Clinical Pharmacology & Therapeutics最新文献

{"title":"Investigational Use of Real-World Data as a Hybrid Control in Pancreatic Ductal Adenocarcinoma from the Randomized Phase Ib/II MORPHEUS Trial.","authors":"Andrew H Ko, Do-Youn Oh, Janet Lau, Shivani K Mhatre, Bo Ci, Robson Machado, Shi Li, Michael T Bretscher, Irmarie Reyes-Rivera, Jiawen Zhu, Xiaosong Zhang, Jilpa Patel, Matthew A Psioda, Mariano Ponz-Sarvise","doi":"10.1002/cpt.3528","DOIUrl":"https://doi.org/10.1002/cpt.3528","url":null,"abstract":"<p><p>Enrolling adequate numbers of patients into the control arm of randomized controlled trials (RCTs) often presents barriers. There is interest in leveraging real-world data (RWD) from electronic health records (EHRs) to construct external control (EC) arms to supplement RCT control arms and form hybrid control (HC) arms. This investigation showed the use of an HC arm in second-line metastatic pancreatic ductal adenocarcinoma (PDAC). The RCT experimental arm (atezolizumab + PEGylated recombinant human hyaluronidase (Atezo + PEGPH20)) was compared with an HC arm consisting of patients treated with modified FOLFOX6 or gemcitabine/nab-paclitaxel from the MORPHEUS PDAC internal control arm supplemented with data from a nationwide EHR-derived de-identified database as the EC arm. The EC arm was constructed by applying key inclusion/exclusion criteria from the MORPHEUS PDAC trial to patients from the real-world cohort. Baseline variables were balanced using propensity score matching and covariate adjustment. Three analysis approaches-Cox model with pooled-control data, Cox model with control arm-specific frailty, and Bayesian analysis using a commensurate prior-were assessed. Overall survival was similar between the treatment arms. The direction and magnitude of hazard ratios (HRs) from the multiple HC analyses (HRs ranged from 1.02 to 1.06) were comparable with the reported trial HR (HR 0.91; 95% CI: 0.56, 1.49). This analysis demonstrates the feasibility and applicability of leveraging RWD in clinical trial design to supplement clinical trial control arms.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Factors Influencing Medication Adherence in Heart Failure Patients-A Survey among Cardiac Healthcare Providers.","authors":"Ingibjorg Gunnthorsdottir, Anna Birna Almarsdottir, Karl Andersen, Anna I Gunnarsdottir, Erla Svansdottir, Hafsteinn Einarsson, Inga Jona Ingimarsdottir","doi":"10.1002/cpt.3526","DOIUrl":"https://doi.org/10.1002/cpt.3526","url":null,"abstract":"<p><p>Adhering to medication regimens is key behavior to alleviate symptoms and slow disease progression in heart failure (HF). This study explores cardiac healthcare providers' perceptions and experiences of factors influencing medication adherence (MA) in HF patients, with findings contributing to developing a HF-specific MA assessment scale. Using a cross-sectional, mixed methods design, we conducted an online survey with both closed and open-ended questions distributed to cardiac healthcare providers, working at the National University Hospital in Iceland. The survey consisted of 103 questions divided into 18 themes. Analysis included descriptive statistics of the participants' responses to closed responses with simplified scoring. Free-text responses were grouped into thematic categories and then into subthemes. Of 104 healthcare providers invited, 73 (70%) participated. Key factors identified as most beneficial for supporting MA included supportive patient-provider relationships (97%), selecting suitable drug formulation (96%), healthcare support at home (95%), and multi-dose dispensing from pharmacies (93%). The youngest and oldest HF patients were believed to be at the highest risk of medication non-adherence, particularly among males. Other patients estimated at increased risk included those with alcohol and/or substance abuse (89%), those with limited knowledge of medication effects (89%), those perceiving medication as useless (88%), and those with cognitive impairment (86%). Most participants (73%) agreed that healthcare providers should assess and document MA in clinical care. These findings provide a comprehensive overview of factors that cardiac healthcare providers believe influence non-adherence in HF patients, contributing to the development of a HF-specific MA scale.