Clinical Pharmacology in Drug Development最新文献

{"title":"Formulation-Dependent Modulation of Ibuprofen Absorption Kinetics in Fixed-Dose Combinations: An Exploratory Analysis of the Dissolution–Absorption Relationship","authors":"Satoko Ueda,&nbsp;Mitsuaki Chujo,&nbsp;Nobuo Miyadai,&nbsp;Clemence Rauch,&nbsp;Valentine Polivka,&nbsp;Yujin Saito,&nbsp;Ichiro Kawase,&nbsp;Naoki Uchida,&nbsp;Shunji Matsuki","doi":"10.1002/cpdd.70112","DOIUrl":"10.1002/cpdd.70112","url":null,"abstract":"<p>We conducted a pharmacokinetic study to compare two fixed-dose combinations of ibuprofen/acetaminophen (IP-TA and IP-TB) with different formulation designs and excipient compositions, and explored how formulation differences influence ibuprofen pharmacokinetics by comparing in vitro dissolution and in vivo absorption profiles. In an open-label, randomized, 2-treatment, 2-period, 2-sequence crossover study, 24 healthy Japanese participants received a single oral dose of IP-TA (ibuprofen 195 mg and acetaminophen 195 mg) or IP-TB (ibuprofen 160 mg and acetaminophen 160 mg) under fasting conditions. Pharmacokinetic data were analyzed using a linear mixed-effects model. Fraction absorbed (F_a) was estimated using the Loo–Riegelman method, and ibuprofen dissolution was evaluated at pH 1.2, 4.0, and 6.8. The relationship between weighted mean dissolution rates (D) and F_a was examined. Ibuprofen absorption from IP-TA was faster than from IP-TB, as reflected by higher C_max and greater early exposure, and these differences remained after dose normalization. Dissolution profiles showed temporal similarity with absorption profiles, particularly for IP-TA. Analysis of F_a also suggested a relatively high degree of synchronization between ibuprofen and acetaminophen absorption in IP-TA. These findings indicate that formulation-dependent differences in dissolution behavior may influence early ibuprofen absorption, although further studies are needed to clarify the underlying mechanisms.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 10","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"When Clinical Pharmacology Cannot Wait for Complete Data: Reflections Following the 2026 ACCP Annual Meeting","authors":"Amalia M. Issa","doi":"10.1002/cpdd.70117","DOIUrl":"10.1002/cpdd.70117","url":null,"abstract":"&lt;p&gt;Another American College of Clinical Pharmacology (ACCP) Annual Meeting is successfully in the books. As always, the meeting offered a wide range of stimulating symposia and sessions as well as many thoughtful conversations that stayed with many of us well after the rooms emptied. Among them, Symposium 1, “Where Are We Now in Pediatric Cancer Drug Development: 5 Years of the RACE for Children Act,” brought together perspectives from FDA, industry, and pediatric oncology on a question that is both technically demanding and deeply human: how do we move promising therapies toward children with cancer when the evidence can never be as abundant as we would like?&lt;/p&gt;&lt;p&gt;That question becomes real when we picture the child in front of us: a child with a serious, life-threatening rare disease and no approved treatment. A therapy may have compelling biology and encouraging adult data, yet the appropriate pediatric dose, exposure target, benefit–risk profile, and durability of response remain incompletely characterized. In that moment, clinical pharmacologists are asked to confront a difficult but increasingly common question: should development wait for conventional evidentiary completeness, or should the available evidence be integrated quantitatively to support a timely, proportionate, and ethically defensible decision?&lt;/p&gt;&lt;p&gt;This question should not be construed as an invitation to lower evidentiary standards. Rather, it requires standards that are fit for purpose when large dose-ranging studies, conventional randomized trials, or extensive pediatric efficacy programs are infeasible, unacceptably slow, or ethically difficult to conduct. In pediatric rare diseases, the relevant goal is not “perfect” evidence. It is an evidence package that is mechanistically coherent, quantitatively rigorous, transparent about uncertainty, and appropriate to the severity of the condition, the unmet need, and the feasibility of obtaining additional data.