The Journal of Clinical Pharmacology最新文献

{"title":"In Vitro and Clinical Evaluations of UGT1A1-, P-gp-, OATP1B1-, and BCRP-Mediated Drug–Drug Interactions of Belumosudil, a Potent ROCK2 Inhibitor","authors":"Olivier Schueller PhD,&nbsp;Lauren Lohmer PhD,&nbsp;Felix Beck MSc,&nbsp;Jeegar Patel PhD,&nbsp;Jasminder Sahi PhD","doi":"10.1002/jcph.70018","DOIUrl":"10.1002/jcph.70018","url":null,"abstract":"<p>Belumosudil is an oral selective rho-associated coiled-coil containing protein kinase 2 inhibitor, approved as a treatment for chronic graft-versus-host disease. Prior clinical studies demonstrated that coadministration with strong CYP3A4 inducers or proton pump inhibitors requires dose modification of belumosudil. In vitro assessments suggested that belumosudil may inhibit uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), P-glycoprotein (P-gp), organic anion transporting polypeptide 1B1 (OATP1B1), and breast cancer resistance protein (BCRP), resulting in drug–drug interactions (DDIs). This three-part clinical DDI study (NCT05806567) was conducted to assess the effect of multiple doses of belumosudil (200 mg daily) on the single-dose pharmacokinetics of raltegravir (UGT1A1-sensitive substrate), dabigatran etexilate (P-gp-sensitive substrate), and rosuvastatin calcium (OATP1B1/BCRP-sensitive substrate). Although there was no marked change in raltegravir exposure after coadministration with belumosudil, exposure to the glucuronide metabolite was decreased by 39.6% (area under the curve from time 0 to the time of last measurable concentration [AUC_0-last]) and 42.4% (maximum observed concentration [C_max]), suggesting that belumosudil is an in vivo inhibitor of UGT1A1. There was an approximate 2-fold increase in C_max, AUC_0-last, and AUC from time 0 extrapolated to infinity (AUC_0-inf) for dabigatran etexilate, suggesting a potential and clinically relevant DDI for belumosudil and sensitive P-gp substrates. C_max and AUC_0-last for rosuvastatin calcium increased by 3.6-fold and 4.6-fold, respectively, suggesting a clinically relevant interaction with drugs that are substrates of OATP1B1 or BCRP. There was no impact of coadministration with raltegravir, dabigatran etexilate, or rosuvastatin calcium on belumosudil pharmacokinetics, and belumosudil was well tolerated.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 8","pages":"1026-1038"},"PeriodicalIF":0.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721438","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":"Once- Versus Twice-Daily Tacrolimus Therapy: Does Improved Adherence Lead to Better Efficacy?—A Pharmacokinetic Perspective","authors":"Zi-yan Dai BSc,&nbsp;Lu Han BSc,&nbsp;Juan Wang BSc,&nbsp;Xiao-qin Liu PhD,&nbsp;Rui Chen PhD,&nbsp;Zheng Jiao PhD","doi":"10.1002/jcph.70021","DOIUrl":"10.1002/jcph.70021","url":null,"abstract":"<p>Tacrolimus, a critical immunosuppressant in organ transplantation, is available in immediate-release (IR-T) and extended-release (ER-T) formulations. While ER-T improves patient adherence, clinical studies have not demonstrated superior outcomes compared to IR-T. However, the underlying reasons for this discrepancy remain unclear. This study aimed to evaluate tacrolimus exposure under non-adherent dosing behaviors with IR-T and ER-T and to provide insights for selecting the optimal tacrolimus formulation. Monte Carlo simulations were conducted to assess the proportion of target attainment (%PTA) and deviation time (DT) from the therapeutic range in scenarios involving delayed or missed doses, based on published population pharmacokinetic models. The influence of renal function, the post-transplantation period, and hematocrit levels on %PTA and DT were also analyzed. Our findings revealed that patients on ER-T exhibited lower %PTA and longer DT than those on IR-T when doses were delayed or missed, reflecting poorer “forgiveness.” This observation elucidates the lack of clinical superiority observed for ER-T in previous studies. Furthermore, fast metabolizers experienced worse forgiveness with ER-T, exacerbating the challenge of maintaining therapeutic levels. Additionally, a web-based dashboard was developed to calculate the %PTA and DT for individual patients and to provide formulation recommendations tailored to their dosing behaviors and clinical characteristics. In conclusion, adherence and forgiveness play a crucial role in the success of pharmacotherapy. This study highlights the significance of pharmacokinetic modeling and simulation in providing evidence-based recommendations for selecting the optimal tacrolimus formulation.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 8","pages":"980-987"},"PeriodicalIF":0.