Clinical Pharmacokinetics最新文献

{"title":"Evaluation of Safety and Pharmacokinetics of DDCI-01, a Phosphodiesterase Type 5 Inhibitor, in Healthy Participants.","authors":"Qian Li, Shen-Shen Huang, Dong-Chuan Zhang, Wei-Yi Zhang, Yi-Min Mao, Rui Chen, Zhi-Cheng Jing","doi":"10.1007/s40262-025-01491-7","DOIUrl":"https://doi.org/10.1007/s40262-025-01491-7","url":null,"abstract":"<p><strong>Aim: </strong>The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics of single escalating oral doses of DDCI-01 (a novel, highly selective, long-acting phosphodiesterase type 5 inhibitor) administered via capsules to healthy volunteers.</p><p><strong>Methods: </strong>This randomized, double-blind, placebo-controlled, single ascending dosing, Phase Ia clinical study involved 52 healthy volunteers who were randomized (3:1 ratio) to receive a single oral dose of DDCI-01 (1.25, 2.5, 5, 10, 20, 40, or 60 mg) or a placebo. Adverse events and pharmacokinetic parameters were evaluated after 14 days post-administration.</p><p><strong>Results: </strong>Within the studied dose range, DDCI-01 was safe and tolerable. Mild adverse events incidence was > 10% in all 39 volunteers receiving DDCI-01: myalgia (eight cases, 20.51%) and spontaneous penile erection (four cases, 10.26%). Drug exposure (C_max, AUC_0-t, and AUC_0-inf) increased with increasing dosage; however, no linear correlation was observed between drug exposure and dosage. The drug exposure increase was less than the expected dose-proportional increase. Terminal half-life of DDCI-01 ranged between 35.5 and 40.6 hours, whereas the values of apparent clearance (CL/F) and apparent volume (V_z/F) were in the range of 1.1-3.0 L/h and 59-175 L, respectively. Both CL/F and V_z/F increased with increasing doses of DDCI-01.</p><p><strong>Conclusions: </strong>DDCI-01 demonstrated favorable safety and pharmacokinetic profiles within the dose range. The findings of this first-in-human study support further research for the indications of DDCI-01, such as pulmonary arterial hypertension and erectile dysfunction.</p><p><strong>Registration: </strong>Chinese Center for Drug Evaluation (CDE) registry number CTR20201564. The date of registration: August 3, 2020.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566226","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":"Opportunities for Precision Dosing of Cytotoxic Drugs in Non-Small Cell Lung Cancer: Bridging the Gap in Precision Medicine.","authors":"M P Kicken, M J Deenen, A J van der Wekken, B E E M van den Borne, M M van den Heuvel, R Ter Heine","doi":"10.1007/s40262-025-01492-6","DOIUrl":"https://doi.org/10.1007/s40262-025-01492-6","url":null,"abstract":"<p><p>Precision dosing of classical cytotoxic drugs in oncology remains underdeveloped, especially in treating non-small cell lung cancer (NSCLC). Despite advancements in targeted therapy and immunotherapy, classical cytotoxic agents continue to play a critical role in NSCLC treatment. However, the current body surface area (BSA)-based dosing of these agents fails to adequately address interindividual variability in pharmacokinetics. By better considering patient characteristics, treatment outcomes can be improved, reducing risks of under-exposure and over-exposure. This narrative review explores opportunities for precision dosing for key cytotoxic agents used in NSCLC treatment: cisplatin, carboplatin, pemetrexed, docetaxel, (nab-)paclitaxel, gemcitabine, and vinorelbine. A comprehensive review of regulatory reports and an extensive literature search were conducted to evaluate current dosing practices, pharmacokinetics, pharmacodynamics, and exposure-response relationships. Our findings highlight promising developments in precision dosing, although the number of directly implementable strategies remains limited. The most compelling evidence supports using the biomarker cystatin C for more precise carboplatin dosing and adopting weekly dosing schedules for docetaxel, paclitaxel, and nab-paclitaxel. Additionally, we recommend direct implementation of therapeutic drug monitoring (TDM)-guided dosing for paclitaxel. This review stresses the urgent need to reassess conventional dosing paradigms for classical cytotoxic agents to better align with the principles of the precision dosing framework. Our recommendations show the potential of precision dosing to improve NSCLC treatment, addressing gaps in the current dosing of classical cytotoxic drugs. Given the large NSCLC patient population, optimising the dosing of these agents could significantly improve treatment outcomes and reduce toxicity for many patients.