&lt;/p&gt;&lt;p&gt;The ACCP Annual Meeting brought renewed focus to this central challenge in drug development. Discussions spanning pediatric oncology, pediatric extrapolation, model-informed dose selection, and rare-disease development underscored an expanding responsibility for clinical pharmacology: to transform sparse, fragmented, and heterogeneous evidence into decisions that are scientifically credible and clinically useful.&lt;/p&gt;&lt;p&gt;For readers of CPDD, this is not a peripheral issue. It lies at the intersection of pharmacokinetics, pharmacodynamics, translational science, quantitative systems pharmacology, regulatory science, and therapeutic decision-making. Clinical pharmacology is increasingly expected not merely to describe variability, but to explain it, predict its consequences, and guide action despite residual uncertainty.&lt;/p&gt;&lt;p&gt;Pediatric drug development has long been constrained by small populations, developmental heterogeneity, ethical limits on research participation, and delayed integration of pediatric plans into","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 10","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.70117","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic and Bioequivalence of Mirtazapine Orally Disintegrating Tablets: A Randomized, Crossover Study","authors":"Kai Bin Liew,&nbsp;Kar Ming Yee,&nbsp;Jeyashanthini Nalaiya,&nbsp;Atiqah Amran,&nbsp;Khairil Aswad Othman","doi":"10.1002/cpdd.70110","DOIUrl":"10.1002/cpdd.70110","url":null,"abstract":"<p>The study aimed to assess the bioequivalence of a new generic orally disintegrating tablet (ODT) formulation containing mirtazapine 30 mg with the reference formulation, and to support biowaiver for an additional 15 mg strength. Fifty-five healthy Malaysian males completed an open-label, balanced, randomized, 2-treatment, 2-period, single oral dose study with a 14-day washout period under fasting conditions. Each participant received a single 30 mg dose of mirtazapine test or reference ODT. Plasma concentrations of mirtazapine up to 72 h post-dose were quantified using a validated high-performance liquid chromatography-tandem mass spectrometry detection method following a liquid-liquid extraction. Non-compartmental analysis was used to derive the pharmacokinetic parameters, which were then compared between the test and reference formulations using a multivariate analysis of variance. The pharmacokinetic parameters of the test formulation were not statistically different from the reference formulation. The 90% confidence intervals of mirtazapine for AUC_0–72 and <i>C</i>_max concentration were within 80%-125% based on the bioequivalence acceptance range criteria. The test and reference formulations of mirtazapine 30 mg ODT are bioequivalent and well tolerated under fasting conditions. These findings support the extrapolation of bioequivalence and the justification of a biowaiver for the additional mirtazapine ODT 15 mg strength.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 10","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics and Exposure–Response Analysis of Arpraziquantel Supporting Dose in Preschool-Aged Children Infected with Schistosoma","authors":"Brigitte Brockhaus,&nbsp;Richard Mills,&nbsp;Ana-Marija Milenković-Grišić,&nbsp;Matthias Bödding,&nbsp;Rainer Strotmann,&nbsp;Wilhelmina Bagchus,&nbsp;Janet R. Wade,&nbsp;Wei Gao,&nbsp;Karthik Venkatakrishnan,&nbsp;Sathej Gopalakrishnan,&nbsp;Akash Khandelwal","doi":"10.1002/cpdd.70106","DOIUrl":"10.1002/cpdd.70106","url":null,"abstract":"<p>Schistosomiasis is an acute and chronic parasitic disease that occurs mainly in sub-Saharan and African countries and for which no treatment is available in preschool-aged children (PSAC). An open-label, Phase III study of arpraziquantel pediatric formulation evaluated safety and efficacy in 280 <i>Schistosoma</i>-infected PSAC (NCT03845140). A population pharmacokinetics (PK) model for arpraziquantel and its active metabolite trans-4-hydroxy-arpraziquantel was developed from concentration measurements (from n = 74 and n = 30 children for arpraziquantel and its metabolite, respectively) after a single dose of 50 or 60 mg/kg arpraziquantel. Extensive PK variability was observed but no significant covariates were identified in the final model other than body weight. Body weight-normalized apparent clearances overlapped across all weight and age