Clinical Pharmacology & Therapeutics最新文献

{"title":"Intracellular Penetration of Atazanavir, Ritonavir and Dolutegravir With Concomitant Rifampicin: A Dose Escalation Study.","authors":"Amedeo De Nicolò, Alice Palermiti, Henry Mugerwa, Shamim Nakabuye, Josephine Namusanje, Josephine Kobusingye, Denis Odoch, Mohammed Lamorde, Allan Kengo, Paolo Denti, Kamunkhwala Gausi, Gary Maartens, Helen McIlleron, Lubbe Wiesner, Saye Khoo, Catriona Waitt, Antonio D'Avolio","doi":"10.1002/cpt.3572","DOIUrl":"https://doi.org/10.1002/cpt.3572","url":null,"abstract":"<p><p>Ritonavir-boosted atazanavir is a victim of drug-drug interaction with rifampicin, a key component of antitubercular treatment. In a recent dose escalation clinical trial, we showed that increasing atazanavir/ritonavir to 300/100 mg b.i.d. compensates for reduced drug exposure in plasma due to rifampicin, but the intracellular effects remained unexplored. This sub-study investigated the intracellular penetration of atazanavir/ritonavir and dolutegravir into peripheral blood mononuclear cells (PBMC). Twenty-six healthy volunteers living with HIV, virologically suppressed, and taking atazanavir/ritonavir containing regimens were enrolled. The trial consisted of four sequential periods: PK1, participants were on atazanavir/ritonavir 300/100 mg q.d.; at PK2, rifampicin 600 mg q.d. and dolutegravir 50 mg b.i.d. were added (2 weeks); at PK3, atazanavir/ritonavir dose was increased to 300/100 mg b.i.d. (1 week); at PK4, rifampicin dose was doubled (1 week). Atazanavir, ritonavir, and dolutegravir were quantified in plasma and PBMC using LC-MS/MS methods to evaluate steady-state concentrations at the end of each period. Atazanavir/ritonavir dose escalation successfully restored intracellular concentrations comparable to those observed without rifampicin, with a geometric mean ratio of 0.99 (CI₉₀ 0.72-1.41) for atazanavir at PK3 compared with PK1. The intracellular concentration of dolutegravir increased significantly with atazanavir/ritonavir dose escalation, similar to plasma. Finally, further, increasing the rifampicin dose did not show an additional impact on atazanavir/ritonavir concentrations in PBMC. The study confirms that increasing the ATV/r dose can be an effective strategy for compensating rifampicin effects even at the intracellular level, supporting its use in clinical settings.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143072953","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 Evaluation of Drug-Drug Interactions with Obeldesivir, an Orally Administered Antiviral Agent.","authors":"Chi-Chi Peng, Rita Humeniuk, Anuja Raut, Anna Kwan, Lily Mak, Caitlin Stacom, Deqing Xiao, Shuguang Chen, Santosh Davies, Sharline Madera, Yiannis Koullias, Amos Lichtman, Joe Llewellyn, Elham Amini, Helen Winter, Luzelena Caro","doi":"10.1002/cpt.3575","DOIUrl":"https://doi.org/10.1002/cpt.3575","url":null,"abstract":"<p><p>Obeldesivir is an oral nucleoside analog prodrug inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase and other viral polymerases. Here, two Phase I studies evaluated potential drug-drug interactions between obeldesivir and substrates or inhibitors of cytochrome P450 and drug transporters in healthy participants. When obeldesivir was tested as a precipitant, pharmacokinetic parameter point estimates for midazolam (CYP3A4 inhibition/induction), caffeine (CYP1A2 inhibition), and metformin (organic cation transporter 1 inhibition) exposures were within 80-125% no-effect bounds representing the interval within which a systemic exposure change does not warrant clinical action based on EMA/FDA guidance. Dabigatran (P-glycoprotein substrate) and pitavastatin (organic anion transporting polypeptide 1B1/1B3 substrate) exposures decreased by approximately 25% and 30%, respectively, with obeldesivir coadministration; these were considered not clinically relevant, as these exposure changes are not associated with dose changes or precautions in the US prescribing information for these drugs. When obeldesivir was evaluated as an object, exposures of GS-441524, the parent nucleoside monophosphate metabolite of obeldesivir, were within the 80-125% no-effect bounds for ritonavir (P-glycoprotein inhibition) and cyclosporin A (breast cancer resistance protein inhibition) coadministration. Famotidine (gastric acid suppression) coadministration decreased GS-441524 exposure by approximately 26%; this was within the range of exposures observed in previous Phase III studies and was considered not clinically relevant. Obeldesivir was well tolerated, and adverse events were mild to moderate. These findings indicate that obeldesivir has low potential for drug-drug interactions. Obeldesivir remains a promising treatment against a broad spectrum of viruses given its antiviral activity and favorable safety profile.