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566227","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":"Ticagrelor is Associated with Increased Rosuvastatin Blood Concentrations in Patients who have had a Myocardial Infarction.","authors":"Tjaša Dermota, Borut Jug, Jurij Trontelj, Mojca Božič Mijovski","doi":"10.1007/s40262-025-01489-1","DOIUrl":"https://doi.org/10.1007/s40262-025-01489-1","url":null,"abstract":"<p><strong>Aims: </strong>The primary objective of this study was to determine whether concomitant therapy with ticagrelor and rosuvastatin affects rosuvastatin plasma concentrations in patients receiving rosuvastatin 40 mg/day after myocardial infarction.</p><p><strong>Methods: </strong>We included 93 patients who had experienced a myocardial infarction and were receiving high-dose rosuvastatin 40 mg/day and a P2Y12 receptor antagonist, either ticagrelor, prasugrel or clopidogrel. We used liquid chromatography with tandem mass spectrometry to measure rosuvastatin plasma concentrations after liquid-liquid extraction.</p><p><strong>Results: </strong>Rosuvastatin plasma concentrations (9.7 ng/mL) were approximately twice as high in patients receiving ticagrelor therapy as in those receiving prasugrel (5.1 ng/mL, p < 0.001) or clopidogrel (5.0 ng/mL, p = 0.009), and ticagrelor was an independent factor influencing rosuvastatin concentrations. In addition, creatinine levels were associated with increased rosuvastatin concentrations (p = 0.039).</p><p><strong>Conclusion: </strong>Our results suggest an important pharmacokinetic interaction between ticagrelor and rosuvastatin, leading to approximately two-fold higher rosuvastatin plasma concentrations in those receiving concomitant ticagrelor than in those receiving prasugrel or clopidogrel. The association is significant and independent of other potential factors influencing rosuvastatin levels, indicating its potential clinical relevance.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540451","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":"Pharmacokinetics of Opioid Infusions in the Adult Intensive Care Unit Setting-A Systematic Review.","authors":"Johannie Beaucage-Charron, Justine Rinfret, Guillaume Trottier, Marie-Maxim Sévigny, Lisa Burry, Amélie Marsot, David Williamson","doi":"10.1007/s40262-025-01490-8","DOIUrl":"https://doi.org/10.1007/s40262-025-01490-8","url":null,"abstract":"<p><strong>Introduction: </strong>Pharmacokinetics (PKs) of drugs are often altered in the intensive care unit (ICU). Opioids are often used in the ICU, particularly as continuous infusions, and their characteristics lead them to undergo PK alterations. We conducted a systematic review to assess the PK of opioid infusions in the ICU.</p><p><strong>Methods: </strong>Embase, MEDLINE, PubMed, CINAHL, and Evidence-Based Medicine Reviews (EBMR) were searched from inception to March 2024. Studies were included if they evaluated PKs of opioid infusions in adult patients in the ICU. Two reviewers independently selected and extracted data.</p><p><strong>Results: </strong>Out of the 1040 records screened, 17 studies were included. Five studies were conducted on fentanyl, seven on morphine, one on hydromorphone, two on remifentanil, two on alfentanil, and one on sufentanil. Most studies where observational studies or case series. The mean age was 56 years old. Duration of the infusion varied between 3 h and 20 days. PKs of fentanyl, sufentanil, and hydromorphone were significantly impaired, whereas the PKs of morphine, alfentanil, and remifentanil were impaired to a lesser degree. The PK parameter that was most affected by critical illness was the half-life (T½).</p><p><strong>Conclusions: </strong>To counter these PK alterations, new therapeutic avenues must be further explored in the ICU to individualize opioid infusions.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536864","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 Pharmacokinetics of Cefepime in Critically Ill Children and Young Adults: Model Development and External Validation for Monte Carlo Simulations and Model-Informed Precision Dosing.","authors":"Ronaldo Morales Junior, H Rhodes Hambrick, Tomoyuki Mizuno, Kathryn E Pavia, Kelli M Paice, Peter Tang, Erin Schuler, Kelli A Krallman, Luana Johnson, Michaela Collins, Abigayle Gibson, Calise Curry, Jennifer Kaplan, Stuart Goldstein, Sonya Tang Girdwood","doi":"10.1007/s40262-025-01485-5","DOIUrl":"https://doi.org/10.1007/s40262-025-01485-5","url":null,"abstract":"<p><strong>Background and objective: </strong>This study aimed to develop a population pharmacokinetic model for cefepime in critically ill pediatric and young adult patients to inform dosing recommendations and to evaluate the model's predictive performance for model-informed precision dosing.