Journal of Clinical Pharmacology最新文献

Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous and Intravenous Garadacimab Following Single-Dose Administration in Healthy Japanese and White Adults. 健康日本人和白人成人单剂量皮下注射和静脉注射加拉达西单抗的药代动力学、药效学和安全性

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2024-11-24 DOI: 10.1002/jcph.6162

Fiona Glassman, John-Philip Lawo, Mihai Alexandru Bica, Anthony Roberts, Dipti Pawaskar, Hideto Akama, Meena Jain, Summer Goodson

{"title":"Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous and Intravenous Garadacimab Following Single-Dose Administration in Healthy Japanese and White Adults.","authors":"Fiona Glassman, John-Philip Lawo, Mihai Alexandru Bica, Anthony Roberts, Dipti Pawaskar, Hideto Akama, Meena Jain, Summer Goodson","doi":"10.1002/jcph.6162","DOIUrl":"https://doi.org/10.1002/jcph.6162","url":null,"abstract":"Garadacimab, an activated factor XII (FXIIa) inhibitor monoclonal antibody, is being evaluated for the long-term prophylaxis of hereditary angioedema. Here, we report the results from a two-part, phase 1, open-label, single ascending dose study assessing the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability after subcutaneous (SC) and intravenous (IV) administration of garadacimab in healthy Japanese and White participants. Part 1 assessed garadacimab PK after SC administration of a 200 mg dose in weight-matched White and Japanese participants, and 600 mg dose in Japanese participants. Part 2 assessed 3 and 10 mg/kg IV doses in Japanese participants. Follow-up for safety was over 84 days post-dose. Overall, 37 participants received garadacimab dosing and 36 completed the study, with one participant lost to follow-up. Following SC administration, time to maximum plasma concentration (tmax) occurred at 7 days post-dose, and garadacimab exposure, based on maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC), increased less than 3-fold when tripling the dose. PK was comparable between Japanese and White participants, with geometric mean ratios for Cmax and AUC close to 100%. Following IV administration, tmax occurred at the end of infusion, and garadacimab exposure increased in a dose-proportional manner. Inhibition of FXIIa-mediated kallikrein activity versus baseline was observed in all participants receiving the SC and IV doses. No anti-drug antibodies against garadacimab were reported. Consistent with pivotal phase 3 (VANGUARD) outcomes, no safety concerns and no difference in the safety profile of garadacimab were observed between healthy Japanese and White participants.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142711549","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}

引用次数: 0

Sentinel Dosing-Time for a Risk-Based Approach? 哨兵剂量--采用基于风险的方法的时机已到？

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2024-11-24 DOI: 10.1002/jcph.6167

Peter L Bonate, Mark Rogge, Jean-Michel Gries, Alexander J Prokopienko, Sudhakar M Pai

引用次数: 0

Relative Bioavailability of Dordaviprone (ONC201) is Not Affected by Co-Administration of the Proton-Pump Inhibitor Rabeprazole. 多达维酮（ONC201）的相对生物利用度不受同时服用质子泵抑制剂雷贝拉唑的影响

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2024-11-22 DOI: 10.1002/jcph.6163

Shamia L Faison, Joelle Batonga, Thangam Arumugham, Angela Bartkus, Marion Morrison, Mark J Mullin, Tim Tippin, Odin Naderer

