curious whether we could achieve a maternal plasma concentration of ∼3–4 mg/dL, which the investigators found to be the optimal window for neonatal cerebral palsy (CP) prophylaxis.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; They also found signal for benefit in CP risk reduction at a minimum dose exposure of 14 g. We therefore aimed to achieve a total dose of ≥14 g MgSO&lt;sub&gt;4&lt;/sub&gt; prior to delivery.&lt;/p&gt;&lt;p&gt;As per the manufacturer, MgSO&lt;sub&gt;4&lt;/sub&gt; 50% can be safely administered at a concentration of ≤20% mass/volume.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; We compounded a 20% MgSO&lt;sub&gt;4&lt;/sub&gt; solution by combining 30 g MgSO&lt;sub&gt;4&lt;/sub&gt; (60 mL of 50% MgSO&lt;sub&gt;4&lt;/sub&gt; solution) with 90 mL of 0.9% sodium chloride (final volume 150 mL/bag). Both patients received a 6 g bolus (30 mL) followed by a 2 g/h maintenance infusion (10 mL/h). Patient 1 received a total dose of 18 g in 90 mL while Patient 2 received a total dose of 44 g in 220 mL.&lt;/p&gt;&lt;p&gt;We assessed maternal plasma magnesium levels prior to and after commencement of IV MgSO&lt;sub&gt;4&lt;/sub&gt;, and assessed umbilical cord blood magnesium levels at time of delivery, to quantify placental drug transfer (Figure 1). Consistent with Brookfield et al.’s model and prior PK data, we observed a maternal plasma Mg 3.6-4.4 mg/dL after bolus + infusion, and observed umbilical cord blood Mg of 3.2–3.8 mg/dL (mean fetal:maternal ratio = 0.875).&lt;span&gt;&lt;sup&gt;2, 5&lt;/sup&gt;&lt;/spa","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70254","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148616831","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 Study of a Long-Acting GLP-1 Receptor Agonist (TE-8105) in Overweight or Obese Adults Without Type 2 Diabetes Mellitus","authors":"Ya-Shan Chuang BSc, PhD,&nbsp;Jon D. Wright BSc (Hons), PhD,&nbsp;Mun-Teng Wong BHSc (Hons), PhD,&nbsp;Kushal J Paneliya BHSc,&nbsp;Wei-Shiung Yang MD, PhD,&nbsp;Hsing-Mao Chu BSc, PhD,&nbsp;Tse Wen Chang BScMScPhD,&nbsp;Thomas M Polasek BSc, BPharm (Hons), MD, PhD, FCP","doi":"10.1002/jcph.70224","DOIUrl":"https://doi.org/10.1002/jcph.70224","url":null,"abstract":"<p>Glucagon-like peptide-1 (GLP-1) receptor agonists have revolutionized weight management and are becoming essential for the treatment of obesity-related medical conditions. This study aimed to determine the pharmacokinetics, preliminary pharmacodynamics, safety, and tolerability of a long-acting GLP-1 receptor agonist, TE-8105, in overweight or obese adults without T2DM. An open-label study of four single ascending dose cohorts (A1-A4, 0.5, 0.75, 1.5, and 3.0 mg TE-8105, respectively) and two multiple dose cohorts (B1 flat dosing, 1.0 mg TE-8105 Q2W SC for 5 doses, and B2 titration dosing, sequence 2 × 1.5, 2 × 2.0, 2 × 2.5, and 3 × 3.0 mg Q2W SC) was conducted using a combination of in-patient and out-patient assessments. The half-life of TE-8105 was about 120 h. There was no accumulation after flat dosing, but mean (SD) accumulation ratios were 3.75 (0.86) for C_max and 3.00 (0.65) for AUC following titration dosing. The mean % decrease in body weight from baseline to the end of study visit for titration dosing was 2.06%, with 4/8 participants maintaining weight loss of ≥5%. Treatment-related treatment emergent adverse effects (TEAEs) were consistent with the mechanism of action of TE-8105 and dose-dependent, including nausea (Part A: 16.7%; Part B: 21.4%), abdominal pain (Part A: 4.2%), constipation (Part A: 4.2%; Part B: 7.1%), and vomiting (Part A: 4.2%; Part B: 7.1%). Overall, TE-8105 was safe and well tolerated with pharmacokinetics potentially allowing for less frequent SC dosing than currently available GLP-1 receptor agonists.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70224","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148616830","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":"Lack of Differences in the Pharmacokinetics of Therapeutic Monoclonal Antibodies Between Japanese and Non-Japanese Individuals","authors":"Paridhi Gupta PhD,&nbsp;Ashish Sharma PhD,&nbsp;Bernd Meibohm PhD, FCP, FAAPS","doi":"10.1002/jcph.70245","DOIUrl":"https://doi.org/10.1002/jcph.70245","url":null,"abstract":"<p>Evaluation of the pharmacokinetics (PK) of new drugs in Japanese individuals is regularly requested by the Japanese regulatory agency prior to participation in global clinical trials or for bridging approaches