European Journal of Drug Metabolism and Pharmacokinetics最新文献

{"title":"Prediction of the First-Pass Metabolism of a Drug After Oral Intake Based on Structural Parameters and Physicochemical Properties.","authors":"Mir Amir Hossein Hosseini, Ali Akbar Alizadeh, Ali Shayanfar","doi":"10.1007/s13318-024-00892-6","DOIUrl":"10.1007/s13318-024-00892-6","url":null,"abstract":"<p><strong>Background and objective: </strong>The oral first-pass metabolism is a crucial factor that plays a key role in a drug's pharmacokinetic profile. Prediction of the oral first-pass metabolism based on chemical structural parameters can be useful in the drug-design process. Developing an orally administered drug with an acceptable pharmacokinetic profile is necessary to reduce the cost and time associated with evaluating the extent of the first-pass metabolism of a candidate compound in preclinical studies. The aim of this study is to estimate the first-pass metabolism of an orally administered drug.</p><p><strong>Methods: </strong>A set of compounds with reported first-pass metabolism data were collected. Moreover, human intestinal absorption percentage and oral bioavailability data were extracted from the literature to propose a classification system that split the drugs up based on their first-pass metabolism extents. Various structural parameters were calculated for each compound. The relations of the structural and physicochemical values of each compound to the class the compound belongs to were obtained using logistic regression.</p><p><strong>Results: </strong>Initial analysis showed that compounds with logD_7.4 > 1 or a rugosity factor of > 1.5 are more likely to have high first-pass metabolism. Four different models that can predict the oral first-pass metabolism with acceptable error were introduced. The overall accuracies of the models were in the range of 72% (for models with simple descriptors) to 78% (for models with complex descriptors). Although the models with simple descriptors have lower accuracies compared to complex models, they are more interpretable and easier for researchers to utilize.</p><p><strong>Conclusion: </strong>A novel classification of drugs based on the extent of the oral first-pass metabolism was introduced, and mechanistic models were developed to assign candidate compounds to the appropriate proposed classes.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"449-465"},"PeriodicalIF":1.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140908765","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":"Model-Based Bioequivalence Analysis to Assess and Predict the Relative Bioavailability of Valproic Acid Formulations.","authors":"Alejandra Schiavo, Pietro Fagiolino, Marta Vázquez, Iñaki Tróconiz, Manuel Ibarra","doi":"10.1007/s13318-024-00901-8","DOIUrl":"10.1007/s13318-024-00901-8","url":null,"abstract":"<p><strong>Background and objective: </strong>Model-based bioequivalence (MBBE) encompasses the use of nonlinear mixed effect models supporting the estimation of pharmacokinetic endpoints to assess the relative bioavailability between multi-source drug products. This application emerges as a valuable alternative to the standard non-compartmental analysis (NCA) in bioequivalence (BE) studies in which dense sampling is not possible. In this work, we aimed to assess the application of MBBE compared to traditional methods in evaluating the relative bioavailability of two formulations with different drug release properties. Additionally, we sought to predict the performance of a modified-release formulation in a multiple-dose scenario, leveraging data from a single-dose study.</p><p><strong>Methods: </strong>MBBE analysis was implemented to estimate the BE endpoints (90% CI for the Test/Reference geometric mean ratio, T/R GMR) in area under the concentration-time curve (AUC) and maximum concentration (Cmax) using data from a single-dose, 2-period, 2-sequence BE study performed in 14 healthy subjects between a locally developed valproic acid extended-release formulation (Test) and the brand-name delayed-release formulation (Reference).</p><p><strong>Results: </strong>Results were compared with the standard approach, revealing that MBBE analysis achieved higher discrimination between formulations for Cmax, addressing limitations of the experimental sampling design and highlighting an advantage for this model-based analysis even when rich data are available. Additionally, the bioequivalence outcome under the multiple-dose scenario was predicted through a simulation-based study for both total and unbound valproic acid concentrations, considering the impact of valproic acid saturable binding on BE conclusions.