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062847","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":"IQ Survey Results on Current Industry Practices-Part 1: Immunogenicity Risk Assessment.","authors":"Christine Grimaldi, Susan Richards, Daniel Baltrukonis, Shelley Sims Belouski, Kelly Coble, Sanjay L Dholakiya, Joanna Grudzinska-Goebel, Gerry Kolaitis, Jocelyn H Leu, Linlin Luo, Stephen Lowe, Tao Niu, Henrik Toft-Hansen, Jianning Yang, Benjamin Wu","doi":"10.1002/cpt.3568","DOIUrl":"https://doi.org/10.1002/cpt.3568","url":null,"abstract":"<p><p>An immunogenicity risk assessment (IRA) is a relatively new expectation of health authorities that is increasingly incorporated into the drug development process across the pharmaceutical/biotech industry. The guiding principle for an IRA includes a comprehensive evaluation of product- and patient-related factors that may influence the immunogenic potential of a biotherapeutic drug and a potential action plan. The Immunogenicity Working Group from the IQ Consortium (Clinical Pharmacology Leadership Group) has conducted a survey to understand the current practices for conducting IRAs and relevant aspects of bioanalysis. Survey results were provided by 19 IQ member companies participating in the Clinical Pharmacology Leadership Group (CPLG) and the Translational and ADME Sciences Leadership Group (TALG). Nearly all the respondents reported experience with monoclonal antibodies (mAb), with 10 other drug modalities including bioengineered protein therapeutics such as fusion and multi-domain proteins, peptides, oligonucleotides as well as gene and cell therapies. The survey results demonstrate that most companies have a defined IRA process, and there was a common understanding that the IRA may need to be revised as more information becomes available or the drug development strategy changes. Some differences found across the respondents are related to the time frame for implementation of IRA document, the types of preclinical data and computational methods used to assess risk, and how the IRA informs clinical plans and documentation practices. These results highlight that while there have been widespread insights gained with performing IRA for mAbs, more experience is needed to perform IRAs for the novel modalities.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057415","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":"Integrated Longitudinal Population Dose-Hemoglobin Response of Daprodustat Following Dose Titration in Patients With Anemia in Chronic Kidney Disease","authors":"Kelly M. Mahar,&nbsp;Martijn van Noort,&nbsp;Paul van den Berg,&nbsp;Shuying Yang,&nbsp;Sandra A. G. Visser,&nbsp;Teun M. Post","doi":"10.1002/cpt.3544","DOIUrl":"10.1002/cpt.3544","url":null,"abstract":"<p>Daprodustat, a novel oral hypoxia-inducible factor prolyl hydroxylase inhibitor is approved in the United States for the treatment of anemia due to chronic kidney disease (CKD) in adults receiving dialysis for at least 4 months. Pharmacodynamic dose-hemoglobin (Dose-Hgb) models were developed as daprodustat progressed through development. To support global phase III development, a dose-titration algorithm, guided by simulations from the initial Dose-Hgb model based on phase II clinical data, was implemented. This work was to update and re-calibrate this model to support the dose titration algorithm. Data from five pivotal phase III studies in CKD patients with anemia treated with daprodustat once daily (q.d.) and/or three times a week (t.i.w.) using a titration dosing schedule were included. The data comprised 2,770 CKD patients with anemia providing 53,535 Hgb observations over a period of 6 months up to 4 years. This final Dose-Hgb model consisted of a precursor cell compartment and 12 transit compartments to describe the red blood cell (RBC) lifespan. Treatment increased the precursor cell production rate (<i>K</i>_in) by a power of allometrically scaled dose. Disease progression, as an exponential decline of Hgb production rate over time, varied with dialysis status. The dose-titration algorithm resulted in comparable response for t.i.w. dosing relative to q.d. dosing. Titration-based visual predictive checks for Hgb target criteria for the analysis dataset and the prediction dataset showed that the model adequately predicted the observed data. This re-calibrated Dose-Hgb model will provide further support for the individualized dosing strategy in CKD patients with anemia treated with daprodustat.