Clinical Pharmacokinetics最新文献

{"title":"SHR-1918, A Monoclonal Antibody Against Angiopoietin-Like 3, in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled Study.","authors":"Ruzhai Qin, Lika Ye, Lian Duan, Mingyan Li, Wenkai He, Xiao Mei, Deen Li, Rong Jin, Chao Lv, Min Zhu, Shihui Wang, Zhihong Xie","doi":"10.1007/s40262-025-01539-8","DOIUrl":"https://doi.org/10.1007/s40262-025-01539-8","url":null,"abstract":"<p><strong>Background and objective: </strong>Angiopoietin-like 3 (ANGPTL3) increases serum low-density lipoprotein cholesterol and triglyceride by reducing their clearance. SHR-1918 is a monoclonal antibody against ANGPTL3. This study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of SHR-1918 in healthy subjects.</p><p><strong>Methods: </strong>Six dose cohorts (100, 300, 450, 750, 900, and 1200 mg) were planned, each containing 12 healthy subjects randomized (9:3) to receive a single dose of subcutaneous SHR-1918 or placebo. Subjects were followed up to day 148 for the 100-mg cohort and day 190 for the other cohorts.</p><p><strong>Results: </strong>A total of 72 subjects were enrolled (SHR-1918, n = 54; placebo, n = 18). SHR-1918 was well tolerated at 100-1200 mg. Treatment-emergent adverse events were comparable between the SHR-1918 (90.7%) and placebo (94.4%) groups. All treatment-emergent adverse events were mild or moderate in severity, with no serious adverse events or treatment-emergent adverse events leading to death. Maximum serum concentration was reached 7.98-10.0 days after injection, and mean half-life was 29.4-53.5 days across the dose range. Serum low-density lipoprotein cholesterol and triglyceride markedly and rapidly decreased upon SHR-1918 administration, whereas those in the placebo group were above baseline at most follow-up visits. The largest median percentage decline in serum low-density lipoprotein cholesterol and triglyceride ranged from - 28.7 to - 49.1% and from - 46.6 to - 82.8%, respectively. For dose levels 300 mg or higher, the low-density lipoprotein cholesterol reduction remained over 30% for 64 days and triglyceride reduction remained over 50% for 85 days.</p><p><strong>Conclusions: </strong>SHR-1918 was well tolerated and showed promising efficacy in lipid reduction among healthy subjects.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov, NCT05432544 (24 June, 2022).</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505041","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":"Model-Informed Precision Dosing of Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria.","authors":"Mendy Ter Avest, Saskia M C Langemeijer, Lambertus P W J van den Heuvel, Laura M Baas, Nicole C A J van de Kar, Rob Ter Heine","doi":"10.1007/s40262-025-01536-x","DOIUrl":"https://doi.org/10.1007/s40262-025-01536-x","url":null,"abstract":"<p><strong>Background and objective: </strong>Eculizumab is an expensive therapeutic monoclonal antibody inhibiting complement C5 and approved for various indications, including the rare disease paroxysmal nocturnal hemoglobinuria. Eculizumab is administered in a \"one-dose-fits-all\" dosing paradigm in adults, which is inflexible and suboptimal in some patients. Therefore, the aim of this study was to develop alternative dosing regimens that may improve patient friendliness or improve cost effectiveness.</p><p><strong>Methods: </strong>A prospective observational pharmacokinetic study was conducted in 27 patients with paroxysmal nocturnal hemoglobinuria. The dataset was enriched with pharmacokinetic and pharmacodynamic data of a previous study of patients with atypical hemolytic uremic syndrome. A population pharmacokinetic/pharmacodynamic model was developed and this model was used to explore alternative and individualized dosing regimens.</p><p><strong>Results: </strong>A two-compartment model with parallel linear and non-linear elimination best described the data. No intra-individual variability in clearance could be observed for patients with paroxysmal nocturnal hemoglobinuria in contrast to patients with atypical hemolytic uremic syndrome. An inhibitory Emax model described the relationship between plasma concentrations and complement activity. We predicted that only 52.0% of patients with paroxysmal nocturnal hemoglobinuria have adequate complement inhibition on day 7 with the standard loading dose, compared with 99.9% of the patients with an alternative weight-based loading dose, without an increase in treatment costs. A 4-weekly dosing regimen was developed and therapeutic drug monitoring will enable interval prolongation to 4 weeks without relevant increases in cumulative drug use compared to the approved dose.