</p><p><strong>Conclusions: </strong>The MBBE analysis was superior to the NCA approach in detecting product-related differences, overcoming limitations in the study experimental design. Predictions for the multiple-dose scenario preclude that the extended-release properties of the Test formulation would persist at steady state, resulting in lower peak-to-trough fluctuation and bioequivalent performance in terms of the extent of drug absorption. Overall, these results should discourage unnecessary experimentation in healthy subjects.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"507-516"},"PeriodicalIF":1.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317129","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":"Model-Informed Clinical Development of 6-Monthly Injection of Paliperidone Palmitate in Patients with Schizophrenia: Dosing Strategies Guided by Population Pharmacokinetic Modeling and Simulation (Part II).","authors":"Huybrecht T'jollyn, Raja Venkatasubramanian, Martine Neyens, Srihari Gopal, Alberto Russu, Partha Nandy, Juan Jose Perez-Ruixo, Oliver Ackaert","doi":"10.1007/s13318-024-00899-z","DOIUrl":"10.1007/s13318-024-00899-z","url":null,"abstract":"<p><strong>Background and objective: </strong>Paliperidone palmitate 6-month (PP6M) intramuscular (IM) injection is the longest-acting treatment available for patients with schizophrenia. A population pharmacokinetic (popPK) modeling and simulation approach was deployed to inform dosing strategies for PP6M.</p><p><strong>Methods: </strong>The extensive analysis database included 15,932 paliperidone samples from 700 patients receiving gluteal paliperidone palmitate 3-month (PP3M) or PP6M injections in the double-blind phase of a phase-3 noninferiority study (NCT03345342). Exposure parameters for paliperidone appeared to increase dose-proportionally within each dosing schedule (PP3M/PP6M). The range of paliperidone exposures after IM administration of PP6M overlaps with that of corresponding doses of oral paliperidone extended release, PP 1-month (PP1M), and PP3M. Model-based simulations were performed to investigate paliperidone exposures in different PP6M dosing scenarios and relevant subpopulations.</p><p><strong>Results: </strong>A dosing window of ≤ 2 weeks earlier and ≤ 3 weeks later than the target 6-month interval for maintenance treatment with PP6M dosing maintains paliperidone exposures at levels that are not expected to substantially impact its safety and efficacy. For missed-dose scenarios, tailored re-initiation regimens are proposed that should be applied before resuming PP6M maintenance dosing. Regarding subpopulations, PP6M 700 mg eq. is the highest dose recommended in mild renal-impairment patients; the paliperidone pharmacokinetics after PP6M administration is not affected by sex, body mass index, or age in a clinically meaningful way.</p><p><strong>Conclusion: </strong>Paliperidone concentration-time profiles after PP6M and PP3M dosing were adequately described by the popPK model. Model-based simulation results provide guidance for clinicians on initiating PP6M therapy, transitioning between paliperidone formulations, the dosing windows to use for maintenance dosing, and managing missed PP6M doses.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"491-506"},"PeriodicalIF":1.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069836","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":"Systematic Evaluation of Osimertinib Population Pharmacokinetic Models in a Cohort of Dutch Adults with Non-Small Cell Lung Cancer.","authors":"Niels Westra, Paul D Kruithof, Sander Croes, Robin M J M van Geel, Lizza E L Hendriks, Daan J Touw, Thijs H Oude Munnink, Paola Mian","doi":"10.1007/s13318-024-00904-5","DOIUrl":"10.1007/s13318-024-00904-5","url":null,"abstract":"<p><strong>Background and objective: </strong>Several population pharmacokinetic (popPK) studies have been reported that can guide the prediction of osimertinib plasma concentrations in individual patients. It is currently unclear which popPK model offers the best predictive performance and which popPK models are most suitable for nonadherence management and model-informed precision dosing. Therefore, the objective of this study was to externally validate all osimertinib popPK models available in the current literature.