European Journal of Drug Metabolism and Pharmacokinetics最新文献

{"title":"Bioequivalence and Safety of Bilastine 20 mg Administered in Three Eight-Hourly Dose Versus a Single Daily Dose: A Randomized Two-Treatment, Two-Period, Cross-Over Comparative Study.","authors":"Ekta Sinha, Sagar Bhagat, Saiprasad Patil, Rahul Kodgule, Vinayak Modi, Hanmant Barkate","doi":"10.1007/s13318-025-00946-3","DOIUrl":"https://doi.org/10.1007/s13318-025-00946-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Antihistamines are an essential treatment option for cough and upper respiratory symptoms. Bilastine is a 2nd-generation antihistamine which is approved as a 20 mg once daily dose. The objective of the current study is to compare the oral bioavailability of bilastine administered thrice daily as a triple combination syrup of test product bilastine + dextromethorphan hydrobromide + phenylephrine hydrochloride (3.3 mg + 10 mg + 5 mg)/5 mL and a reference product of single-dose administration of 2.5 mg/mL (bilastine 2.5 mg) in healthy, adult, male human subjects under fed condition.</p><p><strong>Methods: </strong>This was an open-label, balanced, randomized, two-treatment, two-period, cross-over comparative bioavailability study. Patients were administered 10 mL of three 8-hourly doses of the triple combination test product and once daily dose of the reference product (syrup containing bilastine 2.5 mg). A 7-day washout period was implemented between doses. Blood samples were collected to assess the oral bioavailability of the test and reference products. Each subject received both treatments, serving as their own control, eliminating the need for a separate control group. Blood samples were collected pre-dose and at various intervals post-dose to determine plasma concentrations of bilastine using LC-MS/MS (Liquid Chromatography-Mass Spectrometry/Mass Spectrometry. Primary pharmacokinetic parameters were analyzed for bioequivalence using SAS version 9.4.</p><p><strong>Results: </strong>A total of 34 subjects out of 36 enrolled, successfully completed the study, and were analyzed. The geometric mean ratios of test versus reference product for the areas under the curve (AUC_0-t and AUC_0-∞ ) were 88.42% (84.15-92.91%) and 98.06% (93.63-102.69%), respectively, which are within the bioequivalence acceptance limits of 80.00-125.00%.</p><p><strong>Conclusion: </strong>Our study concluded that the test product, bilastine + dextromethorphan hydrobromide + phenylephrine hydrochloride syrup (3.3 mg + 10 mg + 5 mg)/5 mL, and the reference product, bilastine solution 2.5 mg/mL, are bioequivalent with respect to the extent of absorption and were well tolerated.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic Characterization of Cendakimab Administered with Different Devices and at Different Injection Sites in Healthy Participants.","authors":"Peijin Zhang, Claudia H M C De Oliveira, Kyungha Yu, Shenita Basdeo, Christina M Charriez, Mary Syto, Mark Thomas, Bindu Murthy","doi":"10.1007/s13318-025-00949-0","DOIUrl":"https://doi.org/10.1007/s13318-025-00949-0","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objective: &lt;/strong&gt;The cendakimab (CC-93538, previously RPC4046) phase 3 trial used prefilled syringes (PFS), while the intended commercial product is an autoinjector (AI). This study evaluated the pharmacokinetic (PK) comparability of cendakimab administration by PFS and AI, and at different injection sites.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This was a phase 1, single-center, randomized, open-label, single-dose, two-part parallel-group study (NCT05337345) in healthy adults. In part 1, participants were randomized 1:1 to receive cendakimab 360 mg subcutaneously in the abdomen by PFS (treatment A) or AI (treatment B). In part 2, participants were randomized to receive cendakimab 360 mg subcutaneously in either the upper arm (treatment C) or upper thigh area (treatment D) by AI. Analysis of covariance was used to compare the log-transformed area under the curve (AUC) and peak concentration (C&lt;sub&gt;max&lt;/sub&gt;) between PFS and AI devices. PK parameters based on cendakimab serum concentration were estimated using noncompartmental analysis and actual PK collection time. Immunogenicity was evaluated via measurement of antidrug antibody (ADA) titer over 105 (± 2) days after dosing; the impact of ADAs on the safety and PK of cendakimab was evaluated.