The Journal of Clinical Pharmacology最新文献_第10页

Quantitative Assessment of Drug Efficacy and Emergence of Resistance in Patients with Metastatic Renal Cell Carcinoma Using a Longitudinal Exposure-Tumor Growth Inhibition Model: Apitolisib (Dual PI3K/mTORC1/2 Inhibitor) Versus Everolimus (mTORC1 Inhibitor) 使用纵向暴露-肿瘤生长抑制模型定量评估转移性肾细胞癌患者的药效和耐药性的出现：阿匹替尼（PI3K/mTORC1/2双重抑制剂）与依维莫司（mTORC1抑制剂）

The Journal of Clinical Pharmacology Pub Date : 2024-04-19 DOI: 10.1002/jcph.2444

Anita Moein MS, Jin Y. Jin PhD, Matthew R. Wright PhD, Harvey Wong PhD

{"title":"Quantitative Assessment of Drug Efficacy and Emergence of Resistance in Patients with Metastatic Renal Cell Carcinoma Using a Longitudinal Exposure-Tumor Growth Inhibition Model: Apitolisib (Dual PI3K/mTORC1/2 Inhibitor) Versus Everolimus (mTORC1 Inhibitor)","authors":"Anita Moein MS, Jin Y. Jin PhD, Matthew R. Wright PhD, Harvey Wong PhD","doi":"10.1002/jcph.2444","DOIUrl":"10.1002/jcph.2444","url":null,"abstract":"Cancer remains a significant global health challenge, and despite remarkable advancements in therapeutic strategies, poor tolerability of drugs (causing dose reduction/interruptions) and/or the emergence of drug resistance are major obstacles to successful treatment outcomes. Metastatic renal cell carcinoma (mRCC) accounts for 2% of global cancer diagnoses and deaths. Despite the initial success of targeted therapies in mRCC, challenges remain to overcome drug resistance that limits the long-term efficacy of these treatments. Our analysis aim was to develop a semi-mechanistic longitudinal exposure-tumor growth inhibition model for patients with mRCC to characterize and compare everolimus (mTORC1) and apitolisib's (dual PI3K/mTORC1/2) ability to inhibit tumor growth, and quantitate each drug's efficacy decay caused by emergence of tumor resistance over time. Model-estimated on-treatment tumor growth rate constant was 1.7-fold higher for apitolisib compared to everolimus. Estimated half-life for loss of treatment effect over time for everolimus was 16.1 weeks compared to 7.72 weeks for apitolisib, suggesting a faster rate of tumor re-growth for apitolisib patients likely due to the emergence of resistance. Goodness-of-fit plots including visual predictive check indicated a good model fit and the model was able to capture individual tumor size–time profiles. Based on our knowledge, this is the first clinical report to quantitatively assess everolimus (mTORC1) and apitolisib (PI3K/mTORC1/2) efficacy decay in patients with mRCC. These results highlight the difference in overall efficacy of 2 drugs due to the quantified efficacy decay caused by emergence of resistance, and emphasize the importance of model-informed drug development for targeted cancer therapy.","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"64 9","pages":"1101-1111"},"PeriodicalIF":0.0,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2444","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140623657","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}

引用次数: 0

Population Pharmacokinetic Modeling and Exposure–Efficacy and Body Weight–Response Analyses for Tezepelumab in Patients With Severe, Uncontrolled Asthma 针对未受控制的严重哮喘患者的群体药代动力学模型和暴露-疗效及体重-反应分析

The Journal of Clinical Pharmacology Pub Date : 2024-04-17 DOI: 10.1002/jcph.2433

Yanan Zheng PhD, Lubna Abuqayyas PhD, Angelica Quartino PhD, Ye Guan PhD, Yuying Gao PhD, Lu Liu MBA, Åsa Hellqvist MSc, Gene Colice MD, Alexander MacDonald PhD