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 3","pages":"846-856"},"PeriodicalIF":6.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3544","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057412","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":"Toward Developing Alternative Opioid Antagonists for Treating Community Overdose: A Model-Based Evaluation of Important Pharmacological Attributes","authors":"Anik Chaturbedi,&nbsp;John Mann,&nbsp;Shilpa Chakravartula,&nbsp;Bradlee Thrasher,&nbsp;Ghazal Arabidarrehdor,&nbsp;Joel Zirkle,&nbsp;Hamed Meshkin,&nbsp;Srikanth C. Nallani,&nbsp;Jeffry Florian,&nbsp;Zhihua Li","doi":"10.1002/cpt.3527","DOIUrl":"10.1002/cpt.3527","url":null,"abstract":"<p>In response to increased illicit use of synthetic opioids, various μ-receptor antagonist formulations, with varied pharmacological characteristics, have been and are being developed. To understand how pharmacologic characteristics such as absorption rate and clearance rate affect reversal in treating community opioid overdose, we used our previously published translational opioid model. We adapted this model with <i>in vitro</i> receptor binding data and clinical pharmacokinetic data of three intranasal nalmefene formulations along with an intranasal naloxone formulation to study the reversal of fentanyl and carfentanil-induced respiratory depression in chronic opioid users. Nalmefene has a longer plasma half-life and slower unbinding from the μ-receptor compared to naloxone. For a more rapid reversal of acute overdose-induced respiratory depression, a fast-absorbing antagonist formulation may be of greater utility than a slow-absorbing one containing the same dosage of the antagonist. For preventing renarcotization caused by a long opioid exposure, a slow-clearing antagonist with slow unbinding from the receptor may be of value. While a more potent antagonist with a longer half-life may have the potential to facilitate recovery from respiratory depression for overdose with synthetic opioids, such interventions may also lead to longer and more pronounced withdrawal. This emphasizes the need for a nuanced consideration of several facets while choosing a μ-receptor antagonist, dose, and formulation to treat community opioid overdose cases.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 3","pages":"836-845"},"PeriodicalIF":6.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057417","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":"Investigation of Genomic and Transcriptomic Risk Factors of Clopidogrel Response in African Americans.","authors":"Guang Yang, Cristina Alarcon, Catherine Chanfreau, Norman H Lee, Paula Friedman, Edith Nutescu, Matthew Tuck, Travis O'Brien, Li Gong, Teri E Klein, Kyong-Mi Chang, Philip S Tsao, David O Meltzer, Julie A Lynch, Sony Tuteja, Minoli A Perera","doi":"10.1002/cpt.3552","DOIUrl":"10.1002/cpt.3552","url":null,"abstract":"<p><p>Clopidogrel, an anti-platelet drug, is used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic events, with African Americans (AA) suffering disproportionately. The aim of this study was to discover novel biomarkers of clopidogrel resistance in African Americans using genome and transcriptome data. We conducted a genome-wide association study (GWAS), including local ancestry adjustment, in 141 AA on clopidogrel to identify genetic associations with high on-treatment platelet reactivity (HTPR), with validation of genome-wide significant and suggestive loci in an independent cohort of AA clopidogrel patients (N = 823) from the Million Veteran's Program (MVP) along with in vitro functional analysis. We performed differential gene expression (DGE) analysis in whole blood to identify transcriptomic predictors of response, followed by functional validation in MEG-01 cells. GWAS identified one signal on Chromosome 7 as significantly associated with increasing risk of HTPR. The lead single-nucleotide polymorphism (SNP), rs7807369, within thrombospondin 7A (THSD7A) was associated with an increased risk of HTPR (odds ratio (OR) = 4.02, P = 4.56 × 10^-9). Higher THSD7A gene expression was associated with HTPR in an independent cohort of clopidogrel-treated patients (P = 0.004) and carrying a risk allele showed increased gene expression in primary human endothelial cells. Notably, the CYP2C19*2 variants showed no association with clopidogrel response in the discovery or MVP cohorts. DGE analysis identified an association with decreased LAIR1 and AP3B2 expression to HTPR. LAIR1 knockdown in MEG-01 cells resulted in increased expression of SYK and AKT1, suggesting an inhibitory role of LAIR1 in the Glycoprotein VI pathway. In summary, these findings suggest that other variants and genes outside of CYP2C19 star alleles play an important role in clopidogrel response in AA.