{"title":"Relative Bioavailability of Dordaviprone (ONC201) is Not Affected by Co-Administration of the Proton-Pump Inhibitor Rabeprazole.","authors":"Shamia L Faison, Joelle Batonga, Thangam Arumugham, Angela Bartkus, Marion Morrison, Mark J Mullin, Tim Tippin, Odin Naderer","doi":"10.1002/jcph.6163","DOIUrl":"https://doi.org/10.1002/jcph.6163","url":null,"abstract":"Dordaviprone (ONC201) is a novel, orally administered, anti-cancer, small molecule imipridone with demonstrated antitumor effects in patients with glioma. Dordaviprone in vitro solubility is significantly reduced at pH >4.5. Concomitant use of acid reducing agents (ARAs) may therefore impact dordaviprone solubility and bioavailability. This open-label, single-sequence, three-period crossover study evaluated the effect of proton-pump inhibitor rabeprazole on dordaviprone pharmacokinetics (PK). Periods were consecutive and comprised of period 1 (days 1-3), period 2 (days 4-9), and period 3 (days 10-13). In period 1, participants received a single oral 625 mg dose of dordaviprone on day 1. In period 2, participants received six consecutive days of QD 20 mg rabeprazole alone. In period 3, patients received one oral dose of 20 mg rabeprazole (the seventh consecutive daily dose), followed 2 h later by a single 625 mg dordaviprone oral dose. PK blood samples were collected and analyzed from pre-dose 72 h following dordaviprone administration in periods 1 and 3. Dordaviprone exposure PK parameters were similar following administration of dordaviprone alone or with rabeprazole. Geometric mean ratios and 90% CIs for dordaviprone exposure parameters with and without rabeprazole following dordaviprone administration fell within bioequivalence limits of 80.00%-125.00% for Cmax (97.19% [86.43-109.28]), AUClast (102.21% [95.19-109.75]), and AUCinf (102.27% [95.21-109.86]), indicating no effect of multiple oral doses of rabeprazole on dordaviprone relative bioavailability. Six of the 16 participants reported treatment-emergent adverse events (TEAEs); dordaviprone-related TEAEs were reported by three participants and were limited to mild nausea and dizziness. No dordaviprone dose adjustment or ARA treatment modification is warranted.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693843","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}

引用次数: 0

Patients in Clinical Trials are Sub-Optimally Protected for Drug-Drug Interactions: A Call for Action. 临床试验中的患者受到药物间相互作用的亚光学保护：行动呼吁。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2024-11-21 DOI: 10.1002/jcph.6168

David Burger, Loek de Jong, Daphne van Dijk, Catherijne A J Knibbe, Rob Ter Heine, Elise Smolders, Munir Pirmohamed

引用次数: 0

Results of the ACTION-Galactosemia Kids Study to Evaluate the Effects of Govorestat in Pediatric Patients with Classic Galactosemia. 评估Govorestat对经典半乳糖血症儿童患者疗效的ACTION-半乳糖血症儿童研究结果。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2024-11-21 DOI: 10.1002/jcph.6170

Evan Bailey, Han Phan, Ayesha Ahmad, Janet Thomas, Elizabeth G Ames, Amanda B Pritchard, Shane C Quinonez, Stella Wang, Caleb Dayley, Andrew Salt, Christina Pick, Abe Durrant, Samuel Johnson, Jessie Nicodemus-Johnson, Samuel P Dickson, Riccardo Perfetti, Suzanne B Hendrix, Shoshana Shendelman

{"title":"Results of the ACTION-Galactosemia Kids Study to Evaluate the Effects of Govorestat in Pediatric Patients with Classic Galactosemia.","authors":"Evan Bailey, Han Phan, Ayesha Ahmad, Janet Thomas, Elizabeth G Ames, Amanda B Pritchard, Shane C Quinonez, Stella Wang, Caleb Dayley, Andrew Salt, Christina Pick, Abe Durrant, Samuel Johnson, Jessie Nicodemus-Johnson, Samuel P Dickson, Riccardo Perfetti, Suzanne B Hendrix, Shoshana Shendelman","doi":"10.1002/jcph.6170","DOIUrl":"https://doi.org/10.1002/jcph.6170","url":null,"abstract":"To evaluate the pharmacodynamic effects and clinical outcomes of orally administered once-daily govorestat (AT-007), a central nervous system penetrant aldose reductase inhibitor, the double-blind placebo-controlled ACTION-Galactosemia Kids study (NCT04902781) randomly assigned 47 participants (2-17 years old) with Classic Galactosemia to 18 months of govorestat or placebo (2:1) treatment. Mean change in galactitol was compared between the treatment groups at each post-baseline timepoint using a t-test, with a mixed model for repeated measures (MMRM) analysis as a sensitivity analysis. Changes from baseline in clinical outcomes were compared between treatment groups also using a t-test with two different MMRM models as sensitivity models, one including baseline clinical outcome score. The pharmacodynamic effect of govorestat was assessed by correlating galactitol level at 3 months with change from baseline in clinical measures at 18 months using a Pearson correlation. Govorestat treatment resulted in a rapid and sustained reduction in plasma galactitol. Govorestat treatment stabilized or improved clinical measures of behavior, daily living skills, adaptive skills, cognition, tremor, and fine motor skills, which declined over time in the placebo group. Govorestat treatment did not demonstrate a benefit compared with placebo on speech outcomes or gross motor skills, which improved in both treatment groups over 18 months. Govorestat was safe and well tolerated, with adverse events well balanced between the active and placebo groups. Aldose reductase inhibition with govorestat represents a potential opportunity to lower galactitol and improve clinical outcomes in children with Classic Galactosemia.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683204","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}