{"title":"Population Pharmacokinetic Modeling and Exposure–Efficacy and Body Weight–Response Analyses for Tezepelumab in Patients With Severe, Uncontrolled Asthma","authors":"Yanan Zheng PhD, Lubna Abuqayyas PhD, Angelica Quartino PhD, Ye Guan PhD, Yuying Gao PhD, Lu Liu MBA, Åsa Hellqvist MSc, Gene Colice MD, Alexander MacDonald PhD","doi":"10.1002/jcph.2433","DOIUrl":"10.1002/jcph.2433","url":null,"abstract":"Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. This analysis assessed the suitability of a fixed-dose regimen of tezepelumab 210 mg every 4 weeks (Q4W) in adults and adolescents with severe, uncontrolled asthma. A population pharmacokinetic model was developed using data from 1368 patients with asthma or healthy participants enrolled in 8 clinical studies (phases 1-3). Tezepelumab exposure-efficacy relationships were analyzed in the phase 3 NAVIGATOR study (NCT03347279), using asthma exacerbation rates over 52 weeks and changes in pre-bronchodilator forced expiratory volume in 1 s at week 52. Tezepelumab pharmacokinetics were well characterized by a 2-compartment linear disposition model with first-order absorption and elimination following subcutaneous and intravenous administration at 2.1-420 and 210-700 mg, respectively. There were no clinically relevant effects on tezepelumab pharmacokinetics from age (≥12 years), sex, race/ethnicity, renal or hepatic function, disease severity (inhaled corticosteroid dose level), concomitant asthma medication use, smoking history, or anti-drug antibodies. Body weight was the most influential covariate on tezepelumab exposure, but no meaningful differences in efficacy or safety were observed across body weight quartiles in patients with asthma who received tezepelumab 210 mg subcutaneously Q4W. There was no apparent relationship between tezepelumab exposure and efficacy at this dose regimen, suggesting that it is on the plateau of the exposure-response curve of tezepelumab. In conclusion, a fixed-dose regimen of tezepelumab 210 mg subcutaneously Q4W is appropriate for eligible adults and adolescents with severe, uncontrolled asthma.","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"64 8","pages":"908-921"},"PeriodicalIF":0.0,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2433","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140623661","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}

引用次数: 0

Performance of ChatGPT on Factual Knowledge Questions Regarding Clinical Pharmacy ChatGPT 在有关临床药学的事实性知识问题上的表现

The Journal of Clinical Pharmacology Pub Date : 2024-04-16 DOI: 10.1002/jcph.2443

Merel van Nuland PharmD, PhD, Abdullah Erdogan BSc, Cenkay Aςar PharmD, Ramon Contrucci PharmD, Sven Hilbrants PharmD, Lamyae Maanach PharmD, Toine Egberts PharmD, PhD, Paul D. van der Linden PharmD, PhD

{"title":"Performance of ChatGPT on Factual Knowledge Questions Regarding Clinical Pharmacy","authors":"Merel van Nuland PharmD, PhD, Abdullah Erdogan BSc, Cenkay Aςar PharmD, Ramon Contrucci PharmD, Sven Hilbrants PharmD, Lamyae Maanach PharmD, Toine Egberts PharmD, PhD, Paul D. van der Linden PharmD, PhD","doi":"10.1002/jcph.2443","DOIUrl":"10.1002/jcph.2443","url":null,"abstract":"ChatGPT is a language model that was trained on a large dataset including medical literature. Several studies have described the performance of ChatGPT on medical exams. In this study, we examine its performance in answering factual knowledge questions regarding clinical pharmacy. Questions were obtained from a Dutch application that features multiple-choice questions to maintain a basic knowledge level for clinical pharmacists. In total, 264 clinical pharmacy-related questions were presented to ChatGPT and responses were evaluated for accuracy, concordance, quality of the substantiation, and reproducibility. Accuracy was defined as the correctness of the answer, and results were compared to the overall score by pharmacists over 2022. Responses were marked concordant if no contradictions were present. The quality of the substantiation was graded by two independent pharmacists using a 4-point scale. Reproducibility was established by presenting questions multiple times and on various days. ChatGPT yielded accurate responses for 79% of the questions, surpassing pharmacists' accuracy of 66%. Concordance was 95%, and the quality of the substantiation was deemed good or excellent for 73% of the questions. Reproducibility was consistently high, both within day and between days (>92%), as well as across different users. ChatGPT demonstrated a higher accuracy and reproducibility to factual knowledge questions related to clinical pharmacy practice than pharmacists. Consequently, we posit that ChatGPT could serve as a valuable resource to pharmacists. We hope the technology will further improve, which may lead to enhanced future performance.","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"64 9","pages":"1095-1100"},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140562193","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}

