The Journal of Clinical Pharmacology最新文献

{"title":"Pharmacokinetics and Bioavailability of a Novel Rivastigmine Nasal Spray Compared to Rivastigmine Oral Capsule in Healthy Men","authors":"Timothy M. Morgan PhD,&nbsp;Benjamin Snyder MBBS","doi":"10.1002/jcph.70086","DOIUrl":"10.1002/jcph.70086","url":null,"abstract":"<p>To compare the pharmacokinetics, bioavailability, tolerability, and safety of a novel 4 mg rivastigmine nasal spray to 3 mg rivastigmine oral capsule, a single-dose, open-label, randomized, crossover study was conducted in 16 fasted healthy young men (18 to 55 years). Mean (SD) rivastigmine C_max was 8.39 (6.8) and 13.77 (10.7) ng/mL for oral and nasal, respectively. Rivastigmine AUC_0-inf was 19.6 (14.9) and 40.6 (24.4) ng h/mL for oral and nasal, respectively. The ratio of LS means (nasal test / oral reference; 90% C.I.) for rivastigmine C_max was 185.83% (134.22, 257.28) and for rivastigmine AUC_0-inf was 257.35% (197.26, 335.73). Rivastigmine t_max for nasal (0.7 h) was significantly lower than oral (1.2 h, <i>P</i> &lt; .05), however, NAP226-90 t_max for nasal (1.9 h) and oral (1.8 h) were similar. NAP226-90 C_max was 3.93 (1.1) and 3.01 (0.8) ng/mL for oral and nasal, respectively. NAP226-90 AUC_0-inf was 22.9 (5.3) and 23.2 (5.1) ng h/mL for oral and nasal, respectively. Median NAP226-90 to rivastigmine AUC_0-inf ratio for nasal (0.55) was significantly lower than oral (1.38, <i>P</i> &lt; .05) because nasal bypassed first-pass metabolism. Both single-dose treatments were safe and well tolerated. Nasal and throat irritation were mostly perceived as mild and transient following nasal administration. The 4 mg rivastigmine nasal spray had 1.5- and 2.0-fold higher dose normalized rivastigmine C_max and AUC_0-inf, respectively, and 2.5-fold lower NAP226-90 to rivastigmine AUC_0-inf ratio compared to 3 mg oral capsule. This nasal spray has good potential to improve the local and gastrointestinal tolerability of rivastigmine treatment in Alzheimer's and Parkinson's disease dementia patients.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144754904","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":"Osimertinib Cost Minimization in Non-Small Cell Lung Cancer (NSCLC) Treatment: Hypothesis Generation for a Population Pharmacokinetic Approach for Equivalent Dose Optimization of Osimertinib in Combination with Cobicistat","authors":"Niels Westra PharmD,&nbsp;Paul D. Kruithof PharmD,&nbsp;Sander Croes PharmD, PhD,&nbsp;Robin M. J. M. van Geel PharmD, PhD,&nbsp;Lizza E. L. Hendriks MD, PhD,&nbsp;Daan J. Touw PharmD, PhD,&nbsp;Jos G. W. Kosterink PharmD, PhD,&nbsp;Jasper Stevens PhD,&nbsp;Thijs H. Oude Munnink PharmD, PhD,&nbsp;Paola Mian PharmD, PhD","doi":"10.1002/jcph.70085","DOIUrl":"10.1002/jcph.70085","url":null,"abstract":"<p>Pharmacokinetic boosting can be a strategy to enhance osimertinib exposure and reduce treatment associated costs. The OSIBOOST trial demonstrated that it was feasible to boost low osimertinib plasma trough levels with cobicistat. The current study aims to establish the equivalent dose of cobicistat boosted osimertinib compared to osimertinib 80 mg once daily (QD) by population pharmacokinetic (popPK) modeling. A popPK model was developed on the pharmacokinetic data from the OSIBOOST study using NONMEM 7.4.4. Simulations were performed with cobicistat boosted osimertinib dosing regimens to evaluate their equivalence to the standard of osimertinib 80 mg QD. A dose level was assumed equivalent when the 90% confidence interval (CI) of the geometric mean ratios (GMR) for the area under the curve over 144 h (AUC_0-144h) and maximum osimertinib concentration (C_max) were in the acceptance range of 0.8-1.25. Cobicistat decreased osimertinib CL/F by 29.6% compared to osimertinib monotherapy (<i>P</i> &lt; .0001). Osimertinib 80 mg 2 days on, 1 day off, boosted with cobicistat 150 mg QD was equivalent for osimertinib AUC_0-144h (GMR [90% CI] = 0.96 [0.94-0.98]) and C_max (GMR [90% CI] = 1.06 [1.04-1.08]) compared to osimertinib 80 mg QD monotherapy. However, this regimen was not equivalent for AZ5104 AUC_0-144h (GMR [90% CI] = 0.67 [0.66-0.68]) and C_max (GMR [90% CI] = 0.74 [0.73-0.76]). Theoretically, this reduced dose of cobicistat boosted osimertinib can potentially save approximately 33% in osimertinib treatment associated costs whilst maintaining adequate osimertinib exposure.