</p><p><strong>Conclusions: </strong>The pharmacokinetics of eculizumab are similar in patients with atypical hemolytic uremic syndrome and patients with paroxysmal nocturnal hemoglobinuria, yet less variable in patients with paroxysmal nocturnal hemoglobinuria. Alternative dosing regimens can improve treatment in terms of efficacy and patient friendliness.</p><p><strong>Clinical trial registration: </strong>ClincialTrials.gov identifier: NCT04079257.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483410","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 Binimetinib in Participants with Hepatic Impairment.","authors":"Joseph Piscitelli, Erik Hahn, Lance Wollenberg, Renae Chavira, Laurence Del Frari, Micaela B Reddy","doi":"10.1007/s40262-025-01509-0","DOIUrl":"https://doi.org/10.1007/s40262-025-01509-0","url":null,"abstract":"<p><strong>Background and objective: </strong>Binimetinib is approved for multiple indications at a therapeutic dose of 45 mg twice a day (BID), in combination with encorafenib. A clinical hepatic impairment (HI) study was designed to evaluate the pharmacokinetics (PK), safety, and tolerability of a single oral dose of binimetinib in participants with mild, moderate, and severe HI compared with demographically matched healthy participants with respect to age, gender, and body weight.</p><p><strong>Methods: </strong>Participants were enrolled according to National Cancer Institute (NCI) classification criteria for hepatic function based on their total bilirubin and aspartate aminotransferase levels at screening. Participants enrolled into Group 1 (normal hepatic function) were matched to participants enrolled into Groups 2, 3, and 4 (mild, moderate, and severe HI, respectively) with respect to age, gender, and body weight. Dose-normalized PK parameters were evaluated because of a difference in doses for the severe HI group compared to the other groups, with the dose reduction due to the increased exposures observed in the moderate HI group.</p><p><strong>Results: </strong>Among 27 PK evaluable participants, changes in binimetinib dose-normalized PK parameters C_max/D and AUC_inf/D were minimal in participants with mild HI compared to the normal hepatic function group. Both the moderate and severe HI groups had significant changes as AUC_inf/D increased by 81% and 111%, respectively, compared to the normal hepatic function group. Unbound AUC_last/D for the moderate and severe HI groups increased by 280% and 248% compared to the normal hepatic function group, respectively.</p><p><strong>Conclusion: </strong>Based on these findings on total and unbound exposures, dose reductions are recommended for binimetinib in cancer patients with moderate and severe HI.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov NCT02050815, registered 29 January 2014.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474138","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 and Exposure-Response Analysis of Benralizumab in Chinese Adults, Adolescents, and Pediatric Participants with Severe Eosinophilic Asthma.","authors":"Yuwen Jin, Benjamin Guiastrennec, Miriam Stuke, Yuhui Yao, Yajuan Zhang, Peter Barker, Maria Jison, Robert C Penland, Junjie Ding, Pradeep B Lukka","doi":"10.1007/s40262-025-01538-9","DOIUrl":"https://doi.org/10.1007/s40262-025-01538-9","url":null,"abstract":"<p><strong>Introduction: </strong>Benralizumab is approved as add-on subcutaneous therapy in patients aged ≥ 12 years with severe eosinophilic asthma in > 80 countries, including mainland China.</p><p><strong>Objective: </strong>The study objective was to update benralizumab population pharmacokinetic (popPK) and exposure-response (ER) models in Chinese, Asian (including Chinese), and non-Asian participants.</p><p><strong>Methods: </strong>Benralizumab popPK/ER models for asthma exacerbation rate and pre-bronchodilator forced expiratory volume in 1 second (FEV₁) were updated for three benralizumab trials involving Chinese, Asian (including Chinese), and non-Asian participants. The ER analysis examined correlations between pharmacokinetic quartiles and annual asthma exacerbation rate (AAER) ratios with simulations comparing predicted clinical outcomes.