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence Estimates of Cytochrome P450 Phenoconversion in Youth Receiving Pharmacotherapy for Mental Health Conditions.","authors":"Samuel Gerlach, Abdullah Al Maruf, Sarker M Shaheen, Ryden McCloud, Madison Heintz, Laina McAusland, Paul D Arnold, Chad A Bousman","doi":"10.1002/cpt.3534","DOIUrl":"https://doi.org/10.1002/cpt.3534","url":null,"abstract":"<p><p>Pharmacogenetics-predicted drug metabolism may not match clinically observed metabolism due to a phenomenon known as phenoconversion. Phenoconversion can occur when an inhibitor or inducer of a drug-metabolizing enzyme is present. Although estimates of phenoconversion in adult populations are available, prevalence estimates in youth populations are limited. To address this gap, we estimated the prevalence of phenoconversion in 1281 youth (6-24 years) receiving pharmacotherapy for mental health conditions and who had pharmacogenetics testing completed for four genes (CYP2B6, CYP2C19, CYP2D6, CYP3A4). Self-reported medication and cannabidiol/cannabis use were collected at the time of pharmacogenetics testing. Nearly, half (46%) of the cohort was estimated to be phenoconverted for one of the four genes examined. Comparison of metabolizer phenotype frequencies before and after adjustment for phenoconversion showed significantly more youth had actionable phenotypes for CYP2C19 (60.3% vs. 69.1%; P =< 0.001), CYP2D6 (49.3% vs. 63.0%; P =< 0.001), and CYP3A4 (8.5% vs.12.2%; P = 0.003) after phenoconversion adjustment. Of youth who were phenoconverted, 24% had a change in their metabolizer phenotype that would lead to current pharmacogenetics-based prescribing guidelines recommending a change to standard prescribing (dose adjustment, alternative medication). Our findings indicate a high prevalence of cytochrome P450 phenoconversion among youth receiving pharmacotherapy for mental health conditions. Adjustment for phenoconversion should be considered when implementing pharmacogenetics testing in youth populations to improve the clinical utility of this testing in practice.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Actionability of the NUDT15 *4 (p.R139H) Allele and Its Association With Hispanic Ethnicity.","authors":"Maud Maillard, Jenny Q Nguyen, Wenjian Yang, Keito Hoshitsuki, Mary V Relling, Kelly E Caudle, Kristine R Crews, Sima Jeha, Hiroto Inaba, Ching-Hon Pui, Smita Bhatia, Seth E Karol, Federico G Antillon-Klussmann, Cyrine E Haidar, Deepa Bhojwani, Jun J Yang","doi":"10.1002/cpt.3501","DOIUrl":"10.1002/cpt.3501","url":null,"abstract":"<p><p>Nudix hydrolase 15 (NUDT15) deficiency is strongly associated with thiopurine-induced myelosuppression. Currently, testing for NUDT15 deficiency is based on the genotyping of the most frequent and clinically characterized no-function variants, that is, *2, *3 and *9. The Hispanic/Latino-predominant variant NUDT15 *4 (p.R139H) is classified as \"uncertain function\" by the Clinical Pharmacogenetics Implementation Consortium, because of insufficient data to ascertain its clinical actionability. In this study, we evaluated the association of NUDT15 *4 with mercaptopurine (6-MP) tolerance in a retrospective cohort of 1,399 patients with acute lymphoblastic leukemia (ALL) of diverse ancestries. All patients were wildtype for thiopurine methyltransferase gene. Patients were treated with 6-MP in the context of ALL frontline clinical trials. The tolerated dose of 6-MP was used to assess drug toxicity during the maintenance phase of ALL therapy. Patients with NUDT15 *1/*4 (n = 16, all of whom self-identified as Hispanic/Latino) tolerated a significantly lower dose of 6-MP than did those with NUDT15 *1/*1: median [interquartile range] of 39.0 [21.2-52.8] mg/m², vs. 62.2 [47.9-71.6] mg/m², P value < 0.001. No patient homozygous for *4 was detected. In a separate retrospective validation study, six patients were identified as having NUDT15 *1/*4 by routine clinical pharmacogenetics testing and tolerated a 6-MP median dose of 38.7 mg/m² (IQR, 33.7-54.0), confirming the need for dose reduction attributed to the NUDT15 *4 variant. These results point to the need to include NUDT15 *4 in pharmacogenetics-guided thiopurine dosing algorithms.