Clinical Pharmacology in Drug Development最新文献

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148068350","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 Randomized, Double-Blind, Two-Treatment, Two-Period, Crossover Study Investigating the Systemic Bioavailability of a Novel Cocrystal Ubiquinol Formulation Compared with a Ubiquinone Formulation in Healthy Adults","authors":"Xuefeng Mei,&nbsp;Bingqing Zhu,&nbsp;Kshitij Soni,&nbsp;Kishore Kasaraneni,&nbsp;Nirav Panchal","doi":"10.1002/cpdd.70042","DOIUrl":"10.1002/cpdd.70042","url":null,"abstract":"<p>Coenzyme Q10 (CoQ10) is a naturally occurring biochemical cofactor found in all human cell membranes in two interconvertible forms: oxidized ubiquinone and reduced ubiquinol. Clinical studies indicate that different CoQ10 formulations have different absorption rates, highlighting research comparing their systemic bioavailability. This study compared the oral bioavailability of cocrystal formulation soft gels (test product), a novel ubiquinol formulation, and ubiquinone formulation (reference product) in a randomized, double-blind, two-period crossover study with 12 healthy subjects under fasting conditions. The secondary objective of this study was to evaluate the safety and tolerability of the ubiquinol formulation. The pharmacokinetic analyses indicated that the test ubiquinol formulation demonstrated substantially higher relative systemic bioavailability compared with the ubiquinone reference. The geometric mean ratios (test/reference) for baseline-corrected peak plasma concentration (C_max) and area under the curve from zero to last quantifiable time (AUC_0–t) were 2.20 and 2.01, respectively, with 90% confidence intervals of 1.59–3.04 and 1.51–2.70. The geometric mean ratio for AUC from time zero to infinity (AUC_0–∞) was 3.43 (90% CI: 1.47–8.00). No adverse events were reported in this small pilot study for either of the formulations. These findings demonstrate that ubiquinol has a better systemic bioavailability than ubiquinone, supporting the novel formulation's potential as a promising alternative to traditional CoQ10 supplements.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12965043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147363644","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148065921","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":"Absolute Bioavailability and Absorption, Distribution, Metabolism, and Excretion of [14C]Xevinapant, a Potent, Oral, Small-Molecule IAP Inhibitor","authors":"Annick Menetrey,&nbsp;Valérie Nicolas-Metral,&nbsp;Marie-Claude Roubaudi-Fraschini,&nbsp;Tri Tat,&nbsp;Yuan Zhao,&nbsp;Yulia Vugmeyster,&nbsp;Karthik Venkatakrishnan,&nbsp;Felix Rohdich,&nbsp;Holger Scheible","doi":"10.1002/cpdd.70028","DOIUrl":"10.1002/cpdd.70028","url":null,"abstract":"<p>This Phase 1, open-label, 2-part, single-dose study aimed to investigate the pharmacokinetics, metabolism, and excretion of xevinapant, a small molecule inhibitor of apoptosis proteins (IAPs), in healthy male subjects. Part 1 focused on determining the mass balance recovery, pharmacokinetics, and metabolic profile of [¹⁴C]xevinapant following a single oral dose of 200 mg. Part 2 aimed to determine the absolute oral bioavailability of xevinapant by evaluating the pharmacokinetics of an oral dose of 200 mg xevinapant in comparison to an intravenous microtracer dose of [¹⁴C]xevinapant using accelerator mass spectrometry. After oral administration, xevinapant was rapidly absorbed, with a median time to maximum concentration of 0.5 h and a geometric mean half-life of 13.2 h. The principal route of excretion of drug-related material was fecal, accounting for 60.2% of the administered dose, while 33.3% was excreted in urine. Renal clearance accounted for 18.4% of total clearance. In addition to xevinapant, seven metabolites were structurally characterized in the samples analyzed. The principal route of metabolism was dealkylation to form metabolite D-1143-MET1, with secondary metabolism by oxidation. The major circulating components in plasma were xevinapant and D-1143-MET1 (inactive on IAPs), which represented 28% and 42% of the total drug-related exposure, respectively. The absolute oral bioavailability of xevinapant was determined to be 57.8%. The clearance of [¹⁴C]xevinapant was 12.2 L/h and the volume of distribution at steady-state was 75.3 L. Xevinapant was well tolerated in healthy male subjects, with no clinically significant findings in clinical laboratory evaluations, vital signs, ECG, or physical examinations.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12961726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147354154","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148061649","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":"The FDA Roadmap to Reducing Animal Testing in Preclinical Safety Studies: Where Will It Lead Us?","authors":"Michael J. Fossler,&nbsp;C. Edwin Garner","doi":"10.1002/cpdd.70046","DOIUrl":"10.1002/cpdd.70046","url":null,"abstract":"&lt;p&gt;For several years, the FDA, EMA, and other regulatory agencies have been concerned about the number of animals used in drug research, particularly regarding toxicology studies.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; This concern is not only based on animal welfare considerations; it is also based on the understanding that animal toxicology data does not always accurately predict human toxicity.&lt;/p&gt;&lt;p&gt;Against this backdrop, in April 2025, the FDA published its Roadmap to reduce animal testing in preclinical safety studies.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; The Roadmap outlines a comprehensive long-term plan to reduce or possibly eliminate animal toxicology testing, starting with monoclonal antibodies (mAbs), by using what are termed “New Approach Methodologies” (NAMs), which include the use of human tissue-based systems, such as organs-on-chips (OOCs)—human tissue constructs maintained in a microfluidic environment—&lt;i&gt;in silico&lt;/i&gt; modeling (physiologically based pharmacokinetics modeling [PBPK] and systems pharmacology modeling), and other innovative approaches, such as high-throughput cell-based screening.