引用次数: 0

Assessment of CYP-Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients with Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome 基于对复发或难治性急性髓性白血病或骨髓增生异常综合征患者进行的鸡尾酒疗法研究，评估依那西尼由 CYP 介导的药物相互作用。

The Journal of Clinical Pharmacology Pub Date : 2024-04-02 DOI: 10.1002/jcph.2436

Yiming Cheng PhD, Xiaomin Wang PhD, Atalanta Ghosh PhD, Jie Pu PhD, Leonidas N Carayannopoulos MD, PhD, Yan Li PhD

{"title":"Assessment of CYP-Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients with Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome","authors":"Yiming Cheng PhD, Xiaomin Wang PhD, Atalanta Ghosh PhD, Jie Pu PhD, Leonidas N Carayannopoulos MD, PhD, Yan Li PhD","doi":"10.1002/jcph.2436","DOIUrl":"10.1002/jcph.2436","url":null,"abstract":"As a selective and potent inhibitor targeting the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib obtained approval from the US Food and Drug Administration (FDA) in 2017 for adult patients with acute myeloid leukemia (AML) with an IDH2 mutation. In vitro investigations demonstrated that enasidenib affects various drug metabolic enzymes and transporters. This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. Results showed that following the co-administration of enasidenib (100 mg, once daily) for 28 days, the PK parameters AUC(0-∞) and Cmax of dextromethorphan increased by 1.37 (90% confidence interval (CI): 0.96, 1.96) and 1.24 (90% CI: 0.94, 1.65)-fold, respectively, compared to dextromethorphan alone. For flurbiprofen, these parameters increased by 1.14 (90%CI: 1.01, 1.29) and 0.97 (90% CI 0.86, 1.08)-fold, respectively, when compared to flurbiprofen alone. Conversely, midazolam exhibited decreases to 0.57 (90% CI 0.34, 0.97) and 0.77 (90% CI 0.39, 1.53)-fold, respectively, in comparison to midazolam alone. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)-fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)-fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib.","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"64 8","pages":"984-992"},"PeriodicalIF":0.0,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140337289","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}

引用次数: 0

Using Real-World Data to Externally Evaluate Population Pharmacokinetic Models of Dexmedetomidine in Children and Infants 利用真实世界数据对儿童和婴儿右美托咪定的群体药代动力学模型进行外部评估。

The Journal of Clinical Pharmacology Pub Date : 2024-03-28 DOI: 10.1002/jcph.2434

Sean McCann BS, Victória E. Helfer PhD, Stephen J. Balevic MD, PhD, Chi D. Hornik PharmD, Stuart L. Goldstein MD, Julie Autmizguine MD, Marisa Meyer DO, Amira Al-Uzri MD, MCR, Sarah G. Anderson MS, Elizabeth H. Payne PhD, Sitora Turdalieva MS, Daniel Gonzalez PharmD, PhD, the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee

{"title":"Using Real-World Data to Externally Evaluate Population Pharmacokinetic Models of Dexmedetomidine in Children and Infants","authors":"Sean McCann BS, Victória E. Helfer PhD, Stephen J. Balevic MD, PhD, Chi D. Hornik PharmD, Stuart L. Goldstein MD, Julie Autmizguine MD, Marisa Meyer DO, Amira Al-Uzri MD, MCR, Sarah G. Anderson MS, Elizabeth H. Payne PhD, Sitora Turdalieva MS, Daniel Gonzalez PharmD, PhD, the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee","doi":"10.1002/jcph.2434","DOIUrl":"10.1002/jcph.2434","url":null,"abstract":"Dexmedetomidine is a sedative used in both adults and off-label in children with considerable reported pharmacokinetic (PK) interindividual variability affecting drug exposure across populations. Several published models describe the population PKs of dexmedetomidine in neonates, infants, children, and adolescents, though very few have been externally evaluated. A prospective PK dataset of dexmedetomidine plasma concentrations in children and young adults aged 0.01-19.9 years was collected as part of a multicenter opportunistic PK study. A PubMed search of studies reporting dexmedetomidine PK identified five population PK models developed with data from demographically similar children that were selected for external validation. A total of 168 plasma concentrations from 102 children were compared with both population (PRED) and individualized (IPRED) predicted values from each of the five published models by quantitative and visual analyses using NONMEM (v7.3) and R (v4.1.3). Mean percent prediction errors from observed values ranged from −1% to 120% for PRED, and −24% to 60% for IPRED. The model by James et al, which was developed using similar “real-world” data, nearly met the generalizability criteria from IPRED predictions. Other models developed using clinical trial data may have been limited by inclusion/exclusion criteria and a less racially diverse population than this study's opportunistic dataset. The James model may represent a useful, but limited tool for model-informed dosing of hospitalized children.","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"64 8","pages":"963-974"},"PeriodicalIF":0.0,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140307447","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}

引用次数: 0

Effect of Hepatic Impairment on the Pharmacokinetics of Fenfluramine and Norfenfluramine 肝功能损害对芬氟拉明和诺芬氟拉明药代动力学的影响

The Journal of Clinical Pharmacology Pub Date : 2024-03-25 DOI: 10.1002/jcph.2431

Aravind Mittur PhD, Ryan Madanick MD, Melanie Langlois PhD, Brooks Boyd PhD

{"title":"Effect of Hepatic Impairment on the Pharmacokinetics of Fenfluramine and Norfenfluramine","authors":"Aravind Mittur PhD, Ryan Madanick MD, Melanie Langlois PhD, Brooks Boyd PhD","doi":"10.1002/jcph.2431","DOIUrl":"10.1002/jcph.2431","url":null,"abstract":"Fenfluramine (Fintepla®) is approved for the treatment of seizures associated with the rare epileptic encephalopathies Dravet syndrome and Lennox–Gastaut syndrome. Fenfluramine is extensively metabolized; thus, patients with hepatic impairment (HI) might experience changes in exposure to fenfluramine or its metabolites. In this phase 1 study, we investigated the pharmacokinetics (PK) and safety of a single oral dose of 0.35 mg/kg fenfluramine in subjects with mild (n = 8), moderate (n = 8), or severe (n = 7) HI (Child–Pugh A/B/C, respectively) and healthy control subjects (n = 22) matched for sex, age, and BMI. All subjects underwent serial sampling to determine total plasma concentrations of fenfluramine and its active metabolite, norfenfluramine. Hepatic impairment was associated with increases in fenfluramine exposures, mainly area-under-the-curve (AUC). Geometric least squares mean ratios (90% confidence intervals) for fenfluramine AUC0-∞ in mild, moderate, and severe HI versus healthy controls were 1.98 (1.36–2.90), 2.13 (1.43–3.17), and 2.77 (1.82–4.24), respectively. Changes in exposure to norfenfluramine in mild, moderate, and severe HI were minimal compared with normal hepatic function. Exposures to fenfluramine and norfenfluramine in all HI groups were within the ranges that have been characterized in the overall development program, including ranges examined in exposure–response relationships for efficacy and safety in patients, and determined to have an acceptable safety profile. Mild and moderate HI had a modest effect on fenfluramine exposure that was not clinically meaningful, whereas the higher fenfluramine exposure in severe HI may require dose reduction based on general caution in this population. The modest decrease in norfenfluramine exposure is not considered clinically relevant.","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"64 7","pages":"887-898"},"PeriodicalIF":0.0,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2431","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140208041","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}