</p><p><strong>Results: </strong>Updated data included 17,465 benralizumab concentrations (n = 2855). The updated model predicted a slight, and not clinically relevant, increase (< 14%) in benralizumab exposure for Chinese versus non-Asian adults. Median exposure increased in Chinese adolescents versus adults owing to body weight differences, but no dose adjustment was needed. Chinese children weighing < 35 kg receiving a 10 mg dose had similar exposure to those weighing ≥ 35 kg receiving a 30 mg dose. In Chinese versus non-Chinese participants, there was no trend concerning AAER ratios across different trough concentration quartiles; the maximal treatment effect significantly increased (+127%; p < 0.001), and there was no statistically significant effect on pre-bronchodilator FEV₁. Steady-state simulations showed lower predicted AAER ratios in Chinese (0.38; 95% confidence interval [CI] 0.32-0.45) than in non-Chinese adults (0.64; 95% CI 0.60-0.71), and no relevant differences between Chinese adults (0.46; 95% CI 0.38-0.54) and adolescents (0.46; 95% CI 0.37-0.55).</p><p><strong>Conclusion: </strong>The benralizumab popPK/ER models showed good predictive performance across Chinese demographics.</p><p><strong>Trial registration number: </strong>NCT03186209.</p><p><strong>Trial registration date: </strong>6 July 2017.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474139","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":"Determining the Optimal Dosing of Methyldopa in Pregnancy-Induced Hypertension Using PBPK-PD Modeling.","authors":"Xinyang Liu, Wei Wang, Jinying Zhu, Jingsi Chen, Xiaoyi Wang, Dunjin Chen, Defang Ouyang","doi":"10.1007/s40262-025-01523-2","DOIUrl":"https://doi.org/10.1007/s40262-025-01523-2","url":null,"abstract":"<p><strong>Background: </strong>Pregnancy-induced hypertension is a significant risk factor for adverse maternal and fetal outcomes, with methyldopa being a commonly prescribed antihypertensive for its safety profile. However, the physiological changes during pregnancy may alter the pharmacokinetics (PK) and pharmacodynamics (PD) of methyldopa, complicating the establishment of optimal dosing regimens.</p><p><strong>Objective: </strong>This study aims to develop and validate a pregnancy-specific physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model for methyldopa to optimize dosing strategies and support individualized treatment plans for managing pregnancy-induced hypertension effectively.</p><p><strong>Methods: </strong>The PBPK-PD model for methyldopa was developed using PK-Sim, MoBi, and MATLAB software, incorporating pregnancy-specific physiological parameters from the literature. The development process involved: (a) constructing and validating a PBPK model for non-pregnant individuals based on intravenous and oral administration, including renal clearance, serum clearance, and enzyme clearance; (b) extending the model to a pregnant PBPK model and validating it for oral administration; (c) constructing a PK/PD model using the maximum effect model; and (d) integrating the PBPK and PK/PD models to form a unified PBPK-PD model. This model was then used to simulate mean arterial pressure (MAP) responses across different stages of pregnancy. Finally, the optimal dosing regimen was calculated.</p><p><strong>Results: </strong>The model verification results show a good fit, indicating that the parameters are appropriate. The pregnancy model indicated no significant change in phenol sulfotransferase (PST) activity during pregnancy. The physiologically based pharmacokinetic-pharmacodynamic simulations across different stages of pregnancy show fluctuations in both PK and PD; however, these variations are not particularly significant. Ultimately, the results indicate that 500 mg is the optimal dosing regimen for patients with MAP ≤ 130 mmHg. For MAP > 130 mmHg, additional antihypertensive medications are recommended. Due to its delayed onset, methyldopa should be combined with other antihypertensives during the first 48 hours.</p><p><strong>Conclusion: </strong>The PBPK-PD model developed in this study provides a valuable tool for optimizing methyldopa therapy, supporting personalized treatment strategies, and improving blood pressure management and maternal and fetal health outcomes in pregnancy-induced hypertension.