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721740","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":"Efanesoctocog Alfa Population Pharmacokinetics and Repeated Time-To-Event Analysis of Bleeds in Adults, Adolescents, and Children with Severe Hemophilia A","authors":"Nancy Wong PhD,&nbsp;Pratik Bhagunde PhD,&nbsp;Joakim Nyberg PhD,&nbsp;Suresh Katragadda PhD,&nbsp;Marek Demissie MD, PhD,&nbsp;Annemieke Willemze MD,&nbsp;Craig Benson MD,&nbsp;Sreeraj Macha PhD","doi":"10.1002/jcph.70008","DOIUrl":"10.1002/jcph.70008","url":null,"abstract":"<p>Efanesoctocog alfa is a first-in-class high-sustained factor VIII (HSF) replacement therapy for treatment of hemophilia A. This article presents population pharmacokinetics (PopPK) of efanesoctocog alfa and repeated time-to-event (RTTE) analysis of bleeding episodes in adults/adolescents (≥12 years of age) and children (&lt;12 years). The final PopPK dataset contained pooled data from 277 patients (4405 post-dose factor VIII [FVIII] activity records) from two Phase 1/2a studies (NCT03205163; EudraCT 2018-001535-51), and three Phase 3 studies, XTEND-1 (NCT04161495), XTEND-Kids (NCT04759131), and XTEND-ed (NCT04644575). The PopPK model developed was a linear one-compartment model including body weight effect on clearance and volume of central compartment; Asian race was identified as a statistically significant covariate on clearance. The final PopPK model adequately described the FVIII activity–time profiles in adults, adolescents, and children with once-weekly (QW) efanesoctocog alfa 50 IU/kg, consistent with experience in XTEND-1 and XTEND-Kids. Bleeding episodes in participants in XTEND-1 and XTEND-Kids were characterized by an RTTE model with a Weibull base hazard and effect of FVIII activity modeled by a power effect. The RTTE model showed the probability of being bleed-free in 1 year with efanesoctocog alfa 50 IU/kg QW regimen was &gt;70% across all age groups, consistent with the observed clinical outcomes in the Phase 3 trials of highly effective protection from bleeding episodes in patients with severe hemophilia A, which validates the model's prediction of the long-term bleed hazard.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 7","pages":"860-872"},"PeriodicalIF":0.0,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694243","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":"Population Pharmacokinetics and Exposure-Response Analyses of Sarilumab in Patients with Polymyalgia Rheumatica","authors":"Christine Xu PhD,&nbsp;William S. Denney PhD,&nbsp;Ying Liu PhD,&nbsp;Jennifer Sloane MD,&nbsp;Remco Diab MD, MSc,&nbsp;Hisham Abdallah MPharm, PhD,&nbsp;Sreeraj Macha PhD,&nbsp;Bhaskar Dasgupta MBBS, MD, FRCP","doi":"10.1002/jcph.70019","DOIUrl":"10.1002/jcph.70019","url":null,"abstract":"<p>Sarilumab (interleukin-6 receptor inhibitor) is approved in the United States and Europe for polymyalgia rheumatica (PMR). This study characterized sarilumab pharmacokinetics (PK) and assessed the influence of intrinsic and extrinsic factors on PK in patients with PMR and giant cell arteritis (GCA). Exposure-responses analyses were conducted to evaluate the PK-pharmacodynamic (PD) relationships of sarilumab with key efficacy and safety endpoints in patients with PMR (NCT03600818). Population (Pop) PK analysis was conducted using pooled PK data from two phase III studies including 58 patients with PMR and 40 with GCA (NCT03600805). This Pop PK model was developed by re-estimating parameters from a previous rheumatoid arthritis (RA) model. The main source of intrinsic PK variability in patients with PMR was body weight, with decreasing weight causing increased sarilumab exposure. The population mean apparent clearance for patients with PMR was lower than for patients with RA due to higher albumin, lower creatinine clearance, and lower C-reactive protein (CRP) in PMR than in RA. Individual exposures at steady state overlapped among patients with PMR, GCA, and RA. PK-PD relationships showed that greater sarilumab C_trough in patients with PMR were associated with increasing total sIL-6Rα and decreasing CRP. There was a slight increase in patients achieving sustained remission at Week 52 and a decrease in absolute neutrophil count with increasing sarilumab C_trough plateauing at 20-25 mg/L. The PD effect of sarilumab plateaued at C_trough of 20-25 mg/L for target saturation, efficacy, and safety endpoints, supporting a dosage of 200 mg every 2 weeks for PMR.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 8","pages":"988-998"},"PeriodicalIF":0.