categories, supporting body weight-based dosing. No apparent relationship was discernible between an efficacious response and arpraziquantel and/or trans-4-hydroxy-arpraziquantel exposures. Logistic regression analysis indicated higher incidence of treatment-emergent adverse events (TEAEs) with increasing arpraziquantel exposure. For gastrointestinal TEAEs, the incidence was related to infection type with higher incidence in <i>Schistosoma mansoni</i>-infected children. These population PK and exposure–response analyses performed after administration of arpraziquantel pediatric formulation support the weight-based dosing bands posology and the consistency in therapeutic effect over the range of exposures observed in PSAC.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 10","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic Interaction Between Eperisone and Ojeok-San in Healthy Subjects","authors":"Do Hoon Keum,&nbsp;Minkyu Choi,&nbsp;Kyoung Hoon Mo,&nbsp;Sukyong Yoon,&nbsp;Min Soo Park,&nbsp;Young Woo Kim,&nbsp;Won-Yung Lee,&nbsp;Choon Ok Kim","doi":"10.1002/cpdd.70111","DOIUrl":"10.1002/cpdd.70111","url":null,"abstract":"<p>Ojeok-san is a traditional multiherbal formulation commonly prescribed for musculoskeletal symptoms in East Asian medicine. The concomitant use of herbal medicines and conventional pharmacotherapy is common in patients with musculoskeletal disorders; however, the pharmacokinetic (PK) interactions between eperisone and ojeok-san have not been evaluated. This was an open-label, randomized, single-dose, three-treatment, six-sequence, three-period crossover study designed to evaluate the PK interactions between eperisone and ojeok-san in 24 healthy male participants. In each period, participants received a single oral dose of 150 mg eperisone, 15.0 g ojeok-san, or 150 mg eperisone plus 15.0 g ojeok-san, with 7-day washout periods between treatments. Plasma concentrations of eperisone and ephedrine, a marker constituent of ojeok-san, were quantified using validated liquid chromatography–tandem mass spectrometry. Coadministration with ojeok-san reduced eperisone exposure, with geometric mean ratios (GMRs) for C_max and AUC_last of 0.34 (90% CI: 0.25-0.46) and 0.51 (90% CI: 0.41-0.64), respectively. In contrast, eperisone had little effect on ephedrine exposure, with GMRs for C_max and AUC_last of 1.04 (90% CI: 0.98-1.09) and 1.12 (90% CI: 1.05-1.20), respectively. No adverse events were reported. These findings demonstrated a PK interaction in which ojeok-san reduced systemic exposure to eperisone.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 10","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fed–Fasted Differences in Clindamycin Hydrochloride Capsule Pharmacokinetics: A Pooled Analysis of Publicly Available China CDE Regulatory Summaries","authors":"Rui Li,&nbsp;Deshuang Yang,&nbsp;Lang Zhao,&nbsp;Zhengyi Cao,&nbsp;Xiaoyu Li,&nbsp;Mengxi Yang","doi":"10.1002/cpdd.70105","DOIUrl":"10.1002/cpdd.70105","url":null,"abstract":"<p>We evaluated food-associated differences in clindamycin hydrochloride capsule exposure by pooling publicly available regulatory bioequivalence (BE) summaries from the Center for Drug Evaluation of the National Medical Products Administration in China. Fourteen candidate regulatory identifiers were reviewed; one 0.15-g BE-exempt record without analyzable pharmacokinetic (PK) data was excluded, leaving 13 records (ten 150 mg and three 300 mg). CYHB1901758 and CYHB2140526 were treated as independent 300-mg BE records under the authors’ prespecified working assumption. For each record and endpoint, test and reference formulation fed/fasted ratios were combined on the log scale, and regulatory records were pooled with equal weight. For the 150-mg strength, pooled fed/fasted geometric mean ratios (GMRs) [95% descriptive interval] were 1.31 [1.24, 1.38] for AUC_0–t, 1.30 [1.23, 1.38] for AUC_0–inf, and 0.85 [0.80, 0.90] for C_max. For the 300-mg strength, the corresponding GMRs were 1.17 [0.92, 1.50], 1.19 [0.93, 1.52], and 0.93 [0.88, 0.97]. Thus, the available aggregate summaries showed higher total exposure and lower peak concentration under fed conditions, particularly for the 150-mg strength. These findings describe a food-associated PK pattern but do not constitute a formal regulatory food-effect assessment or support a change in meal-timing recommendations.