</p><p><strong>Methods: </strong>Patients in the pediatric intensive care unit receiving cefepime were prospectively enrolled for clinical data collection and opportunistic plasma sampling for cefepime concentrations. Nonlinear mixed effects modeling was conducted using NONMEM. Allometric body weight scaling was included as a covariate with fixed exponents. Monte Carlo simulations determined optimal initial dosing regimens against susceptible pathogens. The model's predictions were evaluated with an external dataset.</p><p><strong>Results: </strong>Data from 510 samples across 100 patients were best fit with a two-compartment model with first-order elimination. Estimated glomerular filtration rate and cumulative percentage of fluid balance were identified as significant covariates on clearance and central volume of distribution, respectively. Internal validation showed no model misspecification. External validation confirmed that bias and precision for both population and individual predictions were within commonly accepted ranges. Monte Carlo simulations suggested that the usual dose of 50 mg/kg may require a 3-h infusion or a 6-h dosing interval to keep concentrations above the Pseudomonas aeruginosa minimum inhibitory concentration (≤ 8 mg/L) throughout the dosing interval for patients with normal or augmented renal clearance.</p><p><strong>Conclusion: </strong>A cefepime population pharmacokinetic model for critically ill pediatric patients was successfully developed, accounting for patient renal function, fluid status, and body size, using real-world data. The model was internally and externally validated for use in optimal dosing simulations and model-informed precision dosing.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482352","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":"Correction: Clinical Pharmacokinetics of Psilocin After Psilocybin Administration: A Systematic Review and Post‑Hoc Analysis.","authors":"Marije E Otto, Katelijne V van der Heijden, Jan W Schoones, Michiel J van Esdonk, Laura G J M Borghans, Gabriel E Jacobs, J G Coen van Hasselt","doi":"10.1007/s40262-025-01487-3","DOIUrl":"https://doi.org/10.1007/s40262-025-01487-3","url":null,"abstract":"","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467268","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 Pharmacokinetics of Efsubaglutide Alfa in Healthy Subjects and Subjects with Type 2 Diabetes.","authors":"Yan-Ru Lou, Yu-Long Xu, Yifeng Xiong, Chenhui Deng, Qinghua Wang","doi":"10.1007/s40262-025-01475-7","DOIUrl":"https://doi.org/10.1007/s40262-025-01475-7","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objectives: &lt;/strong&gt;Efsubaglutide alfa is a novel long-acting human glucagon-like peptide-1 receptor agonist. Clinical studies in patients with type 2 diabetes (T2D) have shown excellent glucose-lowering effects. This study aims to develop a population pharmacokinetic (popPK) model for efsubaglutide alfa to characterize its pharmacokinetic (PK) profile and assess the impact of intrinsic and extrinsic factors.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A popPK model was developed using a nonlinear mixed-effects model (NONMEM) based on 4173 plasma concentration measurements of efsubaglutide alfa from 911 participants, including 36 healthy subjects and 875 patients with T2D, across four clinical trials. These trials involved once-weekly subcutaneous injections of efsubaglutide alfa at doses ranging from 0.375 mg to 9.0 mg, with treatment durations spanning from 1 to 24 weeks. Diagnostic plots, visual predictive checks, nonparametric bootstrap methods, and simulations were employed to validate the model's robustness and performance. Covariates were identified using stepwise covariate modeling.