for regulatory approval. However, the need for PK assessments in the Japanese population may be less compelling for monoclonal antibodies (mAbs) compared to other drugs, given that the intrinsic properties of immunoglobulin G molecules are generally considered ethnically insensitive. This prompted an evaluation of the currently available evidence for potential PK differences for mAbs between Japanese and Non-Japanese populations. We reviewed 137 mAbs approved in the United States, of which 101 were also approved in Japan, to evaluate whether PK differences between Japanese and non-Japanese individuals have been reported. PK was found to be similar between Japanese and non-Japanese, predominantly Caucasians/Whites, for 59 out of 101 mAbs. Although PK differences were identified for 26 out of 101 mAbs approved in Japan, these differences were largely attributed to body weight differences between Japanese and non-Japanese populations. After adjusting for these body weight differences, most mAbs demonstrated no meaningful PK differences across the ethnic groups. Importantly, the observed differences were reported not to translate into clinically meaningful impact on pharmacodynamics, safety, and efficacy to warrant different dosing recommendations. No differences in dosing recommendations could be detected for any of the 101 mAbs approved in Japan compared to the United States. Overall, these data suggest a lack of a convincing scientific rationale for the necessity of dedicated PK studies in Japanese versus non-Japanese individuals for mAbs.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70245","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148616832","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":"Volumetric Absorptive Microsampling During Spaceflight for Analysis of Acetaminophen Pharmacokinetics in Whole Blood","authors":"David Mampre MD,&nbsp;Robert Guttendorf PhD,&nbsp;Jennifer Zimmer PhD,&nbsp;Brooke Whitson  ,&nbsp;James Huggins  ,&nbsp;Chad Christianson  ,&nbsp;Erik Burns  ,&nbsp;Nicolas Heft MD,&nbsp;Marissa Rosenberg MS, PhD,&nbsp;Amran Asadi MD, PhD,&nbsp;Jaime Mateus PhD,&nbsp;James Rudge PhD,&nbsp;Takako Mizuno PhD,&nbsp;John Donehoo RPh","doi":"10.1002/jcph.70240","DOIUrl":"https://doi.org/10.1002/jcph.70240","url":null,"abstract":"<p>Spaceflight induces altered physiology that has the potential to alter medication pharmacokinetics due to factors including gastrointestinal motility, fluid balance, circulatory dynamics, hormonal changes, and metabolic alterations. Here, we report the first pharmacokinetic analysis using blood samples during spaceflight. The four SpaceX Polaris Dawn crewmembers ingested 500 mg of oral acetaminophen pre-flight, in-flight, and post-flight. Post-ingestion capillary blood samples were collected using volumetric absorptive microsampling (VAMS). Samples were analyzed using liquid chromatography-tandem mass spectrometry. All samples collected in microgravity were adequate for post-flight analysis. Compared to pre-flight baseline, in-flight increases were observed in the C_max (mean [SD] ng/mL: pre-flight = 9110 [3290], in-flight = 43,300 [5700], <b><i>P</i> &lt; .001</b>), AUC_0–last (mean [SD] h ng/mL: pre-flight = 26,100 [4520], in-flight = 109,000 [29,400]), and λ_z (mean [SD] 1/h: pre-flight = 0.227 [0.0688], in-flight = 0.336 [0.0209]). Compared to pre-flight baseline, in-flight decreases were observed in t_max (mean [SD] h: pre-flight = 1.06 [0.657], in-flight = 0.688 [0.239]), t_1/2 (mean [SD] h: pre-flight = 3.27 [0.950], in-flight = 2.07 [0.130]), CL/F (mean [SD] mL/h: pre-flight = 16,200 [2990], in-flight = 3890 [559]), and V_z/F (mean [SD] mL: pre-flight = 74,700 [18,800], in-flight = 11,500 [1100]). Compared to pre-flight baseline, C_max, AUC, and λ_z increased in-flight, while t_max, t_1/2, V_z/F, and CL/F decreased in-flight. C_max, AUC, V_z/F, and CL/F showed residual changes 3 days post-flight (R + 3). Supratherapeutic blood levels with standard terrestrial dosing raises concern for inadvertent toxicity in the spaceflight environment, and highlights the value of further pharmacokinetic study of medications commonly included within spaceflight medical systems. Overall, VAMS enabled pharmacokinetic study during spaceflight and could serve as a platform for future pharmacokinetic studies.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70240","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148616888","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}