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659372","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":"Cherishing Professional Success and Personal Fulfillment: Resilience as a Pivotal Leadership Competency for Clinical Pharmacologists and Beyond","authors":"Karthik Venkatakrishnan PhD, FCP,&nbsp;Jing ‘Daisy’ Zhu PharmD, PhD,&nbsp;Federica Ferrari MD, PhD,&nbsp;Krista Levy BS,&nbsp;Beth Kennedy MS, LMFT","doi":"10.1002/jcph.70017","DOIUrl":"10.1002/jcph.70017","url":null,"abstract":"<p>Resilience is a critical leadership competency directly linked to engagement, sustainable innovation, and productivity. This Commentary presents resilience concepts using the Benatti Resiliency Model^®, which comprises five inter-related dimensions: Well-being, Self-awareness, Brand, Connection, and Innovation. Trust is discussed as a critical leadership competency, with three levels: self-trust, trust in relationships at the team level, and community trust. The concept of Ikigai, representing the intersection of what one loves, what one is good at, what the world needs, and what one can be paid for, is discussed as a framework for self-awareness, brand development, development planning, and mentoring. Time and energy management using the Eisenhower matrix is highlighted as a strategy to build resilience, manage stress, enhance productivity, and prevent burnout. Taken together, the strategies discussed in this commentary are intended to unlock the transformative potential of resilience for sustainable innovation and impact within and beyond the dynamic and interdisciplinary field of clinical pharmacology, ultimately enabling professional success and personal fulfillment.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 8","pages":"1049-1055"},"PeriodicalIF":0.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70017","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659342","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":"Optimal Design of Drug–Drug Interaction Studies for the GLP-1 Receptor Agonist Drug Class for Weight Management: Closing a Potential Data Gap","authors":"Elijah Weber PhD,&nbsp;Ashit Trivedi PhD,&nbsp;April M. Barbour PhD","doi":"10.1002/jcph.70020","DOIUrl":"10.1002/jcph.70020","url":null,"abstract":"&lt;p&gt;The glucagon-like peptide-1 receptor agonist (GLP-1 RA) drug class, originally developed for glycemic control in patients with type 2 diabetes mellitus (T2DM), has recently expanded its indication to weight management. Many members of this class are peptides which do not have mechanism-based drug–drug interaction (DDI) liabilities per se. However, the potential for interactions arises due to their pharmacologic effect of delaying gastric emptying. This delay can impact the absorption of concurrently administered oral medications, necessitating evaluation of the DDI potential during the drug development process. The clinical relevance of a DDI varies by object and risk/benefit such that some objects may have more dire consequences of an interaction. Oral contraceptives, for example, could have clinically significant outcomes if efficacy were to be reduced as a result of gastric-emptying-mediated effects of the GLP-1 RA reducing systemic exposure.&lt;/p&gt;&lt;p&gt;Tirzepatide is a subcutaneously (SC) administered, once-weekly dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) RA with label restrictions regarding concomitant use with oral contraceptives. Specifically, women of reproductive potential are advised to switch to a non-oral method of contraception or add a barrier method for 4 weeks after initiating/escalating the dose of tirzepatide.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; This recommendation was likely based on the results of a combined oral contraceptive (COC) DDI study with ethinyl estradiol/norelgestromin, whereby AUC and Cmax of the progestin component decreased by 22% and 55%, respectively, following a single 5 mg dose of tirzepatide.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; According to the FDA clinical pharmacology application review, this interaction magnitude may significantly reduce the contraception effectiveness of the progestin component.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; The FDA also noted that the studied dose, a 5 mg single dose, is not the maximum therapeutic dose, and therefore the effect at the maximum dose is unknown. Recently the FDA released a guidance on the conduct of DDIs with oral contraceptives recommending that “The investigational drug should be given at the highest proposed dose for labeling and should be dosed for a sufficient duration to ensure maximal modulation effect of the drug on metabolizing pathways of COCs.”&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; For perspective, the maximum dose of tirzepatide for the indication of weight management is 15 mg QW.