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Impact of Postural Restrictions on Tetrabenazine Pharmacokinetics in Healthy Volunteers: A Randomized Crossover Study Emphasizing Variance Minimization Strategies in Good Clinical Practice-Guided Bioequivalence Research 体位限制对健康志愿者四苯那嗪药代动力学的影响：一项强调良好临床实践指导下生物等效性研究中方差最小化策略的随机交叉研究

Future pharmacology Pub Date : 2025-11-10 DOI: 10.3390/futurepharmacol5040067

Nirav Chandegara, Shrikalp Deshpande, Bhupendra G. Prajapati, Anup K. Singh, Dignesh Khunt

{"title":"Impact of Postural Restrictions on Tetrabenazine Pharmacokinetics in Healthy Volunteers: A Randomized Crossover Study Emphasizing Variance Minimization Strategies in Good Clinical Practice-Guided Bioequivalence Research","authors":"Nirav Chandegara, Shrikalp Deshpande, Bhupendra G. Prajapati, Anup K. Singh, Dignesh Khunt","doi":"10.3390/futurepharmacol5040067","DOIUrl":"https://doi.org/10.3390/futurepharmacol5040067","url":null,"abstract":"Background: Tetrabenazine, a VMAT2 inhibitor used for hyperkinetic disorders, shows considerable pharmacokinetic variability due to extensive first-pass metabolism. Standardization of clinical trial conditions, including posture, may reduce variability and improve bioequivalence assessments. Objective: The aim of this study was to determine the impact of postural restriction on the pharmacokinetics of tetrabenazine and its active metabolite, dihydrotetrabenazine (HTBZ), under controlled conditions. Methods: A randomized, open-label, four-period replicate crossover study enrolled 72 healthy fasted adults who received a single 25 mg tetrabenazine dose under two conditions: 4 h semirecumbent posture versus unrestricted movement. Plasma drug concentrations were measured across 36 h using validated LC–MS/MS method. Pharmacokinetic parameters were estimated via non-compartmental analysis and compared with Wilcoxon signed-rank tests. Results: Postural restriction significantly increased tetrabenazine exposure (AUC0–t: +16.4%, p < 0.0001) and half-life (p = 0.002), with a nonsignificant rise in Cmax. For HTBZ, Cmax decreased (−16.2%, p = 0.018), whereas AUC was unchanged. Parent-to-metabolite ratios increased by 24–29%. Replicate design analyses showed reduced intra-subject variability for tetrabenazine AUC with posture control (~24% vs. >28%). Simulation suggested that posture restriction could lower sample size requirements by 15–30% in two-period average bioequivalence trials. Conclusions: Maintaining a semirecumbent posture after dosing enhances tetrabenazine’s bioavailability, attenuates early metabolite formation, and reduces pharmacokinetic variability. Incorporating posture control into bioequivalence trial protocols may optimize study design, reduce participant exposure, and align with ICH-GCP ethical principles.","PeriodicalId":520944,"journal":{"name":"Future pharmacology","volume":"5 4","pages":"67-67"},"PeriodicalIF":0.0,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147333442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Safety Toxicology Study of Reassortant Mopeia-Lassa Vaccine in Guinea Pigs. 重组莫皮亚-拉沙疫苗豚鼠安全性毒理学研究。

Future pharmacology Pub Date : 2025-06-01 Epub Date: 2025-05-31 DOI: 10.3390/futurepharmacol5020026

Bradley S Wahle, Peter Pushko, Katie Albanese, Dylan M Johnson, Irina Tretyakova, Igor S Lukashevich, Thomas Rudge

{"title":"Safety Toxicology Study of Reassortant Mopeia-Lassa Vaccine in Guinea Pigs.","authors":"Bradley S Wahle, Peter Pushko, Katie Albanese, Dylan M Johnson, Irina Tretyakova, Igor S Lukashevich, Thomas Rudge","doi":"10.3390/futurepharmacol5020026","DOIUrl":"10.3390/futurepharmacol5020026","url":null,"abstract":"Background: (1)Mopeia-Lassa reassortant ML29 virus is an investigational, reassortant virus vaccine for the prevention of Lassa fever caused by Lassa virus (LASV).Methods: (2)The vaccine virus ML29-SF was prepared in Vero cells using a serum-free culture medium under Good Manufacturing Practice. A 2-week repeat dose toxicity study was performed in guinea pigs under Good Laboratory Practice (GLP) regulations to assess the local and systemic toxicological effects.Results: (3)Following an intramuscular (IM) or subcutaneous (SC) injection of 104 PFU of ML29-SF LASV vaccine at the start of the study, with a second dose 15 days later, no toxicological response attributable to the vaccine was observed. Vaccine-related effects were not observed in any in-life or post-mortem parameter evaluated, including clinical observations, injection site observations, body temperature, body weight, food consumption, ophthalmology, immunology, hematology, clinical chemistry, gross anatomical pathology, organ weights, and histopathology. An immunogenic response, as measured by the elicitation of IgG antibodies against major LASV immunogens, nucleocapsid and glycoprotein precursor, was observed in all vaccine-treated animals prior to the booster dose (Study Day 15) which endured through the end of the study (Study Day 42). There was no evidence of viral shedding in any vaccinated animal.Conclusions: (4)Overall, this single-dose vaccine was locally and systemically well tolerated even after a two-dose repeat administration, confirming the high level of safety of ML29-SF vaccination and supporting the future evaluation of this LASV vaccine, including in clinical trials.","PeriodicalId":520944,"journal":{"name":"Future pharmacology","volume":"5 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Trifluralin Toxicology Revisited: Microtubule Inhibition, Mitochondrial Damage, and Anti-Protozoan Potential 三氟拉林毒理学重访：微管抑制、线粒体损伤和抗原生动物潜能

Future pharmacology Pub Date : 2025-03-23 DOI: 10.3390/futurepharmacol5020014

Darío Lirussi

{"title":"Trifluralin Toxicology Revisited: Microtubule Inhibition, Mitochondrial Damage, and Anti-Protozoan Potential","authors":"Darío Lirussi","doi":"10.3390/futurepharmacol5020014","DOIUrl":"https://doi.org/10.3390/futurepharmacol5020014","url":null,"abstract":"The aim of this review is to evaluate the therapeutic possibilities of trifluralin and other 2,6-dinitroaniline herbicides by assessing different aspects of trifluralin’s toxicology (including its mitochondrial toxicity), pharmacokinetics, and environmental fate. The particular features of TFL have triggered a wide range of policies about its properties. Is has been banned in some countries and, at the same time, has been proposed as a drug for the cure of parasitic disease by some scientific research articles. The use of this pre-emergence herbicide to control broadleaf weeds and annual grasses is assumed to rely only on its microtubule depolarization or cytoskeleton disassembly abilities (on-target effect), a fact that justifies its inhibition of a wide range of microorganisms (mostly protozoans), sharing a relatively high degree of conservation in tubulin protein sequences with weeds and grasses. Recent studies have confirmed that TFL also affects mitochondrial function (off-target effect), a hypothesis previously suggested in earlier works. Here, we account for the main issues in TFL toxicology, other potential uses of the herbicide outside crops, and its feasibility for use as an antiprotozoal drug.","PeriodicalId":520944,"journal":{"name":"Future pharmacology","volume":"5 2","pages":"14-14"},"PeriodicalIF":0.0,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.mdpi.com/2673-9879/5/2/14/pdf?version=1742803715","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147909475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0