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Overall, 64 and 40 healthy adults were dosed in parts 1 and 2, respectively. In part 1, the geometric least squares mean (LSM) ratios (90% CI) of treatment B versus A were contained within the generally accepted limit of 80-125%; 1.04 (0.90-1.20), 0.98 (0.87-1.12), and 0.99 (0.87-1.12) for C&lt;sub&gt;max&lt;/sub&gt;, AUC from time zero extrapolated to infinity (AUC&lt;sub&gt;∞&lt;/sub&gt;), and AUC from time zero to the time of the last quantifiable concentration (AUC&lt;sub&gt;t&lt;/sub&gt;), respectively. The geometric LSM ratios (90% CI) of treatment C versus B were 1.21 (1.05-1.39), 1.21 (1.07-1.38), and 1.22 (1.08-1.38) for C&lt;sub&gt;max&lt;/sub&gt;, AUC&lt;sub&gt;∞&lt;/sub&gt;, and AUC&lt;sub&gt;t&lt;/sub&gt;, respectively. The geometric LSM ratios (90% CI) of treatment D versus B were 1.23 (1.06-1.41), 1.26 (1.11-1.43), and 1.26 (1.11-1.42) for C&lt;sub&gt;max&lt;/sub&gt;, AUC&lt;sub&gt;∞&lt;/sub&gt;, and AUC&lt;sub&gt;t&lt;/sub&gt;, respectively. Lastly, the geometric LSM ratios (90% CI) of treatment C versus D for C&lt;sub&gt;max&lt;/sub&gt;, AUC&lt;sub&gt;∞&lt;/sub&gt;, and AUC&lt;sub&gt;t&lt;/sub&gt; were contained entirely within 80-125%. In part 1, 43.8% (n = 14) of participants receiving treatment A (PFS, abdomen) and 40.6% (n = 13) receiving treatment B (AI, abdomen) reported ≥ 1 adverse event (AE). In part 2, 35.0% (n = 7) of participants receiving either treatment C (AI, upper arm) or treatment D (AI, upper thigh) reported ≥ 1 AE. There were no serious/severe AEs and no discontinuations due to an AE.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;PK parameters of cendakimab were comparable when using PFS or AI. Cendakimab exposures when administered in the arm or thigh resulted in similar exposure; both were ~ 20% higher than when administering in the abdomen. Both PFS and AI were well t","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of Intraperitoneal Lidocaine for Sustained Postoperative Analgesia in Adults.","authors":"Kenyon W Osborne, Wiremu S MacFater, Brian J Anderson, Darren Svirskis, Andrew G Hill, Jacqueline A Hannam","doi":"10.1007/s13318-025-00948-1","DOIUrl":"https://doi.org/10.1007/s13318-025-00948-1","url":null,"abstract":"<p><strong>Background and objective: </strong>Intraperitoneal lidocaine is an emerging strategy for analgesia following abdominal surgery but its pharmacokinetics are poorly quantified. We aimed to develop a pharmacokinetic model for unbound and total lidocaine by intraperitoneal and intravenous routes.</p><p><strong>Methods: </strong>Unbound and total lidocaine concentrations, and pain scores (visual analogue score 0-10) were from a published randomized control trial of adults (n = 56) undergoing laparoscopic colon resection. Participants received intravenous or intraperitoneal lidocaine (2 mg/kg bolus then 1.5 mg/kg/h infusion) for 72 h postoperatively. Data were pooled with literature-derived alpha-1-acid glycoprotein concentrations (AAG) to support total lidocaine modelling. Unbound kinetics were described using compartmental models with first order absorption between intraperitoneal and plasma compartments. A turnover model described AAG kinetics with constant binding to lidocaine. An inhibitory pharmacodynamic model was explored to link concentration to pain scores.</p><p><strong>Results: </strong>Maximum lidocaine concentrations after intraperitoneal administration were means (range) of 3.0 (0.4-4.5) mg/L total and 0.6 (0.1-0.9) mg/L unbound. Intraperitoneal absorption was incomplete (bioavailability = 0.66, 95% confidence interval (CI) 0.6-0.76) with a half-time of 0.5 (0.4-0.8) h. A two-compartment model with first order elimination fit best, with unbound clearance 121 (108-136) L/h/70 kg. The binding constant to AAG (K_D) was 2.98 (2.69-3.35) µmol/L. A pharmacodynamic model with C₅₀ of 0.21 mg/L and maximal reduction (E_max) of 6 units captured pain scores and was used to simulate dosing strategies.