引用次数: 0

In Vitro Evaluation of CYP-Mediated Metabolism of Fezolinetant and Pharmacokinetic Interaction Between Fezolinetant and Fluvoxamine in Healthy Postmenopausal Smokers and Nonsmokers. 体外评估绝经后健康吸烟者和非吸烟者体内由 CYP 介导的非索内酯代谢以及非索内酯与氟伏沙明之间的药代动力学相互作用。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2024-11-19 DOI: 10.1002/jcph.6157

Megumi Iwai, Jace Nielsen, Mayuko Miyagawa, Melanie Patton, Peter L Bonate, Xuegong Wang, Tomasz Wojtkowski, Angela Sinn, Jiayin Huang

{"title":"In Vitro Evaluation of CYP-Mediated Metabolism of Fezolinetant and Pharmacokinetic Interaction Between Fezolinetant and Fluvoxamine in Healthy Postmenopausal Smokers and Nonsmokers.","authors":"Megumi Iwai, Jace Nielsen, Mayuko Miyagawa, Melanie Patton, Peter L Bonate, Xuegong Wang, Tomasz Wojtkowski, Angela Sinn, Jiayin Huang","doi":"10.1002/jcph.6157","DOIUrl":"10.1002/jcph.6157","url":null,"abstract":"Fezolinetant is an oral, nonhormonal, neurokinin 3 receptor antagonist treatment option for moderate to severe vasomotor symptoms associated with menopause. An in vitro study using human recombinant cytochrome P450 (CYP) enzymes and human liver microsomes showed that fezolinetant is metabolized to its major but inactive metabolite, ES259564, predominantly through CYP1A2, with minor contributions from CYP2C9 and CYP2C19. The clinical impact of CYP1A2 inhibition and induction on single-dose pharmacokinetics of fezolinetant was assessed in an open-label, single-sequence, phase 1 study in healthy postmenopausal women, where the impact of fluvoxamine, a strong CYP1A2 inhibitor, and smoking, a moderate CYP1A2 inducer, were evaluated. In total, 18 participants, 9 of whom were smokers, were enrolled. Fezolinetant pharmacokinetics were evaluated after a single 30-mg dose on Day 1 and Day 7. Fluvoxamine 50 mg was administered as a single dose on Days 3 and 10 and twice daily from Days 4 to 9. Fluvoxamine increased geometric mean ratio of fezolinetant maximum plasma concentrations (Cmax) and area under the curve from time of dosing extrapolated to infinity (AUCinf) to 182% and 939%, respectively, while ES259564 Cmax decreased to 20.1% with no significant change in AUC. In smokers versus nonsmokers, when fezolinetant was administered alone, fezolinetant Cmax and AUCinf decreased to 71.7% and 48.3%, respectively, while ES259564 Cmax increased to 130.2% and AUCinf decreased to 81.8%. A single oral 30-mg dose of fezolinetant was considered safe and well tolerated when co-administered with fluvoxamine in healthy postmenopausal women.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668162","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}

引用次数: 0

Limited Sampling Strategy for Predicting the Area under Plasma Concentration-Time Curve of Nadolol in Healthy Subjects. 预测健康受试者纳多洛尔血浆浓度-时间曲线下面积的有限采样策略

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2024-11-17 DOI: 10.1002/jcph.6164