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Highlighted Articles","authors":"","doi":"10.1002/cpt.3490","DOIUrl":"https://doi.org/10.1002/cpt.3490","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 1","pages":"14-15"},"PeriodicalIF":6.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142868481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-in-Human Dose Selection for T-Cell Engaging Bispecific Antibodies","authors":"Piet H. van der Graaf","doi":"10.1002/cpt.3487","DOIUrl":"10.1002/cpt.3487","url":null,"abstract":"&lt;p&gt;Although bispecific antibodies (“bispecifics,” antibodies that can bind to two different antigens at the same time) are typically coined as novel modalities,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; they were already reported in 1960 by Nisonoff and colleagues.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; However, it was only three decades later for the first clinical investigation to happen and then it took another two to the approval of the first bispecific antibody for human therapeutic use.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; There are now more than 10 bispecific antibodies approved by the US Food and Drug Administration (FDA), the majority for the treatment of cancer (&lt;b&gt;Figure&lt;/b&gt; 1).&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The initial steps and milestones in the development of bispecific therapeutics were mainly fueled by advances and breakthroughs in biotechnology and antibody engineering. More recently biology, translational medicine as well as clinical pharmacology have played an increasingly important role. The most exciting properties of bispecifics are called obligate, since they are dependent on the physical linkage of the two “arms” and cannot be obtained by combining separate antibodies with the same individual binding properties.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; An example is avidity (sometimes referred to as functional affinity), which quantifies the synergy due to multiple simultaneous binding interactions.&lt;span&gt;&lt;sup&gt;3, 5&lt;/sup&gt;&lt;/span&gt; These unique properties of bispecifics offer potential therapeutic advantages but also raise significant drug development challenges. For example, the dose/concentration-response relationship for bispecifics can be bell-shaped, which makes dose-finding more challenging.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Second, due to highly system-dependent pharmacology, the translation of pharmacokinetics-pharmacodynamics (PKPD) of bispecifics is complex and traditional minimal anticipated biological effect level (MABEL) concepts to define first-in-human (FIH) starting dose for conventional monoclonal antibodies do not apply.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Last but not least, how do we predict and manage between-patient variability, which due to the multifactorial mechanism of action may be more pronounced for bispecifics than what is typically observed with conventional monoclonal antibodies.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;A series of recent white papers, reviews, and research articles published in &lt;i&gt;Clinical Pharmacology &amp; Therapeutics&lt;/i&gt; (&lt;i&gt;CPT&lt;/i&gt;) reflects the significant interest of drug developers in this area and provides overviews of current clinical pharmacology best practices and innovation.&lt;span&gt;&lt;sup&gt;4, 7-11&lt;/sup&gt;&lt;/span&gt; In this issue of &lt;i&gt;CPT&lt;/i&gt;, a working group from the &lt;i&gt;American Association of Pharmaceutical Scientists&lt;/i&gt; (&lt;i&gt;AAPS&lt;/i&gt;) presents learnings and recommendations for FIH starting dose selection, early clinical development, and recommended Phase 2 dose (RP2D) selection and bioanalytical and biomarkers strategies for T-cell engaging bispecific antibod","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 1","pages":"11-13"},"PeriodicalIF":6.