</p><p><strong>Conclusions: </strong>A third of the intraperitoneal dose did not reach the central compartment and absorption took ~2 h. Simulations show that 2 mg/kg/h intraperitoneal infusion achieves a 5-point pain score reduction within ~36 min.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Pharmacokinetics and Pharmacodynamics of Vadadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor.","authors":"Slobodan M Janković, Snežana V Janković","doi":"10.1007/s13318-025-00947-2","DOIUrl":"https://doi.org/10.1007/s13318-025-00947-2","url":null,"abstract":"<p><p>Vadadustat is an innovative drug that inhibits prolyl hydroxylase and has been approved for the treatment of anemia in patients with chronic kidney disease. Its pharmacokinetics are linear, i.e., vadadustat's absorption, distribution, and elimination are predictable. Vadadustat is well absorbed from the gastrointestinal tract, with over 99% of the drug bound to plasma proteins. The majority of the drug is conjugated with glucuronic acid in the liver, and these conjugates are primarily excreted through urine, with a smaller portion eliminated through stool. Only 1% of the unchanged drug is found in the urine, while 9% appears in the stool. In clinical trials, vadadustat demonstrated clear effectiveness compared with placebo, significantly increasing hemoglobin levels in patients with anemia due to chronic kidney disease, with an average increase of 1.43 ± 0.05 g/dL after 6 months of treatment. However, its effectiveness is somewhat lower than that of erythropoietin. The rates and severity of adverse events with vadadustat and erythropoietin are similar. Given that vadadustat is taken orally and has a beneficial efficacy and safety profile, it represents a meaningful addition to the standard treatment for anemia associated with renal failure, working alongside erythropoietin.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Physiologically-Based Pharmacokinetic Model for Quantitative Interpretation of Transdermal Drug Delivery of Rotigotine, a Dopamine Agonist for Treating Parkinson's Disease.","authors":"Ji-Hun Jang, Seung-Hyun Jeong","doi":"10.1007/s13318-025-00938-3","DOIUrl":"10.1007/s13318-025-00938-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Rotigotine, a dopamine agonist, is used to treat Parkinson's disease and restless leg syndrome, with transdermal patches being the primary delivery method in clinical practice. However, quantitative information on the in vivo pharmacokinetics of rotigotine across various dosage regimens via transdermal administration remains limited, and this has been identified as a significant barrier to achieving precision medicine. This study aims to develop a novel physiologically-based systematic pharmacokinetic model tailored to rotigotine transdermal drug delivery. Based on the model, we quantitatively predicted rotigotine distribution patterns in target tissues to assess its in vivo efficacy and safety and to interpret the pharmacokinetic variability in transdermal patches according to covariate reflection.</p><p><strong>Methods: </strong>The data used to develop the quantitative model included clinical outcomes from single (2-8 mg/24 h) and multiple doses (0.5-8 mg/24 h) of rotigotine transdermal patches administered to healthy adults and patients with idiopathic Parkinson's disease or restless legs syndrome. The model was designed to represent whole-body physiological systems, incorporate liver and kidney clearance mechanisms, and account for the specific physicochemical properties influencing drug permeation and distribution across various tissues.</p><p><strong>Results: </strong>The model developed in this study effectively quantified the pharmacokinetic profiles of transdermal rotigotine within an acceptable variability. After transdermal application, rotigotine delivery to the target tissue, the brain, occurred rapidly, and the tissue concentrations at steady-state were approximately 10-fold higher than those in plasma. Incorporating weight as a covariate showed that in underweight individuals, tissue exposure to rotigotine increased by 1.61-fold, with a mean half-life extension of 1.50-fold compared to that of the normal weight population.