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293461","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 Amiodarone on Apixaban Exposure in Patients after Cardiac Surgery-A Population Pharmacokinetic Study.","authors":"Benedict Morath, Kathrin I Foerster, Ute Chiriac, Marcin Zaradzki, Torsten Hoppe-Tichy, David Schrey, Jürgen Burhenne, David Czock, Matthias Karck, Walter E Haefeli, Sebastian G Wicha","doi":"10.1007/s40262-025-01534-z","DOIUrl":"https://doi.org/10.1007/s40262-025-01534-z","url":null,"abstract":"<p><strong>Aim: </strong>To investigate the effect of amiodarone on apixaban pharmacokinetics in cardiac surgery patients with postoperative atrial fibrillation.</p><p><strong>Methods: </strong>Apixaban concentrations of postoperative cardiac surgery patients with or without amiodarone therapy were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in clinical routine. A population pharmacokinetic model was built using nonlinear mixed effects modeling in NONMEM^® 7.5 using first-order conditional estimation with interaction. The impact of amiodarone and creatinine clearance (CrCL) on apixaban exposure under various dosing regimens was analyzed using Simulx^® (Lixoft).</p><p><strong>Results: </strong>A total of 33 patients with 76 apixaban concentrations were included. A one-compartment model best described the pharmacokinetics of apixaban with a clearance (CL/F) of 3.05 L/h, apparent volume of distribution (V_d/F) of 23.7 L, and an absorption rate constant (k_a) of 0.652/h. Interindividual variability (IIV) was observed in CL/F but not in V_d/F and k_a. The covariates amiodarone and CrCL were independently associated with apixaban CL/F. Under concomitant amiodarone therapy, simulations predicted an increase of 44-49% in apixaban area under the concentration-time curve (AUC), and AUC nearly doubled at CrCL 35 mL/min. A dose of 2.5 mg apixaban twice daily (b.i.d.) was identified as a potential dosing option in the CrCL range of 15-50 mL/min under amiodarone comedication.</p><p><strong>Conclusions: </strong>Concomitant amiodarone therapy reduced apixaban CL/F and increased the risk of high exposure in patients with impaired renal function. A dose of 2.5 mg apixaban b.i.d. for a CrCL range of 30-50 mL/min under concomitant amiodarone therapy was identified as a new dosing option.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233385","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 Obesity on Pharmacokinetics of Lidocaine and its Active Metabolites in Chinese Patients Undergoing Laparoscopic Bariatric Surgery: A Prospective Clinical Study.","authors":"Mengyu Zhang, Ying Jin, Xueying Yuan, Chaoqun He, Mei Han, Faping Tu, Zhenlei Wang","doi":"10.1007/s40262-025-01510-7","DOIUrl":"https://doi.org/10.1007/s40262-025-01510-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Obesity can alter the physiological profile of individuals, potentially impacting the pharmacokinetics of anesthetic agents. This study compared the pharmacokinetic profiles of lidocaine and its metabolites between obese patients and normal-weight patients following a single intravenous bolus during surgical operation, to inform dosing strategies for the obese Chinese population.</p><p><strong>Methods: </strong>Twenty-nine obese patients scheduled for laparoscopic sleeve gastrectomy and 29 normal-weight patients for laparoscopic cholecystectomy were enrolled. Lidocaine (2%, 1.5 mg/kg) was administered intravenously to obese patients and normal-weight patients on the basis of adjusted body weight (ABW) and total body weight, respectively. Plasma samples were collected to analyze the pharmacokinetic profiles of lidocaine and its metabolites. Adverse events (AEs) were recorded throughout the study.</p><p><strong>Results: </strong>Obese patients had a significantly longer half-life for lidocaine (2.27 ± 0.69 h vs 0.94 ± 0.16 h, p < 0.0001), a higher volume of distribution (105 ± 27.3 L vs 54.9 ± 14.0 L, p < 0.0001), and a lower clearance (33.6 ± 9.08 L/h vs 40.5 ± 8.67 L/h, p = 0.008) compared to normal-weight patients. Although exposure to lidocaine was similar between groups within 2 hours, obese patients had lower metabolite concentrations due to decreased metabolic capacity. The plasma concentrations in all patients remained below the toxic concentration of 5 μg/mL, and no serious lidocaine-related AEs were reported.</p><p><strong>Conclusions: </strong>Obesity significantly affects the pharmacokinetics of lidocaine and its active metabolites, and administering lidocaine intravenously via ABW is safe and reasonable for obese patients.