&lt;/p&gt;&lt;p&gt;As stated in the Roadmap, the goal (3–5 years from the date of publication of this Roadmap) is to make animal studies the exception, rather than the norm, not only for mAbs, but for all therapeutics. We question whether the complete elimination of all animal toxicology studies is a reasonable goal. It is important to remember that, while animal studies might not be perfect, they have been used in science for hundreds of years to very good effect. For the most part, preclinical toxicology studies do a good job of predicting human safety (i.e., absence of toxicological response), and this is why they have been required for decades.&lt;/p&gt;&lt;p&gt;The preclinical in vivo IND-enabling toxicity study program approach to assess the general toxicity of pharmaceuticals has been generally successful in allowing reasonably safe clinical trials to proceed.&lt;span&gt;&lt;sup&gt;7, 8&lt;/sup&gt;&lt;/span&gt; From 2000 to 2010, approximately 18% of all clinical programs were discontinued due to either animal or human toxicity (vs 20%–30% for the 50 years prior). In addition, the general ability of animal toxicity data to identify potential adverse human effects is good,&lt;span&gt;&lt;sup&gt;9, 10&lt;/sup&gt;&lt;/span&gt; and the absence of animal toxicity is particularly good at predicting an &lt;i&gt;absence of toxicities&lt;/i&gt; in human Phase 1 clinical trials.&lt;span&gt;&lt;sup&gt;11&lt;/sup&gt;&lt;/span&gt; That is, a greater than 86% effective rate for human safety of new chemical entities with unknown properties. However, the ability of animal studies to predict a specific &lt;i&gt;toxicity&lt;/i&gt; incidence is about 50%.&lt;span&gt;&lt;sup&gt;11&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;There are currently no alternative predictive toxicological methods that readily allow identification of appropriate dose ranges for clinical exploration and of potential adverse effects over time regarding systemic exposure. As such, there is a very low likelihood of replacing whole animal general toxicity stu","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.70046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324808","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148061650","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 Two Lercanidipine Hydrochloride Tablets in Healthy Chinese Volunteers","authors":"Biao Sun,&nbsp;Li Zhao,&nbsp;Fangliang Gan,&nbsp;Qiong Zhan","doi":"10.1002/cpdd.70045","DOIUrl":"10.1002/cpdd.70045","url":null,"abstract":"<p>Lercanidipine hydrochloride is a third-generation dihydropyridine calcium channel blocker used to treat mild-to-moderate hypertension. The aim of this study is to compare the pharmacokinetic characteristics of lercanidipine hydrochloride tablets (10 mg) in healthy Chinese volunteers after oral administration under fasting conditions with those of a reference formulation, and to evaluate the bioequivalence and safety of the two formulations. A validated liquid chromatography-tandem mass spectrometry method was established to determine the plasma concentration of lercanidipine. Phoenix WinNonlin software (version 7.0) was used to calculate pharmacokinetic parameters based on plasma drug concentration–time data. The geometric mean ratios and 90% confidence intervals of C_max, AUC_0–t, and AUC_0–∞ for the test formulation relative to the reference formulation were 110.37% (99.96%–121.86%), 106.81% (99.65%–114.49%), and 106.91% (99.86%–114.45%), respectively, all within the range of 80.00%–125.00%. The test formulation met the bioequivalence acceptance criteria and was well tolerated by healthy Chinese volunteers under fasting conditions.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324789","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148092342","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 Two Repaglinide Tablets Under Fasting and Fed Conditions in Healthy Chinese Volunteers","authors":"Biao Sun,&nbsp;Li Zhao,&nbsp;Fangliang Gan,&nbsp;Qiong Zhan","doi":"10.1002/cpdd.70044","DOIUrl":"10.1002/cpdd.70044","url":null,"abstract":"<p>Repaglinide, an insulin secretagogue that predominantly lowers postprandial glucose, is approved for patients with type 2 diabetes inadequately controlled by diet, weight loss, and exercise. This study used a single-center, randomized, open-label, two-formulation, single-dose, four-period, fully replicated, crossover design to evaluate the pharmacokinetics, bioequivalence, and safety of generic repaglinide tablets (1 mg) versus the innovator product in healthy Chinese subjects under fasting and fed conditions. Blood samples were assayed by validated liquid chromatography-tandem mass spectrometry. After natural logarithmic transformation of pharmacokinetic parameters (C_max, AUC_0–t, and AUC_0–∞), the bioequivalence of the test formulation and the reference formulation was evaluated using two one-sided t-tests and the 90% confidence intervals (CIs) method. The least-squares geometric mean ratios (test/reference) and 90% CIs for C_max, AUC_0–t, and AUC_0–∞ all fell within the conventional bioequivalence ranges of 0.80–1.25. Both formulations were well tolerated, with no serious adverse events reported, and the food effect on repaglinide pharmacokinetics is further discussed. In summary, test and reference repaglinide tablets are bioequivalent and demonstrate similar pharmacokinetic characteristics and safety in healthy Chinese volunteers under both fasting and fed states.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147303026","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}