Clinical Pharmacokinetics最新文献

{"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":"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":"1231-1243"},"PeriodicalIF":4.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263781/pdf/","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":"OA","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":"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":"1179-1190"},"PeriodicalIF":4.6,"publicationDate":"2025-08-01","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":"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":"1165-1178"},"PeriodicalIF":4.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263802/pdf/","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":"OA","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":"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":"1191-1201"},"PeriodicalIF":4.6,"publicationDate":"2025-08-01","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":"Population Pharmacokinetics Model of Thioguanine in Patients with Inflammatory Bowel Disease.","authors":"A B Bayoumy, N K H de Boer, R J Keizer, L J J Derijks","doi":"10.1007/s40262-025-01532-1","DOIUrl":"10.1007/s40262-025-01532-1","url":null,"abstract":"<p><strong>Background: </strong>Thioguanine (TG) has recently been rediscovered as an immunosuppressive agent in the treatment of inflammatory bowel disease (IBD). This prodrug is directly converted into its active metabolites, 6-thioguanine nucleotides (6-TGNs), targeting the inhibition of RAC1 GTPase in inflammatory conditions, disrupting key cellular signaling pathways necessary for T-cell activation and survival, thereby contributing to its immunosuppressive action. In IBD, TG is used fixed dose and may benefit from model-informed precision dosing (MIPD) to optimize treatment efficacy and minimize toxicity. However, a population pharmacokinetic (PopPK) model to do so is lacking.</p><p><strong>Objective: </strong>To develop a PopPK model for TG in IBD patients, enhancing the understanding of TG's pharmacokinetics and supporting the implementation of model-informed precision dosing (MIPD).</p><p><strong>Methods: </strong>We employed a dataset comprising 131 6-TGN trough concentrations from 28 IBD patients treated with TG. The data were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate pharmacokinetic parameters and explore the influence of covariates such as weight and 5-ASA use on drug disposition. Model fit-for-purpose was evaluated through computation of the model's forecasting performance.</p><p><strong>Results: </strong>The developed PopPK model was a one-compartment model with first-order absorption. A one-compartment TG model was stable, and able to estimate pharmacokinetic parameters with good precision (relative standard error [RSE] 15%) with weight and aminosalicylic acid (5-ASA) use significantly affected TG clearance. Forecasting performance was also adequate with a relative root mean squared error (rRMSE) of 24.1% and practically no systematic bias (mean percentage error [MPE] 0.2%).</p><p><strong>Conclusion: </strong>This study presents the first PopPK model of thioguanine for IBD, offering a novel tool for MIPD in clinical settings. Future studies should explore additional covariates such as TPMT genotype and drug interactions to further refine dosing recommendations for diverse patient populations.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1255-1262"},"PeriodicalIF":4.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526696","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":"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":"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":"1203-1216"},"PeriodicalIF":4.6,"publicationDate":"2025-08-01","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":"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":"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":"1245-1253"},"PeriodicalIF":4.6,"publicationDate":"2025-08-01","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":"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":"1139-1147"},"PeriodicalIF":4.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263743/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetic Analysis of an Octreotide Depot (CAM2029) in the Treatment of Acromegaly.","authors":"Anaïs Glatard, Sofia Friberg-Hietala, Lina Keutzer, Anna Hansson, Markus Johnsson, Fredrik Tiberg","doi":"10.1007/s40262-025-01522-3","DOIUrl":"10.1007/s40262-025-01522-3","url":null,"abstract":"<p><strong>Introduction: </strong>Octreotide is a first-generation somatostatin receptor ligand (SRL) approved for acromegaly treatment. CAM2029 is a sustained-release subcutaneous octreotide injection designed to improve treatment convenience for patients and bioavailability over alternative SRL treatments. The aim of this analysis was to characterise the pharmacokinetic (PK) properties of CAM2029.