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045107","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":"Effect of Target-Mediated Disposition on Iptacopan Clinical Pharmacokinetics in Participants with Normal or Impaired Hepatic Function.","authors":"Elise Burmeister Getz, Richard R Stein, Martin Fink, Kenneth Kulmatycki, Irina Baltcheva, Wendy Weis, Bharti Shah, Eric Lawitz, Robert Schmouder","doi":"10.1002/cpt.3559","DOIUrl":"https://doi.org/10.1002/cpt.3559","url":null,"abstract":"<p><p>Iptacopan, a first-in-class complement factor B inhibitor acting proximally in the alternative complement pathway, has been shown to be safe and effective for patients with complement-mediated diseases. Iptacopan selectively binds with high affinity to factor B, a soluble, plasma-based, hepatically produced protein. Factor B is abundant in the circulation but can be saturated at the iptacopan clinical dose of 200 mg twice daily. Iptacopan pharmacokinetics (PK) are influenced by target binding. This target-mediated drug disposition (TMDD) behavior makes PK data useful for understanding target occupancy and motivates modeling of drug-target binding to connect exposure with pharmacological effect. A phase I hepatic impairment (HI) PK study measuring both total and unbound iptacopan PK profiles provided an opportunity to characterize the effect of variation in target concentration (due to varying hepatic function) on iptacopan PK. HI caused no change in total iptacopan exposure but increased unbound iptacopan exposure 1.38- to 3.72-fold in participants with mild, moderate, or severe HI relative to demographically matched participants with normal hepatic function, with the largest increases in severe HI. A two-site competitive binding model was developed to elucidate the relationship between iptacopan PK and factor B occupancy to characterize exposure thresholds for maximal target engagement. The model was used to assess alternative dose regimens to provide insight into how to approach dose recommendations for patients with severe HI. This study provides an example of small-molecule TMDD, a behavior typically associated with targeted biologics; its importance is too often underappreciated in small-molecule drug development.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035472","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":"Duration of Time Intervals for Risk Minimization Measure Effectiveness Studies","authors":"Sharon C. M. Essink,&nbsp;Inge M. Zomerdijk,&nbsp;Thomas Goedecke,&nbsp;Sabine M. J. M. Straus,&nbsp;Helga Gardarsdottir,&nbsp;Marie L. De Bruin","doi":"10.1002/cpt.3569","DOIUrl":"10.1002/cpt.3569","url":null,"abstract":"<p>Insights into the time needed for evaluation of risk minimization measures' (RMMs) effectiveness might identify areas for improvement. We assessed the duration of time intervals between regulatory milestones for RMM effectiveness studies assessed by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA). We included completed RMM effectiveness post-authorization safety studies (PASSs) assessed by PRAC between 2016 and 2022. Regulatory documents submitted by marketing authorization holders and assessment reports were extracted from non-public EMA databases. To calculate the duration of time intervals, we collected the dates of study request, protocol assessment start, protocol approval, study start, final study report assessment start, and final study report PRAC outcome. We identified 98 PASSs. The median duration from study request to final study report PRAC outcome was 52 months (Q1–Q3: 40–70). The median duration from study request to study start was 21 months (Q1–Q3: 15–30; <i>n</i> = 95) and from study start to final study report assessment start was 21 months (Q1–Q3: 13–36; <i>n</i> = 95). The final study report assessment often comprised &lt;6 months (median: 4; Q1–Q3: 1–6). For PASSs with a PRAC-approved protocol (<i>n</i> = 80, 81.6%), the median duration of protocol assessment was 7 months (Q1–Q3: 4–10). Concluding, the median duration from study request to RMM effectiveness PASS completion exceeded 4 years. Next to the study conduct duration, the period from study request until study start was the most time-consuming. The duration of this period might be minimized by improved guidance on RMM effectiveness PASSs and encouraging timely protocol submission.