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 10","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic and Bioequivalence Evaluation of Febuxostat 40 mg Tablets in Healthy Chinese Subjects Under Fasting and Fed Conditions","authors":"Ying Cao,&nbsp;Wenping Wang,&nbsp;Xiaobin Li,&nbsp;Huawei Wang,&nbsp;Xiaoyan Dou,&nbsp;Ming Yu,&nbsp;Xiujun Wu,&nbsp;Ran Ma,&nbsp;Caixia Jiang,&nbsp;Jing Yu","doi":"10.1002/cpdd.70104","DOIUrl":"10.1002/cpdd.70104","url":null,"abstract":"<p>The objective of the current study was to evaluate the rate and extent of absorption, and confirm the bioequivalence of a test formulation and a reference formulation of febuxostat 40 mg tablets in healthy Chinese subjects under both fasting and fed conditions. An open-label, randomized, single-dose, single-center, two-sequence, two-period crossover Phase I study was implemented to assess the pharmacokinetic bioequivalence of the two formulations in 64 healthy volunteers (32 for fasting group, 32 for fed group). Subjects received a single oral dose of either the test or reference febuxostat 40 mg tablet under the corresponding condition, with a 7-day washout period between cycles. The geometric mean ratios and their 90% confidence intervals (CIs) of the peak plasma concentration (<span></span><math>\u0000 <semantics>\u0000 <msub>\u0000 <mi>C</mi>\u0000 <mi>max</mi>\u0000 </msub>\u0000 <annotation>${{{mathrm{C}}}_{{mathrm{max}}}}$</annotation>\u0000 </semantics></math>), area under the plasma concentration–time curve from time 0 to the last quantifiable time point (<span></span><math>\u0000 <semantics>\u0000 <mrow>\u0000 <mi>AU</mi>\u0000 <msub>\u0000 <mi>C</mi>\u0000 <mrow>\u0000 <mn>0</mn>\u0000 <mo>−</mo>\u0000 <mi>t</mi>\u0000 </mrow>\u0000 </msub>\u0000 </mrow>\u0000 <annotation>${mathrm{AU}}{{{mathrm{C}}}_{{mathrm{0-t}}}}$</annotation>\u0000 </semantics></math>), and area under the plasma concentration–time curve from time 0 to infinity (<span></span><math>\u0000 <semantics>\u0000 <mrow>\u0000 <mi>AU</mi>\u0000 <msub>\u0000 <mi>C</mi>\u0000 <mrow>\u0000 <mrow>\u0000 <mn>0</mn>\u0000 <mo>−</mo>\u0000 </mrow>\u0000 <mi>∞</mi>\u0000 </mrow>\u0000 </msub>\u0000 </mrow>\u0000 <annotation>${mathrm{AU}}{{{mathrm{C}}}_{{mathrm{0-}}infty }}$</annotation>\u0000 </semantics></math>) for the test versus reference formulation were calculated for bioequivalence evaluation. All 90% CIs fell within the pharmacokinetic bioequivalence acceptance range of 80%–125%. A total of 12 adverse events (AEs) were reported in 10 subjects in the fasting group and nine AEs in eight subjects in the fed group, all of which were mild in severity with no serious AEs observed. The test formulation of febuxostat 40 mg tablets was bioequivalent to the reference formulation in healthy Chinese subjects under both fasting and fed conditions, and both formulations were well tolerated.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 10","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic Bioavailability of Topical Diclofenac: Sodium 1% Versus Diethylamine 1.16% and the Effect of Heat or Exercise in a Randomized Cross-Over Study","authors":"Karin Nicholson,&nbsp;Marianna Armogida,&nbsp;Morris S. Gold,&nbsp;Paul J. Desjardins","doi":"10.1002/cpdd.70091","DOIUrl":"https://doi.org/10.1002/cpdd.70091","url":null,"abstract":"<p>Diclofenac is a widely used topical nonsteroidal anti-inflammatory drug (NSAID) for pain and inflammation. This study evaluated the relative bioavailability of diclofenac from diclofenac sodium (DS) gel 1% versus diclofenac diethylamine (DEA) gel 1.16% and assessed whether adjunct heat or moderate exercise influences systemic absorption of diclofenac from DS gel 1%. General and local tolerability of DS gel 1% was also examined. Thirty-six adults aged ≥50 years were enrolled in a single-center, open-label, randomized, two-arm, three-way crossover study consisting of three 7-day treatment periods separated by 14-day washouts. Each sequence included DS gel 1%, DEA gel 1.16%, and DS gel 1% combined with either heat (one arm) or moderate exercise (other arm). Treatments were applied four times daily. Plasma diclofenac levels and 24-h urine samples were collected on Days 1 and 7 using a validated LC-MS/MS assay. Systemic exposure (AUC_0–24) of DEA gel versus DS gel was comparable (GMR 90.7%; 90% CI: 82.7–99.5). Heat resulted in an excursion of the lower bound of the AUC₀-₂₄ 90% confidence interval below the standard lower bioequivalence bound of 80% (GMR 92.5%; 90% CI: 77.3–111.0), while exercise showed no meaningful effect (GMR 103%; 90% CI: 87.8–120.0). As expected, given similar plasma exposure between treatments, urinary excretion was also similar (∼0.5% of the administered dose), supporting comparable systemic disposition.