</p><p><strong>Clinical trial registration: </strong>ChiCTR2200064980, 25 October 2022.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215067","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":"A Population Pharmacokinetic Analysis for Piperacillin/Tazobactam in Patients with End-Stage Kidney Disease Undergoing Intermittent Haemodialysis: Extension of a General-Purpose Model.","authors":"D Kong, J V Koomen, F Vanommeslaeghe, S Delanghe, W Van Biesen, P J Colin, S Eloot","doi":"10.1007/s40262-025-01527-y","DOIUrl":"https://doi.org/10.1007/s40262-025-01527-y","url":null,"abstract":"<p><strong>Background and objective: </strong>End-stage kidney disease (ESKD) patients undergoing haemodialysis (HD) require a dosing regimen that balances the low endogenous clearance with the additional dialyser clearance. This study aimed to expand a previously proposed general-purpose pharmacokinetic model for piperacillin/tazobactam with a new population of ESKD patients undergoing intermittent high-flux haemodialysis.</p><p><strong>Methods: </strong>Inter- and intradialytic blood samples were collected in ESKD patients undergoing intermittent high-flux haemodialysis, in HD or haemodiafiltration (HDF) mode, who received piperacillin/tazobactam during routine care. The previous general-purpose model was expanded to reflect changes in the pharmacokinetics in the new patient population. A covariate search was performed focussing on factors that explained variability between patients in endogenous and dialysis clearance. Simulations were performed to determine the probability of target attainment with current dosing recommendations in this specific population.</p><p><strong>Results: </strong>In 20 ESKD patients, 195 piperacillin/tazobactam concentrations were determined. The general-purpose model was successfully expanded, wherein endogenous piperacillin/tazobactam clearance in patients with/without residual diuresis was 63% (95% confidence interval [CI] 49.5-73.0%) and 78.6% (95% CI 66.3-86.4%) lower compared with the general population, respectively. Extraction ratios of piperacillin and tazobactam ranged from 64 to 80%. Differences in probability of target attainment (PTA) for piperacillin were observed between patients with normal kidney function and ESKD patients undergoing haemodialysis with current dosing recommendations.</p><p><strong>Conclusion: </strong>We successfully expanded a general-purpose model to reflect the piperacillin/tazobactam pharmacokinetics in ESKD patients undergoing intermittent haemodialysis using high-flux dialysers. The current dosing recommendations provide inconsistent probability of target attainment in ESKD patients compared with the general population.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207847","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":"Maternal-Fetal Physiologically Based Population Pharmacokinetics Model Development of Lopinavir/Ritonavir in HIV/HBV Co-infected Pregnant Women to Quantitatively Describe the Gestational PK Characteristics and Predict the Potential Disease-Drug-Drug Interaction (DDDI).","authors":"Ling Song, Xuan Guo, Wei Yang, Jie Song, Dongyang Liu","doi":"10.1007/s40262-025-01493-5","DOIUrl":"10.1007/s40262-025-01493-5","url":null,"abstract":"<p><strong>Background and objective: </strong>Lopinavir/ritonavir (LPV/r) has been widely used in HIV/HBV co-infected pregnant-women. We aim to characterize the maternal-fetal (m-f) pharmacokinetic (PK) of LPV/r and support the dose optimization and potential drug-drug interaction (DDI) evaluation in this population.</p><p><strong>Methods: </strong>Lopinavir PK characteristics in human immunodeficiency virus/hepatitis B virus (HIV/HBV) co-infected pregnant women (n = 35) and fetus were calculated using non-compartmental analysis followed by quantification of maternal PK characteristics using population PK (PopPK) analysis. A maternal-fetal lopinavir physiologically based pharmacokinetic (PBPK) model was developed by incorporating trans-placental transfer, disease- and pregnancy-related physiological changes. This final population PBPK model was applied to simulate different dose regimens of LPV/r and potential DDI risks under different drug combination scenarios.