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 4","pages":"1106-1114"},"PeriodicalIF":6.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035399","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":"Palbociclib Is Safe for Breast Cancer Patients With Mild Hepatic Impairment: A Multicenter Retrospective Study Using Real-World Data","authors":"Alieke K. Bos,&nbsp;Annelieke E.C.A.B. Willemsen,&nbsp;Loes E. Visser,&nbsp;Lennart J. Stoker,&nbsp;Jurjen S. Kingma,&nbsp;Mirjam K. Rommers,&nbsp;Emile M. Kuck,&nbsp;Paul D. van der Linden,&nbsp;Merel van Nuland","doi":"10.1002/cpt.3574","DOIUrl":"10.1002/cpt.3574","url":null,"abstract":"<p>The liver is crucial for metabolizing the anticancer drug palbociclib, but limited information is available on the impact of hepatic impairment on its toxicity and efficacy, with no real-world data available. This study aims to evaluate how hepatic impairment affects hematological toxicity and progression-free survival (PFS) of palbociclib in advanced hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, using the National Cancer Institute scoring system, in a large real-world dataset. This multicenter retrospective observational study included female patients treated with palbociclib between August 2017 and February 2024. Regression analysis was used to compare the risk of developing grade 3/4 hematological toxicity and PFS between patients with normal and mild impaired liver function. In total, 478 female patients were included. Patients with mild hepatic impairment (<i>n</i> = 205) did not have an increased risk of developing grade 3/4 neutropenia compared with patients with normal hepatic function (<i>n</i> = 273) (hazard ratio (HR) = 1.11; 95% CI 0.83–1.47). In addition, the PFS was not significantly different between both groups (HR = 1.15; 95% CI 0.93–1.42). In real-world settings, patients with mild hepatic impairment do not have a higher risk of developing palbociclib-induced neutropenia or disease progression than patients with normal hepatic function. These findings can guide clinicians when treating breast cancer patients with mild hepatic impairment.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 4","pages":"1115-1122"},"PeriodicalIF":6.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035474","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":"On the Concepts, Methods, and Use of “Probability of Success” for Drug Development Decision-Making: A Scoping Review","authors":"Aysun Cetinyurek Yavuz,&nbsp;Muhammad Bergas Nur Fayyad,&nbsp;Ce Jiang,&nbsp;Florie Brion Bouvier,&nbsp;Celine Beji,&nbsp;Sonia Zebachi,&nbsp;Ghinwa Y. Hayek,&nbsp;Billy Amzal,&nbsp;Raphael Porcher,&nbsp;Julien Tanniou,&nbsp;Kit Roes,&nbsp;Laura Rodwell","doi":"10.1002/cpt.3571","DOIUrl":"10.1002/cpt.3571","url":null,"abstract":"<p>Drug development is a lengthy process with considerable uncertainty at each milestone. Several trials are needed to progress to confirmatory evaluation and establish a positive benefit–risk balance. One of the critical milestones is the decision to progress to phase III based on phase II trial results. Use of probability of success is becoming standard in pharmaceutical companies to support this decision. However, the lack of consistency in terminology makes it difficult to assess the comparative value of different approaches. By leveraging the availability of high-quality external data (e.g., real-world data, historical clinical trial data, etc.), probability of success-based procedures may further improve decision-making. We performed a scoping review of approaches to calculate the probability of success of a phase III trial depending on the available data sources and the availability of specific endpoints. Calculation of probability of success is relatively straightforward if data for the primary endpoint of the phase III trial are also available in phase II trials. Often, phase II trials are based on biomarker or surrogate outcomes, due to challenges associated with study duration and required sample size. Probability of success-based procedures as reviewed can incorporate external data sources, for example, from clinical trials testing the same or similar drug or real-world data on the targeted population—optimizing the calculation of probability of trial success and the projected drug candidate value. We conclude the paper by reflecting on alternative approaches and ideas for uses within pharmaceutical companies and academia.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 4","pages":"967-977"},"PeriodicalIF":6.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035473","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}