引用次数: 0

Pharmacokinetics and Safety of Firsocostat, an Acetyl-Coenzyme A Carboxylase Inhibitor, in Participants with Mild, Moderate, and Severe Hepatic Impairment 乙酰辅酶 A 羧化酶抑制剂 Firsocostat 在轻度、中度和重度肝功能不全患者中的药代动力学和安全性。

The Journal of Clinical Pharmacology Pub Date : 2024-03-22 DOI: 10.1002/jcph.2427

Islam R. Younis PhD, FCP, Cara Nelson PhD, Elijah J. Weber PhD, Ann R. Qin PhD, Timothy R. Watkins MD, Ahmed A. Othman PhD, FCP

{"title":"Pharmacokinetics and Safety of Firsocostat, an Acetyl-Coenzyme A Carboxylase Inhibitor, in Participants with Mild, Moderate, and Severe Hepatic Impairment","authors":"Islam R. Younis PhD, FCP, Cara Nelson PhD, Elijah J. Weber PhD, Ann R. Qin PhD, Timothy R. Watkins MD, Ahmed A. Othman PhD, FCP","doi":"10.1002/jcph.2427","DOIUrl":"10.1002/jcph.2427","url":null,"abstract":"Firsocostat is an oral, liver-targeted inhibitor of acetyl-coenzyme A carboxylase in development for the treatment of metabolic dysfunction-associated steatohepatitis. Hepatic organic anion transporting polypeptides play a significant role in the disposition of firsocostat with minimal contributions from uridine diphospho-glucuronosyltransferase and cytochrome P450 3A enzymes. This phase 1 study evaluated the pharmacokinetics and safety of firsocostat in participants with mild, moderate, or severe hepatic impairment. Participants with stable mild, moderate, or severe hepatic impairment (Child–Pugh A, B, or C, respectively [n = 10 per cohort]) and healthy matched controls with normal hepatic function (n = 10 per cohort) received a single oral dose of firsocostat (20 mg for mild and moderate hepatic impairment; 5 mg for severe hepatic impairment) with intensive pharmacokinetic sampling over 96 h. Safety was monitored throughout the study. Firsocostat plasma exposure (AUCinf) was 83%, 8.7-fold, and 30-fold higher in participants with mild, moderate, and severe hepatic impairment, respectively, relative to matched controls. Firsocostat was generally well tolerated, and all reported adverse events were mild in nature. Dose adjustment is not necessary for the administration of firsocostat in patients with mild hepatic impairment. However, based on the observed increases in firsocostat exposure, dose adjustment should be considered for patients with moderate or severe hepatic impairment, and additional safety and efficacy data from future clinical trials will further inform dose adjustment.","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"64 7","pages":"878-886"},"PeriodicalIF":0.0,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.2427","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194878","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}

引用次数: 0

First-in-Human Phase 1 Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of DISC-0974, an Anti-Hemojuvelin Antibody, in Healthy Participants 评估抗血菊素抗体 DISC-0974 在健康参与者中的安全性、药代动力学和药效学的首次人体 1 期研究。

The Journal of Clinical Pharmacology Pub Date : 2024-03-21 DOI: 10.1002/jcph.2432

Natasha Novikov MD, PhD, Akshay Buch PhD, Hua Yang PhD, Michelle Andruk MBA, Guowen Liu PhD, Min Wu PhD, Haley Howell BSBA, Brian MacDonald MBChB, PhD, Will Savage MD, PhD