</p><p><strong>Methods: </strong>Published popPK models for osimertinib were constructed using NONMEM version 7.4.4. The predictive quality of the identified models was assessed with goodness-of-fit (GoF) plots, conditional weighted residuals (CWRES) plots and a prediction-corrected visual predictive check (pcVPC) for osimertinib and its active metabolite AZ5104. A subset from the Dutch OSIBOOST trial, where 11 patients with low osimertinib exposure were included, was used as evaluation cohort.</p><p><strong>Results: </strong>The population GoF plots for all four models poorly followed the line of identity. For the individual GoF plots, all models performed comparable and were closely distributed among the line of identity. CWRES of the four models were skewed. The pcVPCs of all four models showed a similar trend, where all observed concentrations fell in the simulated shaded areas, but in the lower region of the simulated areas.</p><p><strong>Conclusion: </strong>All four popPK models can be used to individually predict osimertinib concentrations in patients with low osimertinib exposure. For population predictions, all four popPK models performed poorly in patients with low osimertinib exposure. A novel popPK model with good predictive performance should be developed for patients with low osimertinib exposure. Ideally, the cause for the relatively low osimertinib exposure in our evaluation cohort should be known.</p><p><strong>Clinical trials registration: </strong>NCT03858491.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"517-526"},"PeriodicalIF":1.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11199264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327330","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":"Comparative Pharmacokinetic Study of Standard Astaxanthin and its Micellar Formulation in Healthy Male Volunteers.","authors":"Mohamed T Khayyal, Mahmoud H Teaima, Hoda M Marzouk, Rania M El -Hazek, Frank Behnam, Dariush Behnam","doi":"10.1007/s13318-024-00898-0","DOIUrl":"10.1007/s13318-024-00898-0","url":null,"abstract":"<p><strong>Background and objective: </strong>Astaxanthin is a naturally occurring carotenoid with high anti-oxidant properties, but it is a very lipophilic compound with low oral bioavailability. This study was conducted to compare the pharmacokinetic parameters of a novel astaxanthin preparation based on micellar solubilization technology, NovaSOL^® 400-mg capsules (Test product), and those of astaxanthin 400-mg capsules (reference product), after single oral dose administration to healthy male adults.</p><p><strong>Methods: </strong>A single oral dose (400 mg equivalent to 8 mg astaxanthin) of test and reference astaxanthin were administered with 240 mL of water to 12 volunteers according to crossover design, in two phases, with a washout period of 1 week in between. Blood samples were collected at hourly intervals for the first 12 h, then at 24.0, 48.0, and 72.0 h after administration. Aliquots of plasma were centrifuged and the clear supernatant was injected into the high performance liquid chromatography-diode array detection (HPLC-DAD) system. Plasma concentration of astaxanthin versus time profiles were constructed, and the primary pharmacokinetic parameters, maximum concentration (C_max), area under concentration time curve from time of administration (0) to time (t) [AUC_0-t] or to infinity ∞, [AUC_0-∞],  half-life (T_½) and time to reach C_max (T_max) were calculated.</p><p><strong>Results: </strong>The test micellar astaxanthin reached a C_max of 7.21 µg/ml after 3.67 h compared to only 3.86 µg/ml after 8.5 h for the reference native astaxanthin.</p><p><strong>Conclusion: </strong>Micellar formulation of astaxanthin is capable of producing a high concentration of astaxanthin in plasma in a shorter time, thereby expected to provide faster potential therapeutic efficacy.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"467-475"},"PeriodicalIF":1.