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 12","pages":"1687-1698"},"PeriodicalIF":0.0,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144754903","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":"Landscape of FDA-Approved Targeted Therapies for the Treatment of Diseases with Low Frequency Molecular Subsets","authors":"Lois S. Akinola PhD,&nbsp;Sarah Ridge PhD,&nbsp;Issam Zineh PharmD, MPH,&nbsp;Michael A. Pacanowski PharmD, MPH,&nbsp;Anuradha Ramamoorthy PhD, FCP","doi":"10.1002/jcph.70081","DOIUrl":"10.1002/jcph.70081","url":null,"abstract":"&lt;p&gt;Targeted approaches to drug development, built on a strong scientific foundation of pharmacology and molecular biology and relying on clinical trial enrichment, have enabled development and approval of many innovative therapies in the past decade. By virtue of their mechanism of action, many of these therapies have been developed and approved for subsets of patients with a clinically defined disease who are identified by genetic or other molecular biomarker testing. The development and approval of these “targeted therapies” present unique challenges from a regulatory perspective. Scientifically, all the molecular alterations associated with the pathobiology of a disease, or its outcomes, may not be well characterized experimentally or clinically. Practically, even when well characterized, certain molecular alterations may be present at a low frequency such that they will not be represented in clinical trials, or the devices used in clinical trials or practice (i.e., companion diagnostic devices) may be designed to detect only the most common molecular alterations. As a result, patients with molecular alterations that could be responsive to treatment may go unstudied in efficacy and safety trials, raising questions about generalizability of benefits and risks.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Acknowledging the complexity of drug development for rare molecular subsets, the FDA published a guidance in 2018 titled “Developing Targeted Therapies in Low Frequency Molecular Subsets of a Disease” (herein referred to as the “targeted therapies guidance”).&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; This guidance provides a framework for grouping patients with various molecular alterations for enrollment in clinical trials and describes general approaches that can be used to assess the benefit and risk profile of targeted therapies when molecular alterations occur at low frequencies. Although randomized, controlled clinical trials with adequate representation of applicable patient populations are considered the strongest type of evidence, it may not be feasible or practical to obtain such data in all situations. Consequently, the targeted therapies guidance highlights other types of evidence that can help identify patients for inclusion in clinical trials and support generalizing efficacy results in case of low frequency molecular subsets of a disease.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; This includes evidence from early clinical studies and mechanistic evidence such as from nonclinical studies, in silico modeling, other drugs in the same pharmacological class, or phenotypic characterization of molecular alterations.&lt;/p&gt;&lt;p&gt;The approaches described in the targeted therapies guidance have been utilized in the development of targeted therapies for some cancers and rare genetic diseases. This has resulted in the regulatory approval of drugs for use in subsets of patients with specific molecular alterations not studied in the clinical trials.&lt;span&gt;&lt;sup&gt;1, 3, 4&lt;/sup&gt;&lt;/span&gt; For example, the","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 12","pages":"1908-1911"},"PeriodicalIF":0.