{"title":"First-in-Human Phase 1 Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of DISC-0974, an Anti-Hemojuvelin Antibody, in Healthy Participants","authors":"Natasha Novikov MD, PhD, Akshay Buch PhD, Hua Yang PhD, Michelle Andruk MBA, Guowen Liu PhD, Min Wu PhD, Haley Howell BSBA, Brian MacDonald MBChB, PhD, Will Savage MD, PhD","doi":"10.1002/jcph.2432","DOIUrl":"10.1002/jcph.2432","url":null,"abstract":"Pathologic elevations in hepcidin, a key regulator of iron homeostasis, contribute to anemia of inflammation in chronic disease. DISC-0974 is a monoclonal antibody that binds to hemojuvelin and blocks bone morphogenetic protein signaling, thereby suppressing hepcidin production. Reduction of systemic hepcidin levels is predicted to increase iron absorption and mobilize stored iron into circulation, where it may be utilized by red blood cell (RBC) precursors in the bone marrow to improve hemoglobin levels and to potentially alleviate anemia of inflammation. We conducted a first-in-human, double-blind, placebo-controlled, single-ascending dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of DISC-0974 in healthy participants. Overall, 42 participants were enrolled and received a single dose of placebo or DISC-0974 at escalating dose levels (7-56 mg), administered intravenously (IV) or subcutaneously (SC). DISC-0974 was well tolerated, with a safety profile comparable to that of placebo. Pharmacokinetic data was dose and route related, with a terminal half-life of approximately 7 days. The bioavailability of SC dosing was ∼50%. Pharmacodynamic data showed dose-dependent decreases in serum hepcidin, with reductions of nearly 75% relative to baseline at the highest dose level tested, and corresponding increases in serum iron in response to DISC-0974 administration. Dose-dependent changes in serum ferritin and hematology parameters were also observed, indicating mobilization of iron stores and downstream effects of enhanced hemoglobinization and production of RBCs. Altogether, these data are consistent with the mechanism of action of DISC-0974 and support the selection of a biologically active dose range for evaluation in clinical trials for individuals with anemia of inflammation.","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"64 8","pages":"953-962"},"PeriodicalIF":0.0,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140186062","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}

引用次数: 0

Efficacy, Safety, and Population Pharmacokinetics of Eltrombopag in Children with Different Severities of Aplastic Anemia 艾曲波帕对不同程度再生障碍性贫血患儿的疗效、安全性和群体药代动力学研究

The Journal of Clinical Pharmacology Pub Date : 2024-03-18 DOI: 10.1002/jcph.2430

Wei Zhang MS, Li-Xian Chang MD, Bei-Bei Zhao MS, Yi Zheng PhD, Dan-Dan Shan MS, Bo-Hao Tang PhD, Fan Yang MS, Yue Zhou PhD, Guo-Xiang Hao PhD, Ya-Hui Zhang MS, John van den Anker MD, PhD, Xiao-Fan Zhu MD, Li Zhang MD, Wei Zhao PharmD, PhD