Shingen Misaka, Yuko Maejima, Kenju Shimomura

{"title":"Limited Sampling Strategy for Predicting the Area under Plasma Concentration-Time Curve of Nadolol in Healthy Subjects.","authors":"Shingen Misaka, Yuko Maejima, Kenju Shimomura","doi":"10.1002/jcph.6164","DOIUrl":"https://doi.org/10.1002/jcph.6164","url":null,"abstract":"Nadolol is a hydrophilic β-adrenoceptor blocker with a relatively long half-life and negligible metabolism. It is a substrate of P-glycoprotein and organic anion transporting polypeptide 1A2, and may serve as an in vivo probe drug for the assessment of drug-drug and food-drug interactions mediated by these transporters. In the present study, we aimed to develop limited sampling strategy (LSS) models for predicting the area under the plasma concentration-time curve (AUC0-∞) of nadolol. Plasma concentration data (Ct) in healthy volunteers reported in four previous studies were randomly divided into a training dataset for model development (n = 15) and a test dataset for model validation (n = 16). By multiple linear regression analysis, we confirmed that four out of the eight models using two time points and all models using three time points met the acceptable criteria. In particular, the three time point models using (C3, C6, and C24) and (C4, C8, and C24) showed better predictive performances with r2 values of 0.983 and 0.980, respectively. In drug interaction studies of nadolol with itraconazole, rifampicin, grapefruit juice, and green tea extract, both LSS models accurately predicted the AUC0-∞ with percent mean absolute error ≤11% and percent root mean square error ≤12%. In addition, using digitized pharmacokinetic data of nadolol, both LSS models were further validated by predicting the AUC0-∞ in different doses. The results suggest that the LSS models using three time points allow a reliable prediction of AUC0-∞ of nadolol in healthy individuals.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649022","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}

引用次数: 0

Meta-Analysis of Exposure-Adverse Event Relationships for Antibody-Drug Conjugates. 抗体药物共轭物暴露与不良事件关系的 Meta 分析。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2024-11-13 DOI: 10.1002/jcph.6160

Cheng Wang, Linda Irons, Holly Kimko, Dhaval K Shah

{"title":"Meta-Analysis of Exposure-Adverse Event Relationships for Antibody-Drug Conjugates.","authors":"Cheng Wang, Linda Irons, Holly Kimko, Dhaval K Shah","doi":"10.1002/jcph.6160","DOIUrl":"https://doi.org/10.1002/jcph.6160","url":null,"abstract":"Antibody-drug conjugates (ADCs) have become a vital class of therapeutics in oncology because of their ability to selectively deliver potent drug molecules to tumor cells. However, ADC-associated toxicities cause high failure rates in the clinic and hinder their full potential. Due to the complex structure and pharmacokinetics of ADCs, it is challenging to identify the drivers of their toxicities. Here, quantitative analysis was performed to correlate the incidence of clinical adverse events (AEs) with nine different commonly measured exposure parameters collected from study-level summary data. We considered ADC analytes for different classes of ADCs, to identify ADC analytes that are strongly associated with the AEs for ADCs. Published clinical exposure and safety data for any grade and grade ≥3 AEs from 40 publications across six ADCs and three payloads were collected and analyzed. Exposure-AE relationships were quantified using logit models, and the strength of the correlations and rank order were determined. The analysis suggests that deruxtecan ADC-related toxicities correlated most strongly with the exposure of the free payload; monomethyl auristatin E (MMAE) ADC-related toxicities correlated with the free MMAE area under the curve; and pyrrolobenzodiazepine ADC-related toxicities correlated with no specific analyte but the dose. These findings agree with the published literature and support the notion that AE profiles are often shared by ADCs that deliver the same cytotoxic payload. The exposure-AE relationships presented here, together with identification of the most informative ADC analytes, may facilitate more focused mechanistic studies on the drivers of clinical AEs and could support dosing decisions during clinical development of ADCs.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630722","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}

引用次数: 0

Training the Next Generation of Pediatric Clinical Pharmacologists: Insights and Trainee Perspectives Over 10 Years. 培训下一代儿科临床药理学家：10 年来的见解和受训人员的观点。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2024-11-13 DOI: 10.1002/jcph.6155

Rachel L Randell, Rose Gelineau-Morel, Sydney Thomas, Daniel Gonzalez, J Steven Leeder, Christoph P Hornik