</p><p><strong>Methods: </strong>Using nonlinear mixed-effects modelling, 4098 observations from three trials, including 216 healthy participants and participants with acromegaly, were used to develop a population PK model of octreotide after administration of CAM2029 or immediate-release (IR) octreotide. Simulated octreotide plasma concentration profiles after administration of clinically justified dosing regimens of CAM2029 and octreotide IR were compared.</p><p><strong>Results: </strong>Octreotide disposition was best described by a two-compartmental distribution with a first-order elimination model. The rapid initial and slow subsequent drug release of CAM2029 was best characterised by two simultaneous first-order absorption processes, whereas octreotide IR absorption was described by a single first-order pathway. The model was qualified to describe octreotide concentrations and supported the robustness of dosing CAM2029 every 4 weeks (Q4W) ± 1 week. Simulations indicated that the average concentration during a dosing interval at steady state for 20 mg CAM2029 Q4W was similar to 0.25 mg octreotide IR every 8 h, but with reduced daily fluctuation.</p><p><strong>Conclusions: </strong>This population PK model supports the use of CAM2029 as a potential alternative treatment option to both octreotide IR and long-acting repeatable (LAR) for acromegaly treatment. The octreotide bioavailability for CAM2029 was similar to octreotide IR and approximately 5 to 6 fold higher than octreotide LAR, with a more rapid onset.</p><p><strong>Trial registrations: </strong>2020-002643-35 (EudraCT), NCT04076462 (date of registration: 3rd September 2019), NCT04125836 (date of registration: 14th October 2019).</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1079-1092"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12185581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141556","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":"Optimizing Nortriptyline Dosing: A Comparison between Pharmacogenetics-Based, Phenotype-Based, and Standard Dosing.","authors":"Cornelis F Vos, Marieke J H Coenen, Sophie E Ter Hark, Arnt F A Schellekens, Rob E Aarnoutse, Joost G E Janzing, Rob Ter Heine","doi":"10.1007/s40262-025-01528-x","DOIUrl":"10.1007/s40262-025-01528-x","url":null,"abstract":"<p><strong>Background and objective: </strong>Nortriptyline, a tricyclic antidepressant, has an important role in the pharmacotherapy of major depressive disorder (MDD). Individualized dosing approaches, such as pharmacogenetics-based and phenotype-based dosing, may enhance early achievement of therapeutic plasma concentrations, but their comparative accuracy has not been investigated. Our objective was to compare the accuracy of three nortriptyline dosing strategies: pharmacogenetics-based, phenotype-based, and standard dosing.</p><p><strong>Methods: </strong>Using pharmacokinetic modeling based on data from a randomized controlled trial, we assessed and compared the following dosing strategies: pharmacogenetics-based dosing depending on the cytochrome P-450 (CYP) 2D6 genotype, phenotype-based dosing determined by the plasma concentration measured after a single nortriptyline administration, and standard dosing (125 mg/day). A population pharmacokinetic model was developed to assess phenotype-based dosing recommendations. We evaluated the dosing strategies by comparing the number of participants with predicted therapeutic, subtherapeutic, and supratherapeutic plasma concentrations using Chi-squared (χ²) tests. Variability in plasma concentrations was assessed using F-tests.</p><p><strong>Results: </strong>Both pharmacogenetics-based (χ² (1) = 8.0, p = 0.01) and phenotype-based dosing (χ² (1) = 5.3, p = 0.02) significantly increased the likelihood of achieving therapeutic plasma concentrations compared with standard dosing while reducing plasma concentration variability. No significant difference was found in the prediction of therapeutic concentrations between the two individualized dosing strategies (χ² (1) = 0.33, p = 0.56).</p><p><strong>Conclusions: </strong>Pharmacogenetics-based and phenotype-based dosing demonstrate greater accuracy in predicting therapeutic nortriptyline plasma concentrations than standard dosing. Further research is warranted to explore the clinical application of model-informed precision dosing for nortriptyline and other psychotropic medications.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1071-1078"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12185566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141554","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}