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11199261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920671","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":"Influence of UGT2B7, UGT1A4 and ABCG2 Polymorphisms on the Pharmacokinetics and Therapeutic Efficacy of Lamotrigine in Patients with Epilepsy.","authors":"Jing Yang, Jinxingyi Wang, Lijie Ning, Changsong Wu, Yang Liu, Jie Xia, Yanping Guan, Qian Liu, Jianghuan Zheng","doi":"10.1007/s13318-024-00894-4","DOIUrl":"10.1007/s13318-024-00894-4","url":null,"abstract":"<p><strong>Background and objectives: </strong>A substantial inter-individual variability has been observed in the pharmacokinetics of lamotrigine. The aim of the study was to investigate the impact of genetic polymorphism of the metabolizing enzymes (UGT2B7, UGT1A4) and transporter (ABCG2) on the pharmacokinetics and therapeutic efficacy of lamotrigine in patients with epilepsy.</p><p><strong>Methods: </strong>The genetic analysis of single-nucleotide polymorphisms was conducted using polymerase chain reaction sequence. High-performance liquid chromatography/tandem mass spectrometry was employed to measure the plasma concentrations of lamotrigine. The efficacy of lamotrigine was assessed by evaluating the reduction rate of epileptic seizure frequency.</p><p><strong>Results: </strong>This study included a cohort of 331 patients who were treated with lamotrigine as monotherapy. A linear correlation was observed between the lamotrigine concentration and daily dose taken (r = 0.58, p < 2.2e^-16). Statistically significant differences were found in both the median plasma concentration and dose-adjusted concentration (C/D ratio) when comparing the ineffective to the effective group (p < 0.05). Multivariate analysis showed that UGT1A4 rs2011425, ABCG2 rs2231142 polymorphisms and age had a significant relationship with the lamotrigine concentrations (p < 0.05). Age was a predictive factor for C/D ratio (p < 0.001). Lamotrigine concentration and weight were good predictive factors for effective seizure outcomes (odds ratio [OR] = 0.715, 95% CI 0.658-0.776, p < 0.001; OR = 0.926, 95% CI 0.901-0.951, p < 0.001, respectively). The cut-off values of lamotrigine trough concentrations for clinical outcomes in the age-related groups were determined as 2.49 μg/ml (area under the receiver-operating characteristic curve [AUC]: 0.828, 95% CI 0.690-0.966), 2.70 μg/ml (AUC: 0.805, 95% CI 0.745-0.866) and 3.25 μg/ml (AUC: 0.807, 95% CI 0.686-0.928) for the adult group, adolescent group, and toddler and school-age group, respectively.</p><p><strong>Conclusions: </strong>UGT1A4 rs2011425 and ABCG2 rs2231142 were correlated with lamotrigine concentrations. Lower lamotrigine trough concentration was found in the ineffective group and the troughs were associated with seizure outcomes.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"437-447"},"PeriodicalIF":1.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140855656","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":"A Phase I Clinical Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of GB221 Injection and Trastuzumab (Herceptin^®) in Healthy Chinese Adults.","authors":"Yu Zhu, Chen Li, Liming Chen, Haiyan Liu, Lun Ou, Tong Li, Xuan Wang, Tenghua Wang, Jingyuan Tian, Xintong Liang, Zhiqin Hu, Yaoxuan Zhan, Shuangshuang Xiao, Xiaole Wang, Yongmei Li, Jin He, Qingshan Zheng, Haifeng Song, Xianbo Li, Yi Fang","doi":"10.1007/s13318-024-00889-1","DOIUrl":"10.1007/s13318-024-00889-1","url":null,"abstract":"<p><strong>Background and objective: </strong>GB221 is a recombinant humanized anti-HER2 monoclonal antibody. The purpose of this study was to evaluate the pharmacokinetic, safety, and immunogenicity of GB221 in healthy Chinese adults in comparison to trastuzumab (Herceptin^®).</p><p><strong>Methods: </strong>In this randomized, double-blind, parallel-group phase I clinical trial, 88 subjects were randomized 1:1 to receive a single intravenous infusion (90-100 min) of GB221 or trastuzumab (6 mg/kg). The primary pharmacokinetic parameters-maximum observed serum concentration (C_max), area under the serum concentration-time curve from zero to the last quantifiable concentration at time t (AUC_0-t), and area under the serum concentration-time curve from time zero to infinity (AUC_0-∞)-of GB221 and trastuzumab were compared to establish whether the 90% confidence interval (CI) attained the 80-125% bioequivalence standard. Safety and immunogenicity were also evaluated.