{"title":"Training the Next Generation of Pediatric Clinical Pharmacologists: Insights and Trainee Perspectives Over 10 Years.","authors":"Rachel L Randell, Rose Gelineau-Morel, Sydney Thomas, Daniel Gonzalez, J Steven Leeder, Christoph P Hornik","doi":"10.1002/jcph.6155","DOIUrl":"https://doi.org/10.1002/jcph.6155","url":null,"abstract":"The limited number of researchers with expertise necessary toaddress treatment gaps for children presents an ongoing challenge. The NationalInstitutes of Health established a national Pediatric Clinical Pharmacology T32Training Program in 2012 to train a multidisciplinary, collaborative pediatricclinical pharmacology workforce. We surveyed all current T32 trainees andgraduates since inception to identify strengths and opportunities to enhanceworkforce development. A total of 85 out of 155 (55%) responded, with themajority of respondents being female gender (61%), white race (75%), andworking in academia (75%). Nearly all (97%) reported using clinicalpharmacology in their current position, with 88% planning to remain in clinicalpharmacology in the long term, reinforcing current training efforts. Lifestylefactors and student debt appeared to influence career decisions. Mentors werecritical for introduction and future success in the field. Time and fundinglimitations were perceived as barriers to successful training. There was also apressing need to improve diversity. For workforce development, we suggestsupporting: (1) trainees' lifestyle, by offsetting financial pressures ofresearch training and expanding the geographic footprint of pediatric clinicalpharmacology training; (2) mentorship, by identifying mentors in the field andproviding dedicated support for mentorship; (3) efficiency, by evaluatingcurrent training activities and focusing on activities that maximizeopportunities for future funding; and (4) diversity, by examining barriers todiversity in the workforce in general and expanding early enrichmentopportunities.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630676","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}

引用次数: 0

A Phase I Study of the Pharmacokinetics, Pharmacodynamics, and Safety of Liposomal Bupivacaine for Sciatic Nerve Block in the Popliteal Fossa for Bunionectomy. 拇趾外翻切除术中用于腘窝坐骨神经阻滞的脂质体布比卡因的药代动力学、药效学和安全性的 I 期研究。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2024-11-08 DOI: 10.1002/jcph.6159

Daniel I Sessler, Xiaodong Bao, David Leiman, Jia Song, Jason Chittenden, Alexander Voelkner, Alparslan Turan, Jeffrey Gadsden

{"title":"A Phase I Study of the Pharmacokinetics, Pharmacodynamics, and Safety of Liposomal Bupivacaine for Sciatic Nerve Block in the Popliteal Fossa for Bunionectomy.","authors":"Daniel I Sessler, Xiaodong Bao, David Leiman, Jia Song, Jason Chittenden, Alexander Voelkner, Alparslan Turan, Jeffrey Gadsden","doi":"10.1002/jcph.6159","DOIUrl":"https://doi.org/10.1002/jcph.6159","url":null,"abstract":"This trial assessed the pharmacokinetics, pharmacodynamics, and safety of liposomal bupivacaine given via ultrasound-guided popliteal sciatic nerve block with or without immediate-release bupivacaine hydrochloride in adults having bunionectomies. Forty-five adults were enrolled into four sequential cohorts: (1) liposomal bupivacaine 266 mg with bupivacaine hydrochloride 50 mg; (2) liposomal bupivacaine 133 mg with bupivacaine hydrochloride 50 mg; (3) liposomal bupivacaine 266 mg; or (4) bupivacaine hydrochloride 100 mg. Outcomes included pharmacokinetics (e.g., bupivacaine maximum plasma concentration [Cmax]), onset and duration of motor and sensory nerve block, and safety. Liposomal bupivacaine admixed with bupivacaine hydrochloride produced biphasic bupivacaine plasma disposition profiles with two distinct peaks. Geometric mean Cmax of the early peak ranged from 235 to 421 ng/mL and the geometric mean of the late Cmax was ∼30%-50% lower than the early peak. Median time to sensory block onset was 18 to 29 min in all cohorts. Sensory blocks lasted about twice as long with liposomal bupivacaine (median, 119-167 h) than with bupivacaine hydrochloride alone (median, 67 h). There were no serious adverse events. In conclusion, liposomal bupivacaine provided prolonged sensory nerve block when given as popliteal sciatic nerve blocks with or without bupivacaine hydrochloride, and bupivacaine plasma concentrations were well below the lower bound of the toxicity threshold of 2000 ng/mL for all cohorts.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630720","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}

引用次数: 0