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144709616","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":"Four Pharmacogenomic Variants Strongly Linked to Corticosteroid-Induced Avascular Necrosis in Children with Cancer","authors":"Miguel Cordova-Delgado PhD,&nbsp;Erika N. Scott PhD,&nbsp;Shahrad R. Rassekh MD,&nbsp;Catrina M. Loucks PhD,&nbsp;Wan-Chun Chang PhD,&nbsp;Edward J. Raack MSc,&nbsp;Jessica N. Trueman MSc,&nbsp;Colin J. D. Ross PhD,&nbsp;Bruce C. Carleton PharmD, FCP,&nbsp;the Canadian Pharmacogenomics Network for Drug Safety Consortium","doi":"10.1002/jcph.70084","DOIUrl":"10.1002/jcph.70084","url":null,"abstract":"<p>Corticosteroids are effective anti-cancer agents for treating hematologic malignancies in children. However, avascular necrosis (AVN) is a common and debilitating adverse effect, leading to bone death and impacting long-term quality of life. This study aimed to uncover the genetic factors contributing to corticosteroid-induced AVN in a well-characterized cohort of pediatric cancer patients. We conducted a genome-wide association study (GWAS) on 972 patients, including 108 with AVN grade ≥2 and 864 dose-matched controls. The GWAS of 6.4 million genetic markers identified four significant AVN-associated loci (<i>P</i> &lt; 5 × 10⁻⁸): <i>WNT7B</i> (OR = 9.2; 95% CI, 3.8-22.0), <i>POGK</i> (OR = 8.4; 95% CI, 3.6-19.5), <i>ZNF37A</i> (OR = 6.0; 95% CI, 2.9-12.5), and a synonymous variant in <i>FAM240C</i> (OR = 5.0; 95% CI, 2.6-9.5). A multi-marker predictive model combining single nucleotide polymorphisms (SNPs) and clinical factors showed an area under the ROC curve (AUC) of 78.7%, outperforming SNP-only (67.8%) and clinical-only (68.4%) models. The osteogenic processes regulated by <i>WNT7B</i>, part of the Wnt signaling pathway, may contribute to AVN-related disrupted bone development and repair. Similarly, <i>POGK</i> and <i>ZNF37A</i>, both containing the KRAB domain, are hypothesized to affect osteoblast differentiation and skeletal development in AVN. Developing a predictive model for individual susceptibility to corticosteroid-induced AVN will enhance the monitoring and management of corticosteroid use in children with cancer.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 12","pages":"1844-1854"},"PeriodicalIF":0.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144709615","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":"Impact of Dapagliflozin on Heart Failure with Reduced Ejection Fraction: A Real-World Study","authors":"Francisca Augusto MS,&nbsp;Patrícia Paiva MD,&nbsp;Carolina Félix MD,&nbsp;Inês Jordão MD,&nbsp;Miguel Costa MD,&nbsp;Patrícia Dias MD,&nbsp;Francisco Parente MD,&nbsp;Lino Gonçalves PhD,&nbsp;Francisco Machado PharmD,&nbsp;Natália António PhD","doi":"10.1002/jcph.70082","DOIUrl":"10.1002/jcph.70082","url":null,"abstract":"<p>Dapagliflozin has demonstrated multiple benefits in clinical trials for heart failure with reduced ejection fraction (HFrEF), but older patients with multiple comorbidities were often excluded. This study aimed to evaluate the effectiveness and safety of dapagliflozin in a real-world population of HFrEF patients. This retrospective study included HFrEF patients from a tertiary hospital, who initiated dapagliflozin between January 202 and December 2022. The mean follow-up was 15.3 ± 8.3 months. Each patient served as their own control to compare left ventricular ejection fraction (LVEF), laboratory parameters, and time-dependent events, such as heart failure (HF) readmissions. A total of 155 HFrEF patients (mean age 68.5 ± 14.5 years; 75.5% male) were included. Of these, 47.1% had non-ischemic heart disease, 49.0% had type 2 diabetes mellitus, and most were on beta-blockers, loop diuretics and angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, or angiotensin receptor neprilysin inhibitor. LVEF improved from 29.2% to 34.3% (<i>P</i> &lt; .001), with significant reductions in body weight and heart rate (<i>P</i> &lt; .001). HF-related emergency room visits decreased (0.68 ± 1.06 to 0.58 ± 0.96; <i>P</i> = .329). Renal function declined, with glomerular filtration rate decreasing from 67.6 ± 25.2 to 55.2 ± 30.8 mL/min/1.73 m² (<i>P</i> &lt; .001), particularly in older patients (HR 1.033; 95% CI: 1.004-1.063) and those with higher baseline heart rate (HR 1.028; 95% CI: 1.011-1.045). Severe adverse drug reactions occurred in 3.9% of patients, with hypotension (12.9%) being the most common. In conclusion, dapagliflozin demonstrated a favorable safety profile and significant hemodynamic benefits, improving LVEF and stabilizing HF progression in a real-world HFrEF population.