</p><p><strong>Results: </strong>The GB221 group (n = 43) and the trastuzumab group (n = 44) showed similar pharmacokinetic characteristics. The geometric mean ratios (90% CI) of C_max, AUC_0-t, and AUC_0-∞ between the two groups were 107.53% (102.25-113.07%), 108.31% (103.57-113.26%), and 108.34% (103.57-113.33%), respectively. The incidence of treatment-emergent adverse events (TEAEs) was 83.7% (36/43) of the subjects in the GB221 group and 95.5% (42/44) of the subjects in the trastuzumab group. No subjects withdrew from the trial due to TEAEs, and there were no occurrences of serious adverse events. All subjects tested negative for antidrug antibodies (ADA).</p><p><strong>Conclusion: </strong>GB221 demonstrated similar pharmacokinetics to trastuzumab and comparable safety and immunogenicity in healthy Chinese adults.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"383-392"},"PeriodicalIF":1.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140335225","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 Study of Ultrasmall Superparamagnetic Iron Oxide Nanoparticles HY-088 in Rats.","authors":"Xin Song, Minglan Zheng, Heping Hu, Lei Chen, Shuzhe Wang, Zhao Ding, Guangyi Fu, Luyao Sun, Liyuan Zhao, Ling Zhang, Bohua Xu, Yunliang Qiu","doi":"10.1007/s13318-024-00884-6","DOIUrl":"10.1007/s13318-024-00884-6","url":null,"abstract":"<p><strong>Background and objective: </strong>HY-088 injection is an ultrasmall superparamagnetic iron oxide nanoparticle (USPIOs) composed of iron oxide crystals coated with polyacrylic acid (PAA) on the surface. The purpose of this study was to investigate the pharmacokinetics, tissue distribution, and mass balance of HY-088 injection.</p><p><strong>Methods: </strong>The pharmacokinetics of [⁵⁵Fe]-HY-088 and [¹⁴C]-HY-088 were investigated in 48 SD rats by intravenous injection of 8.5 (low-dose group), 25.5 (medium-dose group), and 85 (high-dose group) mg/100 μCi/kg. Tissue distribution was studied by intravenous injection of 35 mg/100 μCi/kg in 48 SD rats, and its tissue distribution in vivo was obtained by ex vivo tissue assay. At the same time, [¹⁴C]-HY-088 was injected intravenously at a dose of 25.5 mg/100 μCi/kg into 16 SD rats, and its tissue distribution in vivo was studied by quantitative whole-body autoradiography. [¹⁴C]-HY-088 and [⁵⁵Fe]-HY-088 were injected intravenously into 24 SD rats at a dose of 35 mg/100 μCi/kg, and their metabolism was observed.</p><p><strong>Results: </strong>In the pharmacokinetic study, [⁵⁵Fe]-HY-088 reached the maximum observed concentration (C_max) at 0.08 h in the low- and medium-dose groups of SD rats. [¹⁴C]-HY-088 reached C_max at 0.08 h in the three groups of SD rats. The area under the concentration-time curve (AUC) of [⁵⁵Fe]-HY-088 and [¹⁴C]-HY-088 increased with increasing dose. In the tissue distribution study, [⁵⁵Fe]-HY-088 and [¹⁴C]-HY-088 were primarily distributed in the liver, spleen, and lymph nodes of both female and male rats. In the mass balance study conducted over 57 days, the radioactive content of ⁵⁵Fe from [⁵⁵Fe]-HY-088 was primarily found in the carcass, accounting for 86.42 ± 4.18% in females and 95.46 ± 6.42% in males. The radioactive recovery rates of [¹⁴C]-HY-088 in the urine of female and male rats were 52.99 ± 5.48% and 60.66 ± 2.23%, respectively.</p><p><strong>Conclusions: </strong>Following single intravenous administration of [⁵⁵Fe]-HY-088 and [¹⁴C]-HY-088 in SD rats, rapid absorption was observed. Both [⁵⁵Fe]-HY-088 and [¹⁴C]-HY-088 were primarily distributed in the liver, spleen, and lymph nodes. During metabolism, the radioactivity of [⁵⁵Fe]-HY-088 is mainly present in the carcass, whereas the ¹⁴C-labeled [¹⁴C]-HY-088 shell PAA is eliminated from the body mainly through the urine.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"317-330"},"PeriodicalIF":1.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139930641","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":"Safety, Tolerability, and Pharmacokinetics of the Monoamine Oxidase B Inhibitor, HEC122505, and its Major Metabolite After Single- and Multiple- Ascending Dose, and Food Effect Study in Healthy Chinese Subjects.","authors":"Chuanfei Jin, Chao Yi, Kangzhi Chen, Haiping Liang","doi":"10.1007/s13318-024-00880-w","DOIUrl":"10.1007/s13318-024-00880-w","url":null,"abstract":"<p><strong>Background and objectives: </strong>HEC122505 is a potent and selectively monoamine oxidase B inhibitor that is safe and well-tolerated in preclinical models of Parkinson's disease. The objectives of single ascending dose and multiple dose pharmacokinetic trials of HEC122505 oral tablets were to determine the safety and tolerability of HEC122505, and to examine the food effect on the pharmacokinetic parameters of HEC122505 and its major metabolite HEC129870.