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A two-compartment model with first-order absorption and first-order elimination adequately described the PK characteristics of efsubaglutide alfa. Efsubaglutide alfa exhibited favorable absorption (K&lt;sub&gt;a&lt;/sub&gt; = 0.0255 per hour) and a relatively large apparent volume of distribution (V&lt;sub&gt;2&lt;/sub&gt;/F of 14.5 L with relative standard error [RSE] of 3%; V&lt;sub&gt;3&lt;/sub&gt;/F of 3.01 L). It showed moderate clearance (CL/F of 0.0680 L/h, RSE of 1%, inter-individual variability of 16.6%) and an extended half-life. In subjects with T2D, the geometric mean half-life was estimated between 182 and 215 h across the 1-3 mg dose range, supporting once-weekly or once-every-two-week dosing. Efsubaglutide alfa exposure increased proportionally with dose and remained consistent across studies. Baseline body weight (WT), baseline estimated glomerular filtration rate (eGFR), neutralizing antidrug antibody (Nab), STUDY, and planned dose (ARM) were identified as significant covariates for CL/F, while baseline WT and STUDY influenced V&lt;sub&gt;2&lt;/sub&gt;/F. Although baseline WT and eGFR affected exposure parameters (AUC&lt;sub&gt;ss&lt;/sub&gt;, C&lt;sub&gt;max,ss&lt;/sub&gt;, and C&lt;sub&gt;min,ss&lt;/sub&gt;), these effects were not clinically significant, suggesting no need for dose adjustment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;The final popPK model, incorporating significant covariates (baseline WT, baseline eGFR, Nab, STUDY, and ARM), provided robust and precise PK parameter estimates, confirming its applicability in both healthy subjects and those with T2D. The minimal and clinically insignificant impact of baseline WT and eGFR on drug exposure supports the conclusion that no dose adjustment is necessary based on these factors. Moreover, the higher absorption rate constant suggests a rapid onset of action, and the extended half-life supports less frequent dosing, potential","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440071","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":"Plasma Concentrations of Direct Oral Anticoagulants in Patients with Nonvalvular Atrial Fibrillation and Different Degrees of Obesity.","authors":"Danilo Menichelli, Arianna Pannunzio, Erminia Baldacci, Vittoria Cammisotto, Valentina Castellani, Rosaria Mormile, Ilaria Maria Palumbo, Antonio Chistolini, Francesco Violi, Job Harenberg, Daniele Pastori, Pasquale Pignatelli","doi":"10.1007/s40262-025-01474-8","DOIUrl":"https://doi.org/10.1007/s40262-025-01474-8","url":null,"abstract":"<p><strong>Background: </strong>Atrial fibrillation (AF) has multiple cardio-metabolic comorbidities, including obesity. The use of direct oral anticoagulants (DOACs) in patients with AF and obesity is still uncertain owing to the concern of possible ineffective DOAC plasma concentration. We evaluated the peak and trough plasma concentrations of DOACs in AF patients with different degrees of obesity.</p><p><strong>Methods: </strong>Observational single-center study including patients with obesity and AF, between April 2022 and April 2024. Obesity was defined as body mass index (BMI) ≥ 30.0 kg/m². The 2-hour peak and trough DOAC plasma concentrations were assessed. Intake of DOAC was verified on site. Multivariable logistic regression analysis was used to assess the odds ratio (OR) and 95% confidence interval (95% CI) of factors associated with below-range trough concentration (BRTC) and below-range peak concentration (BRPC).</p><p><strong>Results: </strong>In total, 160 patients (33.8% women) with a mean age of 73.2 ± 9.1 years were included. The median BMI was 32.3 kg/m². DOACs prescribed were apixaban (46.8%), rivaroxaban (21.8%), dabigatran (16.4%), and edoxaban (15.0%); 18.1% and 14.4% had BRTC and BRPC concentrations, respectively. Patients with BRTC were more frequently treated with edoxaban and dabigatran and had a higher BMI. On multivariable logistic regression analysis, dabigatran [hazard ratio (HR) 3.039, 95% CI 1.155-7.999, p = 0.024) and BMI ≥ II class (OR 2.625, 95% CI 1.087-6.335, p = 0.032] were associated with BRTC. Dabigatran (OR 4.296, 95% CI 1.523-12.120, p = 0.006) and apixaban (OR 0.277, 95% CI 0.096-0.802, p = 0.018) were directly and inversely associated with BRPC, respectively.</p><p><strong>Conclusions: </strong>A nonnegligible proportion of patients with obesity and AF have below-range plasma concentrations of DOACs. Assessment of DOAC plasma concentration in obesity class ≥ II may be useful in these patients.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398555","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 Exploration and Physiologically Based Modelling of the Impact of Hepatic Impairment on Entrectinib Pharmacokinetics.","authors":"Agustos C Ozbey, Georgina Meneses-Lorente, Brian Simmons, Sam McCallum, Pieter Annaert, Neil Parrott, Kenichi Umehara","doi":"10.1007/s40262-024-01468-y","DOIUrl":"https://doi.org/10.1007/s40262-024-01468-y","url":null,"abstract":"<p><strong>Background and objectives: </strong>This study investigates the pharmacokinetics (PK) of entrectinib and its metabolite M5 (CYP3A4 substrates) in patients with hepatic impairment (HI) and applies physiologically based pharmacokinetic (PBPK) modelling to understand the observed changes mechanistically.