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 12","pages":"1900-1907"},"PeriodicalIF":0.0,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692176","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":"Establishing a Quantitative Framework for Combined Oral Contraceptives: Evaluating the Impact of Drug–Drug Interactions on Exposure and Clinical (Surrogate) Efficacy Endpoints","authors":"Dain Chun PhD,&nbsp;Huili Chen PhD,&nbsp;Brian Cicali PhD,&nbsp;Serge Guzy PhD,&nbsp;Joachim Hoechel PhD,&nbsp;Tianze Jiao PhD,&nbsp;Valvanera Vozmediano PhD,&nbsp;Stephan Schmidt PhD","doi":"10.1002/jcph.70063","DOIUrl":"10.1002/jcph.70063","url":null,"abstract":"<p>According to the FDA Guidance for Industry on Clinical Drug Interaction (DDI) Studies with Combined Oral Contraceptives (COCs), sponsors are expected to conduct dedicated clinical DDI studies if in vitro findings suggest weak or moderate CYP3A induction, while concomitant use of COCs with strong inducers should be avoided. The guidance further suggests that a negative DDI result for drospirenone (DRSP) may be extrapolated to other progestins that are less sensitive to CYP3A modulation, such as levonorgestrel (LNG). This approach assumes that DDI-mediated changes in exposure directly translate into clinical efficacy across progestins. To evaluate the validity of this assumption, we established a quantitative link between dose, exposure, and response (Pearl Index [PI] and ovulation rate [OR]) via an integrated model-based meta-analysis, physiologically based pharmacokinetic, and pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation approach using data from 51 clinical studies in 36,040 women receiving LNG or DRSP. COCs containing LNG and DRSP were selected because they represent clinically relevant progestins at the lower and the upper end of the fraction metabolized via CYP3A4. The results of our analysis show a moderate correlation (Pearson's r = 0.52, 95% CI 0.46-0.58, <i>P</i> &lt; 0.001) between PI and OR, which enables the use of OR as an ethically measurable endpoint, even at subtherapeutic doses/exposures, to predict efficacy outcomes. They further show that DDI-induced changes in exposure do not directly translate into clinical response. Therefore, DDIs with COCs should be interpreted in a PK/PD rather than a PK-only context. The quantitative framework developed in this study can serve as the scientific basis to do so.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 12","pages":"1855-1863"},"PeriodicalIF":0.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70063","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683500","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":"Precision Pharmacokinetics of Quetiapine: A Physiologically Based Model Incorporating Liver Cirrhosis and CYP3A4 Polymorphisms","authors":"Seung-Min Lee BS,&nbsp;Ji-Hun Jang PhD,&nbsp;Seung-Hyun Jeong PhD","doi":"10.1002/jcph.70079","DOIUrl":"10.1002/jcph.70079","url":null,"abstract":"<p>Quetiapine, an atypical antipsychotic primarily metabolized by <i>CYP3A4</i>, exhibits altered pharmacokinetics (PK) in patients with liver cirrhosis and individuals with <i>CYP3A4</i> polymorphisms. This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model to predict the effects of hepatic impairment and <i>CYP3A4</i>*22 variants on quetiapine PK. A model was developed using data from healthy individuals administered a single 25 mg dose and validated against 19 independent clinical datasets. Subsequently, the model was adapted to simulate PK in patients with liver cirrhosis (Child-Pugh A, B, and C) and those with <i>CYP3A4</i>*1/*22 and *22/*22 genotypes. Simulation results showed a significant increase in systemic exposure and a corresponding decrease in apparent clearance as hepatic impairment worsened