&lt;/p&gt;&lt;p&gt;It is notable that upon initiation or dose escalation, the COC label restriction is only for 4 weeks. We believe this limited restriction is supported from DDI data with another orally administered medication commonly used to characterize gastric-emptying effects, acetaminophen,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; showing that the apparent reduction in exposure observed after the first dose of tirzepatide is no longer evident after 4 weeks at the same dose. For example, when comparing Cmax and AUC of acetamino","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 8","pages":"1056-1058"},"PeriodicalIF":0.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659346","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":"Dose Ranging in Pediatric Drug Development Trials Submitted to the US FDA 2012–2020","authors":"Carlton K. K. Lee PharmD, MPH,&nbsp;Eugenia Kwon PharmD,&nbsp;Francis G. Green PharmD,&nbsp;Connor M. I. Kelley PharmD,&nbsp;Jennifer Pham PharmD, MPH,&nbsp;Gelareh Abulwerdi PhD,&nbsp;Sherbet Samuels PhD,&nbsp;Dionna J. Green MD,&nbsp;Gilbert J. Burckart PharmD, FCP","doi":"10.1002/jcph.70016","DOIUrl":"10.1002/jcph.70016","url":null,"abstract":"<p>Dose selection is a critical process within pediatric drug development and dose-ranging studies are integral to establish a reasonable dose. The objective of this analysis was to examine the dose-ranging trials utilized in pediatric drug development and to determine (1) the dose-ranging strategies that were used in all available pediatric dose-ranging studies, (2) the success of achieving pediatric labeling in those submissions to the US Food and Drug Administration, and (3) ethical aspects of providing a prospect of direct benefit to pediatric patients in dose-ranging studies. Of the 275 programs that previously surveyed pediatric drug development programs from 2012 to 2020, it was determined that dose-ranging studies were used for 97 (35.3%) programs. The three categorizations of these 97 programs included the parallel dose design (n = 66; 68%), the dose-escalation design (n = 18; 18.6%), and the crossover design (n = 13; 13.4%). In the 66 that used a parallel design, 41 of these products were approved for use in pediatric patients. In 13 out of the 41 drugs (31.7%) approved for pediatric use using parallel dose ranging, the lowest parallel dose (patient on the dose for the entire study) was lower than the approved dose. Dose ranging remains an important strategy for optimizing dosing, but ethical considerations and the need to optimize benefit for individual patients should drive decisions about dosing approaches in pediatric patients. The inclusion of adaptive designs is one possible approach to optimizing dose-ranging studies for pediatric patients.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 8","pages":"955-960"},"PeriodicalIF":0.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143598113","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 Fenofibrate in Participants with Mild Hepatic Impairment or with Advanced Fibrosis due to Metabolic-Associated Fatty Liver Disease","authors":"Islam R. Younis PhD, FCP,&nbsp;Elijah J. Weber PhD,&nbsp;Cara Nelson PhD,&nbsp;Ann R. Qin PhD,&nbsp;Timothy R. Watkins MD, MSc,&nbsp;Ahmed A. Othman PhD, FCP","doi":"10.1002/jcph.70005","DOIUrl":"10.1002/jcph.70005","url":null,"abstract":"<p>Fenofibrate is contraindicated in patients with advanced hepatic fibrosis due to limited clinical data. We evaluated the pharmacokinetics and safety of fenofibrate in participants with mild hepatic impairment (phase 1 study) or advanced fibrosis due to metabolic-associated fatty liver disease (MAFLD; phase 2a study). In the phase 1 study, participants with mild hepatic impairment and healthy matched controls (each n = 10) received a single, oral dose of fenofibrate 48 mg. In the phase 2a study, participants with hypertriglyceridemia and advanced fibrosis due to MAFLD were randomly assigned (1:1) fenofibrate 48 mg (n = 15) or fenofibrate 145 mg (n = 16) combined with firsocostat 20 mg, taken orally once daily for 24 weeks. Pharmacokinetics and safety were assessed in both studies. In the phase 1 study, the AUC_inf of fenofibric acid was 25% higher in participants with mild hepatic impairment than in healthy matched participants. In the phase 2a study, the AUC_ss,0-24 of fenofibric acid (fenofibrate 48 mg dose) in participants with F3 fibrosis and F4 cirrhosis was approximately 60% and 80%, respectively, higher than the AUC_inf in healthy participants in the phase 1 study, and was 20% higher in participants with F4 cirrhosis than in participants with F3 fibrosis. In both studies, most adverse events and laboratory abnormalities were grade 1-2. In the phase 2a study, three participants had grade 3 hypertriglyceridemia. Fenofibrate was well tolerated, and modest differences were observed in fenofibric acid exposure in participants with mild hepatic impairment or advanced fibrosis due to MAFLD.