</p><p><strong>Method: </strong>After a single oral administration of entrectinib at 100 mg, measured plasma concentrations for entrectinib and M5 in control subjects and HI patients were compared to predictions made with Simcyp^®. Model sensitivity analyses explored the possible reasons for mismatches to observed data. Reduced oral absorption due to lower bile salt (BS) levels in the intestinal lumen in hepatic impairment was examined.</p><p><strong>Results: </strong>Physiologically based pharmacokinetic model simulations overestimated the 80% increase in entrectinib area under the plasma concentration curve between 0h to infinity (AUC_inf) observed in patients with severe HI, predicting a > 2-fold rise. Observed maximal plasma concentration (C_max) increased by 25% from controls to mild HI but decreased by 61% from mild to severe HI. Although the model predicted C_max within a 2-fold range, there was a trend to greater over-prediction with increasing HI severity. For M5, PBPK modelling did not capture the observed trends well. The C_max and AUC_inf were overestimated in HI patients and the trend to reduction of C_max with minimal change in AUC_inf with increasing severity of HI was not well captured. Decreasing Simcyp^® default luminal BS concentrations by 2-, 6-, and 8.7-fold for mild, moderate, and severe HI improved the predictions for both entrectinib and M5.</p><p><strong>Conclusion: </strong>Physiologically based pharmacokinetic model simulations tended to overestimate the observed moderate changes in entrectinib exposures due to HI. For improved prediction of poorly soluble lipophilic drugs like entrectinib there is a need for PBPK models of HI to account for additional pathophysiological changes such as reduced intestinal BS levels.</p><p><strong>Trial registration: </strong>NCT number: NCT04226833.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398552","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 Hepatic Impairment or Renal Impairment on the Pharmacokinetics of Aficamten.","authors":"Donghong Xu, Justin D Lutz, Punag Divanji, Jianlin Li, Youcef Benattia, Adrienne Griffith, Stephen B Heitner, Stuart Kupfer, Polina German","doi":"10.1007/s40262-025-01481-9","DOIUrl":"https://doi.org/10.1007/s40262-025-01481-9","url":null,"abstract":"<p><strong>Background and objective: </strong>Aficamten, a small-molecule, selective cardiac myosin inhibitor, is under development for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Aficamten is primarily eliminated by hepatic metabolism with renal excretion playing a minor role. The objective of this investigation was to evaluate the pharmacokinetics (PK) of aficamten in moderate hepatic impairment or mild to moderate renal impairment to inform dosing recommendations in HCM patients with mild or moderate hepatic impairment or mild to moderate renal impairment.</p><p><strong>Methods: </strong>The impact of hepatic impairment on the PK of single-dose aficamten 20 mg was evaluated in a phase 1 single-dose, open-label, parallel-group study, in healthy participants with moderate (n = 8) hepatic impairment (Child-Pugh B classification) versus participants with normal hepatic function (n = 8). Safety was monitored throughout. The effect of renal impairment on aficamten PK was assessed using population PK (PopPK) modelling of phase 2/3 clinical data in patients with oHCM.</p><p><strong>Results: </strong>Aficamten PK was similar in participants with moderate hepatic impairment and those with normal hepatic function. No serious or severe treatment-emergent adverse events or clinically significant laboratory abnormalities were reported. There were no clinical meaningful differences in aficamten exposure in patients with oHCM with mild or moderate renal impairment and those with normal renal function.</p><p><strong>Conclusions: </strong>No clinically relevant changes in aficamten PK were observed in participants with moderate hepatic impairment. Population PK analysis indicated mild or moderate renal impairment and had no statistically or clinically significant impact on aficamten PK in patients with oHCM. Aficamten dose adjustment may not be necessary in patients with mild or moderate hepatic or renal impairment.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188156","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}