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 10","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase I Study of Nimotuzumab Combined with Irinotecan in Chinese Patients with Advanced Solid Tumors","authors":"Zhichao Jiang,&nbsp;Wen Zhang,&nbsp;Chunxia Du,&nbsp;Yongkun Sun,&nbsp;Aiping Zhou","doi":"10.1002/cpdd.70108","DOIUrl":"https://doi.org/10.1002/cpdd.70108","url":null,"abstract":"<p>Nimotuzumab is an anti-epidermal growth factor receptor antibody. This Phase I study evaluated the pharmacokinetics and safety of nimotuzumab plus irinotecan in Chinese patients with advanced solid tumors. At single ascending dosage (SAD) stage, four cohorts (100, 200, 400, and 600 mg) of patients received nimotuzumab intravenously on Day 1, alongside irinotecan 180 mg/m² on Day 8. Three weeks later, all patients in the four cohorts transferred to multiple ascending dosage (MAD) stage: nimotuzumab was administrated weekly for 6 weeks, alongside irinotecan (Days 1, 15, 29, 43, and 57, 180 mg/m²). Primary objective was pharmacokinetics, safety and tolerability was also examined. From December 2012 to October 2014, in SAD and MAD stages, there were 28 and 39 patients with Stage IV solid tumors. The area under the concentration curve (AUC_0–∞) for a single dose of nimotuzumab was 10.2 ± 2.7 (100 mg), 37.6 ± 10.0 (200 mg), 114.8 ± 35.5 (400 mg), 197.6 ± 32.0 (600 mg) (×100 h µg/mL), and for multiple dose, it was 26.7 ± 3.4 (100 mg), 87.1 ± 12.0 (200 mg), 193.4 ± 46.9 (400 mg) and 446.3 ± 100.7 (600 mg) (×100 h µg/mL). There was low incidence of rash and no dose-limiting toxicities occurred. This study indicated that nimotuzumab at doses ranging from 100 to 600 mg exhibited a manageable and tolerable safety profile.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 10","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions Between Cofrogliptin and Metformin in Healthy Subjects: A Single-Center, Single-Arm, Phase I Study in China","authors":"Cheng Cui,&nbsp;Na Liu,&nbsp;Chang Chu,&nbsp;Shu Niu,&nbsp;Yang Huang,&nbsp;Fangqiong Li,&nbsp;Yaming Li,&nbsp;Haiyan Li,&nbsp;Dongyang Liu","doi":"10.1002/cpdd.70092","DOIUrl":"https://doi.org/10.1002/cpdd.70092","url":null,"abstract":"<p>This single-center, single-arm, Phase I study evaluated drug–drug interactions (DDIs) between cofrogliptin and metformin in healthy Chinese subjects. Twenty-two subjects sequentially received metformin monotherapy (Days 1–4), cofrogliptin monotherapy (Days 6–34), and combination therapy (Days 38–47). Serial blood/urine samples were collected for pharmacokinetic (PK) and pharmacodynamic (PD) analyses. Cofrogliptin showed no significant impact on metformin's PK and PD properties: the geometric mean ratios (GMRs, metformin + cofrogliptin/metformin) with 90% confidence intervals (CIs) for metformin AUC_0–8 h, AUC_0–12 h, C_{SS (max)}, Ae_0–8 h and Ratio_0–8 h, were 0.872 (0.809, 0.941), 0.900 (0.834, 0.971), 0.840 (0.743, 0.950), 0.899 (0.782, 1.032), and 0.994 (0.871, 1.136), respectively; 90% CIs for plasma glucose AUEC_0–4 h, AUEC_0–0.5 h, and EC_max of combination (combination vs cofrogliptin monotherapy) all fell within 0.80–1.25. Metformin did not statistically affect cofrogliptin's PK and PD properties, as the GMRs (metformin + cofrogliptin/cofrogliptin) (90% CIs) for cofrogliptin AUC over the dosing interval and C_{ss (max)} were 1.12 (1.072, 1.169) and 1.14 (1.057, 1.220), and AUEC_0–168 h, EC_max, and EC_min for dipeptidyl peptidase-4 inhibition rate were 1.01 (1.003, 1.015), 1.00 (1.001, 1.009), and 1.03 (1.005, 1.040), respectively. No deaths, serious adverse events, or severe hypoglycemia occurred. In conclusion, the combination of cofrogliptin and metformin had no clinically significant PK or PD DDIs in healthy Chinese subjects.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 10","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.70092","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}