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 7","pages":"850-859"},"PeriodicalIF":0.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574419","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":"Contemporary Use of Oral Inotropes in the Outpatient Treatment of Heart Failure: Analysis of a Japanese Nationwide Database","authors":"Michikazu Nakai PhD,&nbsp;Yoshitaka Iwanaga MD, PhD,&nbsp;Koshiro Kanaoka MD, PhD,&nbsp;Yoko Sumita  ,&nbsp;Yuichi Nishioka MD, PhD,&nbsp;Tomoya Myojin MD, PhD,&nbsp;Katsuki Okada MD, PhD,&nbsp;Tatsuya Noda MD, PhD,&nbsp;Tomoaki Imamura MD, PhD,&nbsp;Yoshihiro Miyamoto MD, PhD","doi":"10.1002/jcph.70015","DOIUrl":"10.1002/jcph.70015","url":null,"abstract":"<p>Clinical evidence of oral inotrope use for advanced heart failure (HF) is limited. This study investigated the contemporary use and association of oral inotropes with prognosis in the outpatient treatment of advanced HF using a nationwide administrative claims database in Japan. Patients hospitalized with acute HF between 2014 and 2021 were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Associations of the drug use after discharge with the 2-year prognosis were examined in a propensity-matching cohort, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Of the 428,650 patients discharged with HF in 4433 hospitals, 14,374 (3.4%) had taken oral inotropes, most of whom (95.0%) took pimobendan. Patients taking oral inotropes were younger and more likely to receive HF drugs. Cardiomyopathy as the etiology and the use of intravenous inotropes during hospitalization were more frequently observed. In the 2-year prognosis, oral inotrope use was associated with higher all-cause mortality and HF rehospitalization rates (HR [95% CI]: 1.59 [1.51, 1.66] and 1.54 [1.48, 1.61], respectively). Concomitant use of pimobendan and β-blockers was associated with lower mortality and HF rehospitalization (0.81 [0.74, 0.88] and 0.85 [0.79, 0.92], respectively) compared with pimobendan without β-blockers. Although no association was found between oral inotrope use and favorable prognosis, concomitant use of β-blockers may be a better strategy for oral inotrope use in advanced HF.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 8","pages":"1039-1048"},"PeriodicalIF":0.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544166","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":"A Physiologically Based Pharmacokinetic Model of an Oral Tyrosine Kinase 2 Inhibitor Deucravacitinib in Healthy Adults","authors":"Xinyue Chen MS,&nbsp;Zhoumeng Lin PhD","doi":"10.1002/jcph.70014","DOIUrl":"10.1002/jcph.70014","url":null,"abstract":"<p>This study presents the first physiologically based pharmacokinetic (PBPK) model for deucravacitinib, a novel oral selective tyrosine kinase 2 (TYK2) inhibitor approved for treating moderate-to-severe plaque psoriasis. Using GastroPlus, we developed and validated a comprehensive PBPK model incorporating multiple elimination pathways and enterohepatic circulation. The model was calibrated using single-dose pharmacokinetic data (3-40 mg) from healthy adults and validated against external datasets from multiple clinical studies across different populations. Model predictions demonstrated strong agreement with observed data, with simulated/observed ratios for the area under the curve (AUC) and maximum plasma concentration (C_max) consistently falling within 0.5-2.0 across all dosing regimens. Linear regression analysis showed a robust correlation between simulated and observed plasma concentrations for both single (R² ≈ 0.78) and multiple (R² ≈ 0.77) dosing scenarios. While the model accurately predicted early-phase pharmacokinetics and exposure metrics, slight underestimation was observed during the terminal elimination phase. The successful validation across Western and Chinese populations demonstrates the capability of the model to account for population-specific physiological differences. This validated PBPK model provides a mechanistic framework for investigating deucravacitinib pharmacokinetics in various clinical scenarios and could support future investigations in special populations, particularly those with renal or hepatic impairment where significant exposure changes have been observed clinically.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 8","pages":"1011-1025"},"PeriodicalIF":0.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544160","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}