</p><p><strong>Results: </strong>(AUC_last) of lopinavir in co-infected pregnancy was first reported to be 34.1 and 31.0 mg/L/h for the 2nd and 3rd trimesters. The PBPK-simulated PK parameters were within 0.75 to ~ 1.16-fold of the observations at different stages of pregnancy. The m-f PBPK model-simulated umbilical vein:maternal plasma (UV:MP) ratio of lopinavir was around 0.16 at late trimester, which is consistent with the PopPK model-simulated individual value of 0.116. Simulated results indicated that a standard dose of LPV/r (400/100 mg Q12 h) might not target the effective therapeutic concentration. Model-simulated DDI results suggested that lopinavir increased dose or shortened dosing interval when co-administered with rifampicin in HIV/HBV co-infected pregnancy.</p><p><strong>Conclusions: </strong>This work successfully applied model-informed approaches to quantitatively assess lopinavir m-f PK and also provided a novel strategy for DDI risk evaluation and dosing optimization for other P-gp substrates in HIV/HBV co-infected pregnant women.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"885-898"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957393","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 and Lung Deposition After Administration of Inhaled Mosliciguat (BAY 1237592): Results from Randomized Phase I Studies in Healthy Men.","authors":"Soundos Saleh, Tobias Mundry, Johannes Nagelschmitz, Ulf Buetehorn, Stephan Holzschuh, Sylvia M Nikkho","doi":"10.1007/s40262-025-01503-6","DOIUrl":"10.1007/s40262-025-01503-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Mosliciguat is the first soluble guanylate cyclase activator designed for dry powder inhalation. It is currently under development for the treatment of pulmonary hypertension; the inhaled route of administration delivers the drug to the pulmonary vasculature with the aim of improving pulmonary hemodynamics. We conducted three phase I trials in healthy male volunteers to characterize the pharmacokinetic profile of mosliciguat, focusing on lung deposition after inhalation with a low-resistance device in a lactose carrier-based dry powder formulation.</p><p><strong>Methods: </strong>Study 1 was a randomized, open-label, four-way crossover study (Part 2) comparing the pharmacokinetics of mosliciguat by inhalation (1000 μg), inhalation (1000 μg) with charcoal block, in oral solution (1000 μg), and intravenously (100 μg). (The oral and intravenous doses were selected in Part 1 of the study.) Study 2 was an 8-day, randomized, single-blind, placebo-controlled, multiple-dose escalation study of once-daily inhaled mosliciguat (480, 1000, and 2000 μg). Study 3 was a 2-week, multiple-dose, randomized, placebo-controlled, single-blind study of once-daily inhaled mosliciguat 1000 μg.</p><p><strong>Results: </strong>In Study 1 (Part 2) the absolute bioavailability of inhaled mosliciguat was 18.8% without charcoal block and 16.3% with charcoal block. The absolute bioavailability of oral mosliciguat was 23.1%. Pharmacokinetic parameters showed low-to-moderate inter-subject variability. Time to maximum plasma concentration (t_max) was 2.0 h after inhalation and 1.0 h after oral administration; half-life was 15.1 and 4.4 h, respectively. Based on accumulation ratios in Study 2, the area under the concentration-time curve (AUC) and maximum plasma concentration (C_max) increased by 45-51% and 15-21%, respectively, across doses at day 8. In Study 2 the half-life of inhaled mosliciguat with multiple dosing was 57.4 and 42.3 h at doses of 1000 and 2000 µg, respectively. Data showed moderate variability in AUC and C_max (geometric coefficients of variation, 26.6% and 24.7%, respectively, in study 3 on day 1). Trough levels showed accumulation ratios of 1.7-2.1 in Study 2 (day 8) and 2.5 in Study 3 (day 14). In all three studies, mosliciguat was well tolerated, without major systemic effects on heart rate or blood pressure.</p><p><strong>Conclusions: </strong>Inhaled mosliciguat had a longer t_max and half-life than oral mosliciguat. Accumulation data suggest formation of a mosliciguat depot in the lungs and continuous transfer to the systemic circulation, with an indication of an increase in accumulation ratio with longer duration of treatment.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"909-924"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12158843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119087","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}