or in the presence of <i>CYP3A4</i>*22 alleles. Model-based dose adjustments were proposed and validated, effectively aligning drug exposure levels in specific populations with those observed in healthy controls. In severe cases (Child-Pugh C with <i>CYP3A4</i>*22/*22), only 5% of the standard dose was required to achieve reference exposure levels. This study demonstrates that PBPK modeling is a valuable tool for optimizing individualized dosing in patients with hepatic impairment or genetic variability. These findings offer clinically relevant insights for safer and more effective quetiapine therapy through evidence-based dose adjustments.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 12","pages":"1719-1731"},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144643932","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":"Development of a Physiologically Based Pharmacokinetic Model to Evaluate Dosing Regimens of Cyclosporine as a Precipitant of Organic Anion Transporting Polypeptide 1B (OATP1B)- and CYP3A4-Mediated Drug–Drug Interactions","authors":"Pooja V. Hegde PhD,&nbsp;Jessica Rehmel MS,&nbsp;Stephen D. Hall PhD,&nbsp;Bridget L. Morse PharmD, PhD","doi":"10.1002/jcph.70076","DOIUrl":"10.1002/jcph.70076","url":null,"abstract":"<p>Cyclosporine (cyclosporin A or CsA), a clinically relevant but nonspecific inhibitor of hepatic organic anion transporting polypeptides (OATPs), is used for assessing transporter-mediated drug–drug interactions (DDIs) at varying dosing regimens. We developed a physiologically based pharmacokinetic model to reproduce CsA pharmacokinetics (PK) and effect of CsA on substrates of OATPs and cytochrome P450 (CYP)3A4. The model was built using intravenous and oral CsA clinical PK and DDI data in healthy volunteers. The model reproduces single- and multiple-dose clinical CsA PK from numerous studies with simulated/observed AUC and C_max within 0.59-1.75 following oral CsA dosing. As an object of CYP3A4, the model reproduces the observed effect of ketoconazole and grapefruit juice on CsA PK. CsA inhibition constants against CYP3A4 and hepatic OATPs were estimated to reproduce clinical DDIs with CYP3A index substrate midazolam (MDZ) and OATP1B biomarker coproporphyrin-I, and confirmed with felodipine and pitavastatin, verifying the model for inhibition of hepatic CYP3A4 and OATPs in healthy volunteers. A review of clinical data herein indicates that most clinical DDI studies utilize a single dose of CsA and for certain clinical substrates, a counterintuitive decrease in half-life following CsA administration has been observed (similar to single-dose rifampin DDIs). Using the currently developed CsA model, we predicted the effect of various single- and multiple-dose CsA regimens against OATP1B substrate and MDZ models. Depending on the OATP1B substrate characteristics, 200 mg CsA twice daily or a single 600 mg dose reasonably mimic simulated continuous OATP1B inhibition and single-dose rifampin, albeit with predicted weak-to-moderate CYP3A4 inhibition.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 11","pages":"1544-1560"},"PeriodicalIF":0.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144620965","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":"Characterizing Cellular Expansion of Idecabtagene Vicleucel and Association with Clinical Efficacy and Safety in Patients with Triple-Class-Exposed Relapsed/Refractory Multiple Myeloma","authors":"Fan Wu PhD,&nbsp;Xirong Zheng PhD,&nbsp;Joseph Burnett PhD,&nbsp;Madhan Masilamani PhD,&nbsp;Wanying Zhang MS,&nbsp;Xiaobo Zhong PhD,&nbsp;Andrea Caia MS,&nbsp;Mark Cook MBChB, PhD,&nbsp;Julia Piasecki BA,&nbsp;Anna Kondic PhD,&nbsp;Manisha Lamba PhD,&nbsp;Jian Zhou PhD","doi":"10.1002/jcph.70075","DOIUrl":"10.1002/jcph.70075","url":null,"abstract":"<p>Idecabtagene vicleucel (ide-cel, ABECMA) is an autologous, B-cell maturation antigen-directed, chimeric antigen receptor (CAR) T-cell therapy, which has demonstrated significantly improved progression-free survival (PFS) and overall response rate (ORR) in patients with triple-class-exposed relapsed/refractory multiple myeloma (TCE RRMM). Here, we characterize