{"title":"Efficacy, Safety, and Population Pharmacokinetics of Eltrombopag in Children with Different Severities of Aplastic Anemia","authors":"Wei Zhang MS, Li-Xian Chang MD, Bei-Bei Zhao MS, Yi Zheng PhD, Dan-Dan Shan MS, Bo-Hao Tang PhD, Fan Yang MS, Yue Zhou PhD, Guo-Xiang Hao PhD, Ya-Hui Zhang MS, John van den Anker MD, PhD, Xiao-Fan Zhu MD, Li Zhang MD, Wei Zhao PharmD, PhD","doi":"10.1002/jcph.2430","DOIUrl":"10.1002/jcph.2430","url":null,"abstract":"Eltrombopag was approved as a first-line treatment for patients older than 2 years old with severe aplastic anemia (SAA). However, data on eltrombopag in children with different types of aplastic anemia (AA), especially non-severe AA (NSAA), are limited. We performed a prospective, single-arm, and observational study to investigate eltrombopag's efficacy, safety, and pharmacokinetics in children with NSAA, SAA, and very severe AA (VSAA). The efficacy and safety were assessed every 3 months. The population pharmacokinetic (PPK) model was used to depict the pharmacokinetic profile of eltrombopag. Twenty-three AA children with an average age of 7.9 (range of 3.0-14.0) years were enrolled. The response (complete and partial response) rate was 12.5%, 50.0%, and 100.0% after 3, 6, and 12 months in patients with NSAA. For patients with SAA and VSAA, these response rates were 46.7%, 61.5%, and 87.5%. Hepatotoxicity occurred in one patient. Fifty-three blood samples were used to build the PPK model. Body weight was the only covariate for apparent clearance (CL/F) and volume of distribution. The allele-T carrier of adenosine triphosphate-binding cassette transporter G2 was found to increase eltrombopag's clearance. However, when normalized by weight, the clearance between the wild-type and variant showed no statistical difference. In patients with response, children with NSAA exhibited lower area under the curve from time zero to infinity, higher CL/F, and higher weight-adjusted CL/F than those with SAA or VSAA. However, the differences were not statistically significant. The results may support further individualized treatment of eltrombopag in children with AA.","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"64 8","pages":"932-943"},"PeriodicalIF":0.0,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140144373","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}

引用次数: 0

Daptomycin Dose Optimization in Pediatric Staphylococcus aureus Bacteremia: A Pharmacokinetic/Pharmacodynamic Investigation 小儿金黄色葡萄球菌菌血症中的达托霉素剂量优化：药代动力学/药效学研究。

The Journal of Clinical Pharmacology Pub Date : 2024-03-18 DOI: 10.1002/jcph.2425

Katie B. Olney PharmD, BCIDP, Joel I. Howard MD, David S. Burgess PharmD, FCCP, FIDP

{"title":"Daptomycin Dose Optimization in Pediatric Staphylococcus aureus Bacteremia: A Pharmacokinetic/Pharmacodynamic Investigation","authors":"Katie B. Olney PharmD, BCIDP, Joel I. Howard MD, David S. Burgess PharmD, FCCP, FIDP","doi":"10.1002/jcph.2425","DOIUrl":"10.1002/jcph.2425","url":null,"abstract":"Daptomycin is an antibiotic with Gram-positive activity, including methicillin-resistant Staphylococcus aureus, for which optimal pediatric dosing is unknown. This study aimed to evaluate daptomycin exposures achieved with package label dosing and to identify dosing regimens necessary to enhance efficacy and minimize toxicity in children with S. aureus bacteremia. Monte Carlo simulations were performed to determine probability of target attainment (PTA) for six pediatric age cohorts. Area under the curve to minimum inhibitory concentration ratio (AUC0-24:MIC) ≥666 was used to determine the PTA for efficacy (PTAE). Minimum concentration (Cmin) ≥24.3 mg/L determined the PTA for toxicity (PTAT). Acceptable dosing regimens were those which achieved the combined target of ≥90% PTAE and ≤5% PTAT. Package label dosing of daptomycin yielded insufficient efficacy with only 26.3% PTAE in children 13-24 months, 39.5% PTAE in children 2-6 years, 30.1% PTAE in children 7-11 years, and 50.1% PTAE in adolescents ≥12 years. To achieve the combined efficacy and safety target, doses of 18-24 mg/kg in children 3-12 months, 20-24 mg/kg in children 13-24 months, 19-24 mg/kg in children 2-6 years, 17-19 mg/kg in children 7-11 years, and 10-14 mg/kg in adolescents ≥12 years are necessary. Package label dosing resulted in suboptimal exposure for the majority of pediatric patients in all age groups evaluated. If targeting validated efficacy and safety endpoints, daily daptomycin doses of at least 20 mg/kg in children ≤6 years, 17 mg/kg in children 7-11 years, and 10 mg/kg in adolescents ≥12 years are necessary. Clinical studies evaluating these higher doses are needed.","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"64 7","pages":"860-865"},"PeriodicalIF":0.0,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140144372","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}

引用次数: 0