</p><p><strong>Conclusion: </strong>The quantitative model proposed in this study serves as a foundational tool for advancing precision medicine, reliably characterizing the in vivo pharmacokinetics of rotigotine transdermal delivery across various doses and regimens.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"187-204"},"PeriodicalIF":1.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of Machine Learning Algorithms and Bayesian Estimation in Predicting Tacrolimus Concentration in Tunisian Kidney Transplant Patients During the Early Post-Transplant Period.","authors":"Nadia Ben-Fredj, Issam Dridi, Ichrak Dridi, Noureddine Ben-Yahya, Karim Aouam","doi":"10.1007/s13318-025-00942-7","DOIUrl":"10.1007/s13318-025-00942-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Model-informed precision dosing (MIPD), based on a Bayesian approach and machine learning (ML) algorithms, is a suitable approach to personalize dosage recommendations and to improve the concentration target attainment for each patient. The objective of this study is to compare the predictive performance of two ML approaches, XGBoost and LSTM, with a previously developed Bayesian model of tacrolimus (Tac) in a cohort of Tunisian kidney transplant patients during the early post-transplant period (0-3 months) METHOD: This was a cross-sectional study conducted at the Pharmacology department in Fattouma Bourguiba's hospital in Monastir, Tunisia. We included patients who had undergone kidney transplantation in the Nephrology department of Monastir Hospital and received the Tac immunosuppressant protocol, for whom routine therapeutic drug monitoring (TDM) during the early post-transplant period (0-3 months) had been performed in our department.</p><p><strong>Results: </strong>A total of 187 Tac predose concentration (C₀) issued from 56 adult renal transplant patients were included in the present study. The whole population was divided into building (n = 39 patients, 119 C₀) and validation groups (n = 17 patients, 68 C₀). In the validation dataset, the RMSE was 0.76, 0.19, and 0.01, and the MAE was 0.55, 0.36, and 0.06, respectively, for the Bayesian approach, XGBoost, and LSTM.</p><p><strong>Conclusion: </strong>Our study demonstrates that the LSTM approach outperforms XGBoost and Bayesian estimation in predicting tacrolimus concentration in Tunisian kidney transplant patients. Implementing TDM-based LSTM models during the first PT 3 months in clinical practice can significantly enhance patient outcomes and prevent acute kidney rejection in this population.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"243-250"},"PeriodicalIF":1.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Minimal Physiologically-Based Pharmacokinetic Modeling of Atenolol and Metoprolol Absorption in Malnourished Rats.","authors":"Fatma Kir, Selma Sahin, William J Jusko","doi":"10.1007/s13318-025-00943-6","DOIUrl":"10.1007/s13318-025-00943-6","url":null,"abstract":"<p><strong>Background and objective: </strong>The pharmacokinetics of drugs can be altered by pathophysiological changes in the body that result from malnutrition. The objective of this study was to evaluate the profiles derived from in vivo studies conducted on non-malnourished (control) and malnourished rats using minimal physiologically based pharmacokinetic (mPBPK) models.</p><p><strong>Methods: </strong>Single oral doses of atenolol (ATN) and metoprolol (MET) were administered to non-malnourished and malnourished rats. We demonstrate how plasma profiles can be evaluated using mPBPK models with high and low tissue-to-plasma partition coefficients (K_p) and elimination by either kidney or liver. A decrease in blood flow and cardiac output due to beta-blocker administration was assumed. Reference IV profiles from the literature were included to inform the mPBPK model and to help assess the absorption phases of individual oral profiles. Absorption was captured as two or three sequential zero-order processes for both drugs, and IV and oral profiles were assessed by joint fitting. Modeling was performed using both naïve pooling (ADAPT) and population (Monolix) analyses.