cellular expansion of ide-cel in vivo and further evaluate associations between cellular expansion and clinical efficacy and safety endpoints. The exposure parameters of ide-cel were evaluated through non-compartmental analysis methods using the time course data of CAR transgene copy numbers collected from the ide-cel arm of Study KarMMa-3 (NCT03651128). Multivariable regression analyses were conducted between the exposure parameters and clinical responses to characterize relationships between cellular expansion in vivo and clinical outcomes and to evaluate potential effects of covariates on the exposure–response (E-R) relationships. There appears to be lack of a strong association between actual ide-cel dose and cellular expansion at the dose range evaluated in Study KarMMa-3. The multivariable E-R regression models suggest positive relationships between cellular expansion and clinical efficacy and safety endpoints, with higher exposure associated with longer PFS, higher ORR, and higher rates of cytokine release syndrome requiring tocilizumab or corticosteroids. The current analyses do not identify any clinically relevant covariate effects on the E-R relationships. The positive exposure–response relationships were found to be overall similar between KarMMa-3 and a previous study KarMMa. The modeling analyses, paired with clinical data, support extending the dose range from previously approved 300-460 × 10⁶ CAR+ T cells to 300-510 × 10⁶ CAR+ T cells for TCE RRMM patients.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 11","pages":"1568-1576"},"PeriodicalIF":0.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610077","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":"Pharmacokinetics and Safety of Fezolinetant in Women with Hepatic or Renal Impairment","authors":"Megumi Iwai PhD,&nbsp;Xuegong Wang MD,&nbsp;Melanie Patton BSc,&nbsp;Lauren Benner BSc,&nbsp;Nakyo Heo PharmD,&nbsp;Jace C. Nielsen PharmD,&nbsp;Anna Spence MS,&nbsp;Thomas C. Marbury MD,&nbsp;Jiayin Huang PhD","doi":"10.1002/jcph.70070","DOIUrl":"10.1002/jcph.70070","url":null,"abstract":"<p>The neurokinin 3 receptor antagonist fezolinetant is an approved treatment for vasomotor symptoms due to menopause. The impacts of hepatic and renal impairment on the pharmacokinetics and safety of a single oral dose of fezolinetant 30 mg were investigated in two independent studies. The studies enrolled healthy women and women with mild or moderate hepatic impairment (defined by Child–Pugh classification) or mild to severe renal impairment (categorized by estimated glomerular filtration rate). Blood samples for fezolinetant and its metabolite, ES259564, were collected predose and up to 96 h postdose. Safety was assessed using treatment-emergent adverse events (TEAEs). Overall, 26 and 27 women were enrolled in the hepatic and renal studies. Fezolinetant exposure (area under the concentration–time curve from time of dosing to infinity [AUC_inf]) was higher in those with hepatic impairment than women with normal function (geometric mean ratios [90% confidence interval]: mild/healthy control: 155.89% [108.04%-224.92%], moderate/healthy control: 196.11% [131.64%-292.15%]). The AUC_inf results for ES259564 were similar between women who were hepatically impaired and of normal functioning. Renal impairment did not substantially increase the exposure of fezolinetant. However, those with moderate or severe renal impairment had higher AUC_last (from time of dosing to last measurable concentration) results for ES259564 than healthy women (moderate/healthy control: 177.14 [120.02-261.44], severe/healthy control: 478.56 [347.93-658.22]). No serious TEAEs were reported in either study. In conclusion, hepatic impairment affects the metabolism of fezolinetant as shown by progressive increases in systemic exposure. Marginal impacts were noted in women with renal impairment.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 11","pages":"1517-1530"},"PeriodicalIF":0.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70070","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610098","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}