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3487","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Magnetic Resonance Imaging Reveals Novel Insights into the Dual Mode of Action of Bisacodyl: A Randomized, Placebo-controlled Trial in Constipation.","authors":"Abdulsalam Aliyu, Neele Dellschaft, Caroline Hoad, Hannah Williams, Emily Gaudoin, Sarah Sulaiman, Colin Crooks, Penny Gowland, Alexia Aran, Robert Lange, Beatrice Bois De Fer, Maura Corsetti, Luca Marciani, Robin Spiller","doi":"10.1002/cpt.3532","DOIUrl":"https://doi.org/10.1002/cpt.3532","url":null,"abstract":"<p><p>Bisacodyl is a widely used laxative that stimulates both motility and secretion. Our aim was to exploit the unique capabilities of MRI to define bisacodyl's mode of action. Two placebo-controlled cross-over trials were performed, one using a single dose of Bisacodyl 5 mg while the second dosed daily for 3 consecutive days. Serial MRI was performed every 75 minutes. Primary endpoint: ascending colon water content as assessed by T1AC AUC_{300-450 minutes}. Secondary endpoints included: small bowel water content, whole gut transit time (WGTT), colonic volumes, stool frequency, and consistency using Bristol Stool Form Score (BSFS). Exploratory endpoints: changes in the serial segmental volumes were quantified from the number of \"mass movements\" defined as episodes when segmental volume change from the previous scan was > 20% of baseline volume. We also measure the time to defecate after dosing. After 3 days of bisacodyl, ascending colon water content (T1) was 62% greater than after placebo, mean difference T1 AUC_{300-450 minutes} 50.2 (61.0) sec.min, 95% CI (9.2, 91.2), P = 0.02, while after a single dose difference was only 11% (P = 0.58). Both single and repeated doses shortened WGTT (P < 0.049) and time to defecate (P 0.01). Only repeated doses significantly increased small bowel water content (P < 0.03), the number of \"mass movements\" (P = 0.048), bowel frequency (P = 0.006), and BSFS (P = 0.03). Repeated, compared to single dosing of Bisacodyl, additionally increases small bowel and colon water content and increases the number of \"mass movements\" thereby increasing its laxative effect. MRI is a non-invasive, patient-acceptable technique for evaluating drugs which alter secretion and/or motility.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of OATP1B1/3 Rather Than UGT1A1 May Be the Major Cause of the Bilirubin Elevation After Atazanavir Administration.","authors":"Jin Dong, Pradeep Sharma, Rasha Emara, Derek Cheung, Weifeng Tang, Diansong Zhou, David W Boulton, Mats Någård, Miki S Park","doi":"10.1002/cpt.3529","DOIUrl":"https://doi.org/10.1002/cpt.3529","url":null,"abstract":"<p><p>Atazanavir has been reported to increase total serum bilirubin level up to ninefold. It is widely believed that the observed total bilirubin elevation is primarily due to UGT1A1 inhibition. However, UGT enzymes are well-known as a low-affinity and high-capacity system, and the observed drug-drug interaction mediated by UGTs is usually less than twofold. There were discrepancies in the explanation of total bilirubin elevation due to UGT1A1 inhibition alone, suggesting the contribution of other mechanism(s) to the interaction. As atazanavir is a potent OATP1B1/3 inhibitor and the hepatic uptake of both unconjugated and conjugated bilirubin are mediated by OATP1B1/3, these transporters could be involved in the bilirubin-atazanavir interaction. To better understand the roles of UGT1A1 and OATP1B1/3 in this interaction, it would be useful to characterize the contribution of each individual pathway to the interaction. As multiple compounds, pathways, and potentially UGT1A1 polymorphism are involved, a thorough physiologically-based pharmacokinetic (PBPK) analysis was utilized to integrate the information from various relevant in vitro and clinical studies to quantitatively estimate the contribution of UGT1A1 and OATP1B1/3 inhibition to the interaction between bilirubin and atazanavir. The PBPK analysis indicated that UGT1A1 inhibition plays a modest role in bilirubin and atazanavir interaction contributing less than 33%. The results also suggested that unconjugated bilirubin is less sensitive than raltegravir upon UGT1A1 inhibition, therefore, unconjugated bilirubin may not be a useful endogenous biomarker for UGT1A1 inhibition. The analysis demonstrated that the metabolism of unconjugated bilirubin shares common features of other UGT enzyme-mediated reactions.