</p><p><strong>Results: </strong>The experimental data show increased AUC values of MET and ATN in malnourished rats. Accordingly, an increased bioavailability (from 0.43 to 0.67) for ATN and an increased bioavailability (from 0.42 to 0.84) for MET in the malnourished group were related to higher absorption rates in both absorption phases.</p><p><strong>Conclusions: </strong>This study demonstrated advantageous use of mPBPK modeling with malnutrition primarily altering drug absorption in this animal model. Also, our analysis offers a blend of known and assumed components assembled mechanistically to suggest a reasonable interpretation of the PK profiles.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"251-263"},"PeriodicalIF":1.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Vitro and In Vivo Pharmacokinetic Characterization of 7-Hydroxymitragynine, an Active Metabolite of Mitragynine, in Sprague-Dawley Rats.","authors":"Yi-Hua Chiang, Siva Rama Raju Kanumuri, Michelle A Kuntz, Alexandria S Senetra, Erin C Berthold, Shyam H Kamble, Sushobhan Mukhopadhyay, Aidan J Hampson, Christopher R McCurdy, Abhisheak Sharma","doi":"10.1007/s13318-025-00939-2","DOIUrl":"10.1007/s13318-025-00939-2","url":null,"abstract":"<p><strong>Background and objectives: </strong>Kratom, a Southeast Asian tree, has been researched for its potential as a therapeutic for substance use disorders. The most abundant alkaloid in kratom, mitragynine, is being investigated individually for opioid use disorder. However, the active metabolite of mitragynine,7-hydroxymitragynine (7-HMG) has raised concerns because of its high binding affinity to μ-opioid receptors and abuse potential. This study examines various pharmacokinetic parameters of 7-HMG in both in vitro and in vivo models.</p><p><strong>Methods: </strong>In vitro pharmacokinetic properties were investigated using human colorectal adenocarcinoma cell monolayers (Caco-2 cells), rat plasma, rat liver microsomes, and rat hepatocytes to determine the permeability, plasma protein binding, and microsomal and hepatocyte stability of 7-HMG, respectively. Oral and intravenous (IV) pharmacokinetic studies of 7-HMG were performed in male Sprague-Dawley rats.</p><p><strong>Results: </strong>7-HMG exhibits high permeability across Caco-2 cells (19.7 ± 1.0 × 10^-6 cm/s), with a relatively low plasma protein binding of 73.1 ± 0.6% to mitragynine. The hepatic extraction ratio was 0.3 and 0.6 in rat liver microsomes and hepatocytes, respectively, indicating that 7-HMG is an intermediate hepatic extraction compound. Oral and IV pharmacokinetic studies were performed in male rats. The volume of distribution was 2.7 ± 0.4 l/kg and the clearance was 4.0 ± 0.3 l/h/kg after IV administration. After oral dosing (5 mg/kg), a C_max of 28.5 ± 5.0 ng/ml and T_max of 0.3 ± 0.1 h were observed. However, the oral bioavailability of 7-HMG was only 2.7 ± 0.3%. The results demonstrate 7-HMG is rapidly absorbed but has low oral bioavailability. Mitragynine pseudoindoxyl (MGPI) is a metabolite of 7-HMG that is a more potent µ-opioid agonist than 7-HMG. The parent-to-metabolite ratio for MGPI following IV 7-HMG administration was 0.5 ± 0.1%, indicating very limited systemic exposure to MGPI.</p><p><strong>Conclusions: </strong>This study reports the pharmacokinetic parameters of 7-HMG to help with the development of mitragynine, as a therapeutic.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"205-218"},"PeriodicalIF":1.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic/Pharmacodynamic Modeling of the Acute Heart Rate Effects of Delta-9 Tetrahydrocannabinol and Its Major Metabolites After Intravenous Injection in Healthy Volunteers.","authors":"W R Wolowich, R Greif, L Theiler, Maren Kleine-Brueggeney","doi":"10.1007/s13318-025-00941-8","DOIUrl":"10.1007/s13318-025-00941-8","url":null,"abstract":"<p><strong>Background and objectives: </strong>Cannabis consumption is increasing in both the recreational and medical settings. Tetrahydrocannabinol (THC) is known to produce cardiovascular effects, but the specific roles of THC and its metabolites THC-OH and THC-COOH in cannabinoid-induced cardiovascular effects remain unclear. We hypothesized that THC and THC-OH mediate a cannabinoid-induced increase in heart rate in either an additive or synergistic fashion.