</p><p><strong>Methods: </strong>The phase I study (NCT04625361) consisted of three arms: single ascending dose study (5, 20, 50, 100, 200, 300 or 400 mg HEC122505 tablets or placebo), multiple ascending dose study (20, 50 or 100 mg HEC122505 tablets or placebo once daily), and food effect (100 mg HEC122505 tablets single dose after a high-fat, high-calorie meal). All subjects completed all trial arms and were analyzed as planned.</p><p><strong>Results: </strong>Pharmacokinetic analysis showed that HEC122505 rapidly absorbed with the time to peak plasma concentration (T_max) ranged from 0.5 to 1.75 h. In addition, maximum plasma drug concentration (C_max) and area under the plasma concentration-time curve (AUC) increased in a dose proportional manner. Food effect study showed that a high-fat, high-calorie meal had no significant effect on the pharmacokinetics of HEC122505 and its major metabolite HEC129870, suggesting that HEC122505 could be administered in both fasted and fed state in clinical trials. The subsequent multiple-dose study evaluated doses from 20 to 100 mg dose once daily for up to 8 days. HEC122505 reached steady state after approximately 5 days with a once daily dose. In these studies, all dose of HEC122505 was generally safe and well tolerated. No grade ≥ 3 drug related adverse events (AEs) occurred.</p><p><strong>Conclusion: </strong>HEC122505 was generally safe and well tolerated in the single ascending dose (ranging from 5 to 400 mg) and multiple ascending dose (50 to 200 mg once daily doses) studies. All the drug related adverse events (AEs) were Grade ≤ 2. There were no deaths, no subjects discontinued the trial due to AEs, and there were no other serious AEs. The safety and pharmacokinetic profile support once daily administration of HEC122505.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"331-341"},"PeriodicalIF":1.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038985","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":"Predicting Pharmacokinetics of Drugs Using Artificial Intelligence Tools: A Systematic Review.","authors":"Mahnaz Ahmadi, Bahareh Alizadeh, Seyed Mohammad Ayyoubzadeh, Mahdiye Abiyarghamsari","doi":"10.1007/s13318-024-00883-7","DOIUrl":"10.1007/s13318-024-00883-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Pharmacokinetic studies encompass the examination of the absorption, distribution, metabolism, and excretion of bioactive compounds. The pharmacokinetics of drugs exert a substantial influence on their efficacy and safety. Consequently, the investigation of pharmacokinetics holds great importance. However, laboratory-based assessment necessitates the use of numerous animals, various materials, and significant time. To mitigate these challenges, alternative methods such as artificial intelligence have emerged as a promising approach. This systematic review aims to review existing studies, focusing on the application of artificial intelligence tools in predicting the pharmacokinetics of drugs.</p><p><strong>Methods: </strong>A pre-prepared search strategy based on related keywords was used to search different databases (PubMed, Scopus, Web of Science). The process involved combining articles, eliminating duplicates, and screening articles based on their titles, abstracts, and full text. Articles were selected based on inclusion and exclusion criteria. Then, the quality of the included articles was assessed using an appraisal tool.</p><p><strong>Results: </strong>Ultimately, 23 relevant articles were included in this study. The clearance parameter received the highest level of investigation, followed by the  area under the concentration-time curve (AUC) parameter, in pharmacokinetic studies. Among the various models employed in the articles, Random Forest and eXtreme Gradient Boosting (XGBoost) emerged as the most commonly utilized ones. Generalized Linear Models and Elastic Nets (GLMnet) and Random Forest models showed the most performance in predicting clearance.</p><p><strong>Conclusion: </strong>Overall, artificial intelligence tools offer a robust, rapid, and precise means of predicting various pharmacokinetic parameters based on a dataset containing information of patients or drugs.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"249-262"},"PeriodicalIF":1.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140058983","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}