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk of Hypoglycemia Associated with Concomitant Use of Insulin Secretagogues and ACE Inhibitors in Adults with Type 2 Diabetes: A Systematic Review.","authors":"Patricia Y Chu, Emma K Edmondson, James H Flory, Jing Huang, Sean Hennessy","doi":"10.1002/cpt.3530","DOIUrl":"10.1002/cpt.3530","url":null,"abstract":"<p><p>Insulin secretagogues and angiotensin-converting enzyme inhibitors (ACEIs) are commonly co-prescribed for patients with type 2 diabetes (T2D). Case reports suggesting that co-administration of insulin secretagogues with ACEIs is associated with an increased risk of serious hypoglycemia have led to warnings regarding a drug-drug interaction in widely used drug compendia. However, subsequent studies have had inconsistent results. We performed a systematic review to evaluate the evidence that concomitant use of ACEIs and insulin secretagogues increases the risk of serious hypoglycemia. MEDLINE/PubMed and Embase were searched from inception to July 2023 for studies evaluating adults with T2D treated with insulin secretagogues, such as sulfonylureas or meglitinides, and exposed to an ACEI. The primary outcome was serious hypoglycemia. A literature search yielded 472 papers, of which five met the inclusion criteria. The heterogeneity of the studies precluded meta-analysis. Two studies using multiple methods to address bias found no association between hypoglycemia and concomitant use of ACEI and insulin secretagogues. Three studies found potential associations, but only one was statistically significant; these studies were at serious or critical risk of bias due to potential confounding from lack of adjustment for renal dysfunction. The higher quality studies found no association between the concomitant use of insulin secretagogues with ACEI and hypoglycemia. Drug compendia and electronic health records should consider updating and removing alerts warning of a drug-drug interaction between insulin secretagogues as a class and ACEIs.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetic/Pharmacodynamic and Exposure-Response Modeling Analyses of Sotatercept in Healthy Participants and Patients with Pulmonary Arterial Hypertension.","authors":"Sihem Ait-Oudhia, David Jaworowicz, Ziheng Hu, Mitali Gaurav, Heather Barcomb, Shuai Hu, Sébastien Bihorel, Budda Balasubrahmanyam, Bipin Mistry, Janethe de Oliveira Pena, Larissa Wenning, Ferdous Gheyas","doi":"10.1002/cpt.3524","DOIUrl":"https://doi.org/10.1002/cpt.3524","url":null,"abstract":"<p><p>Sotatercept is a breakthrough, first-in-class biologic, recently approved by the Food and Drug Administration (FDA) for the treatment of pulmonary arterial hypertension (PAH). Exposure-response (E-R) analyses and pharmacokinetic/pharmacodynamic (PK/PD) modeling were performed for sotatercept after intravenous and subcutaneous (SC) administrations. Clinical endpoints included 6-minute walk distance (6MWD), pulmonary vascular resistance (PVR), and probability of N-terminal pro-B natriuretic peptide (NT-proBNP) concentrations < 300 pg/mL for efficacy, and hemoglobin (Hgb) for safety from two Phase 1 studies, two Phase 2 studies, and one Phase 3 study. E-R models using nonlinear mixed effect modeling approach were developed for 6MWD and PVR, while Cox proportional hazards model and semi-mechanistic PK/PD model were used for NT-proBNP and Hgb. Covariate analyses were conducted to identify significant predictors of variability for each of these clinical endpoints. Modeling results showed that increasing sotatercept average concentration (C_avg) at week 24 is associated with increased predicted 6MWD, increased probability of NT-proBNP concentration < 300 pg/mL, decreased predicted PVR, and increased Hgb which was clinically manageable. All these responses approached their corresponding plateaus at a C_avg range associated with the dose of 0.7 mg/kg Q3W SC. Statistically relevant covariates included age and iron supplementation which slightly increased Hgb-mediated effect for 6MWD, PAH disease duration, and baseline therapy infusion with prostacyclin for PVR, and WHO functional class for NT-proBNP. The magnitudes of the impact of these covariates are not clinically meaningful. Taken together, these results support an appropriate benefit-risk profile for the FDA-approved target dose for sotatercept of 0.7 mg/kg Q3W SC.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}