</p><p><strong>Methods: </strong>The present study uses prospectively obtained data to evaluate the effect of THC and its metabolites on heart rate in healthy volunteers through non-linear mixed-effect pharmacokinetic/pharmacodynamic (PK/PD) modeling.</p><p><strong>Results: </strong>The PK/PD models reveal that THC, THC-OH and a combination of THC and THC-OH, but not THC-COOH, are responsible for THC-induced tachycardia. The EC50 of the THC Emax model was 0.53 µM, 25-fold the EC50 for the THC-OH Emax model. The General Empiric Dynamic Model indicates that THC and THC-OH act synergistically to increase heart rate. Neither sex nor CYP2C9 polymorphism contributes to THC-induced tachycardia.</p><p><strong>Conclusion: </strong>THC-OH but not THC-COOH contributes to the heart rate effect of THC and THC-OH may be acting in a synergistic manner with THC. This contributes to understanding the cardiovascular effects of THC and cannabis-induced cardiovascular events. Future research including further hemodynamic data will allow a detailed systems pharmacology or response surface model approach.</p><p><strong>Trial registration: </strong>www.isrctn.com ; registration number ISRCTN53019164.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"229-242"},"PeriodicalIF":1.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase I Study to Evaluate the Relative Bioavailability, Pharmacodynamics, and Safety of a Single Subcutaneous Injection of Recaticimab at Three Different Sites in Healthy Chinese Subjects.","authors":"Ying Wang, Yuanzhi Cheng, Yuhan Guo, Yang Fan, Renpeng Zhou, Qian Zhang, Ye Xu, Sheng Feng, Kai Shen, Wei Hu","doi":"10.1007/s13318-025-00944-5","DOIUrl":"10.1007/s13318-025-00944-5","url":null,"abstract":"<p><strong>Background and objectives: </strong>Recaticimab (SHR-1209) is a humanized monoclonal antibody that binds to the proprotein convertase subtilisin/kexin type 9 (PCSK9) with high affinity. This study was conducted to compare the relative bioavailability, pharmacokinetics (PK), pharmacodynamics (PD), and safety of recaticimab following subcutaneous injection at three different sites in healthy Chinese subjects.</p><p><strong>Methods: </strong>In this randomized, parallel, open-label, phase I study, 159 healthy Chinese subjects were randomized to receive a single dose of 450 mg recaticimab subcutaneously into the abdomen, upper-arm, or thigh and were followed up until 113 days postdose. Adverse events were monitored, and serum samples were collected for PK, PD, and immunogenicity evaluation during the study.</p><p><strong>Results: </strong>The PK profiles of recaticimab were similar among different injection site groups. The geometric mean ratios of maximum serum concentration (C_max), area under the serum concentration versus time curve (AUC) from time zero to the time of last quantifiable concentration (AUC_0-last), and AUC from time zero extrapolated to infinity (AUC_0-inf) between groups were all close to 1, with two-sided 90% confidence intervals within 0.8-1.25. Recaticimab showed similar effects on low-density lipoprotein cholesterol levels in all groups, with mean maximum percentage decreases ranging from 56.88% to 59.04%. The percentage changes from baseline in free PCSK9 and other lipid variables were similar across the three groups as well. Treatment-emergent adverse events were reported in 41/53 (77.4%, abdomen), 29/53 (54.7%, upper-arm), and 42/53 (79.2%, thigh) subjects, most of which were mild and resolved without treatment. The incidence of antidrug antibodies among the three groups was comparable.</p><p><strong>Conclusions: </strong>A single subcutaneous injection of 450 mg recaticimab into the abdomen, upper-arm, or thigh was well-tolerated and presented similar PK and PD profiles, which supported the interchangeable use of the three injection sites for patients.</p><p><strong>Clinical trial identifier: </strong>( www.</p><p><strong>Clinicaltrials: </strong>gov ) NCT05370950 2022-05-07.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"265-272"},"PeriodicalIF":1.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}