Clinical therapeutics最新文献

{"title":"Pharmacokinetics, Safety, Tolerability, and Exploratory Efficacy of Upadacitinib in Children with Severe Atopic Dermatitis","authors":"Yuli Qian PhD ,&nbsp;Eliza M. Raymundo MD ,&nbsp;Shuai Hao PhD ,&nbsp;Kristina Unnebrink PhD ,&nbsp;Gweneth F. Levy MD ,&nbsp;Henrique D. Teixeira PhD ,&nbsp;Alvina D. Chu MD ,&nbsp;Zachary A. Zinn MD ,&nbsp;Amy S. Paller MD ,&nbsp;Wei Liu PhD ,&nbsp;Mohamed-Eslam F. Mohamed RPh, PhD, FCP","doi":"10.1016/j.clinthera.2024.07.003","DOIUrl":"10.1016/j.clinthera.2024.07.003","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aims to characterize the pharmacokinetics, safety, tolerability, and exploratory efficacy of upadacitinib, an oral Janus kinase inhibitor approved for treating moderate to severe atopic dermatitis (AD) in adults and adolescents, in children with severe AD.</div></div><div><h3>Methods</h3><div>In an open-label, multiple-dose, Phase 1 study, pediatric patients with severe AD from two age groups (2 to &lt;6 years and 6 to &lt;12 years) received bodyweight-based dosing regimens of upadacitinib using either twice-daily immediate-release (IR) oral solution or once-daily extended-release (ER) tablets. A pharmacokinetic assessment was conducted on Day 7 of the study, which was followed by a long-term safety and exploratory efficacy evaluation for up to 108 weeks. The results reported here are based on an interim analysis when the study had completed enrollment and pharmacokinetic assessment.</div></div><div><h3>Findings</h3><div>A total of 35 patients were enrolled and received upadacitinib. The maximum upadacitinib plasma concentration was attained within a median time of 0.5 to 2 hours and 2 to 2.5 hours for the IR oral solution and ER tablet formulations, respectively. Upadacitinib functional half-life was generally shorter with IR oral solution relative to ER tablets. Upadacitinib apparent oral clearance decreased with decreasing body weight in the pediatric patients enrolled in this study. Upadacitinib was generally safe and well tolerated. The most common (≥3 patients) adverse events were upper respiratory tract infection, COVID-19 infection, headache, abdominal discomfort, vomiting, asthma, and cough. No new safety risks were identified compared to the known safety profile for upadacitinib in adults and adolescents. In the 30 patients with available exploratory efficacy data at Week 12, 36.7% achieved validated Investigator's Global Assessment scale for AD score of 0 or 1 (Validated Investigator Global Assessment for AD 0/1), and 70.0% had Eczema Area and Severity Index (EASI) improvement of at least 75% (EASI 75).</div></div><div><h3>Implications</h3><div>The characterized pharmacokinetic profiles in this study, together with the observed safety and exploratory efficacy results, support further investigation of the current upadacitinib dosing regimen in future confirmatory Phase 3 clinical trials in children with AD.</div><div>Clinical Trial Number: NCT03646604, registered 2018-08-23</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 10","pages":"Pages 733-741"},"PeriodicalIF":3.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981913","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 and Tolerability of Anti–microRNA-328 Ophthalmic Solution, SHJ002, in Pediatric Subjects: First-in-Human Clinical Study","authors":"Jiunn-Liang Chen MD ,&nbsp;Wei-Yu Lai MD ,&nbsp;Reuy-Tay Lin MD ,&nbsp;Suh-Hang H. Juo MD, PhD ,&nbsp;Chung-Ling Liang MD, PhD","doi":"10.1016/j.clinthera.2024.08.015","DOIUrl":"10.1016/j.clinthera.2024.08.015","url":null,"abstract":"<div><h3>Purpose</h3><div>microRNA-328 has been reported as a risk factor for myopia development. SHJ002 is an antisense for microRNA-328, and SHJ002 was formulated as ophthalmic solution for a novel microRNA therapy. We aimed to investigate the safety and tolerability of SHJ002 ophthalmic solution in children.</div></div><div><h3>Methods</h3><div>This was a single-center, open-label, first-in-human trial in healthy children (NCT04928144). All subjects received the study medication. The trial had 2 stages. Stage 1 was an intrasubject dose-escalation study, and stage 2 was the highest tolerable dose study. The SHJ002 ophthalmic solution was instilled in a randomly selected study eye in each participant, whereas the other untreated eye served as a negative control. Three participants were assigned to stage 1, and they received eye drops of 3 concentrations (0.025%, 0.08%, and 0.25%), each of which was used for 3 consecutive days. The highest tolerable dose from stage 1 was used in stage 2 where another 9 participants were recruited for 28-day treatment. Ocular assessments, physical examination, and vital signs were measured to evaluate safety and tolerability.</div></div><div><h3>Findings</h3><div>There were 4 boys and 8 girls with a mean age of 12.3 years and a SD of 1.56. All participants were Asians. All 3 concentrations used in stage 1 were well tolerated, and the dose of 0.25% was used in stage 2. There were no reports of discomfort. There was only 1 mild adverse event (punctate keratitis) in the untreated eye in 1 participant, which was deemed as “unrelated to study drug.”</div></div><div><h3>Implications</h3><div>SHJ002 is a novel microRNA therapy that uses eye drop instillation. SHJ002 ophthalmic solution is generally safe and tolerable, which warrants further investigations in Phase II and III trials. ClinicalTrials.gov identifier: NCT04928144.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 10","pages":"Pages 768-772"},"PeriodicalIF":3.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145353","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":"Pediatric Drug Development: Lessons Learned to Shape the Future of Drug Development Strategies for Our Little Patients","authors":"Yuli Qian PhD","doi":"10.1016/j.clinthera.2024.09.017","DOIUrl":"10.1016/j.clinthera.2024.09.017","url":null,"abstract":"","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 10","pages":"Pages 730-732"},"PeriodicalIF":3.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364680","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":"Efficacy and Safety of Aflibercept and Ranibizumab in the Treatment of Retinopathy of Prematurity","authors":"Tiantian Yang MSc,&nbsp;Jing Zhang MD,&nbsp;Qingfei Hao MD,&nbsp;Shouhui Ma MBBS,&nbsp;Xiuyong Cheng MD","doi":"10.1016/j.clinthera.2024.08.011","DOIUrl":"10.1016/j.clinthera.2024.08.011","url":null,"abstract":"<div><h3>Purpose</h3><div>To compare the efficacy, recurrence rate, and recurrence interval of intravitreal injection of aflibercept (IVA) and ranibizumab (IVR) in patients with retinopathy of prematurity (ROP).</div></div><div><h3>Methods</h3><div>This is a single-center retrospective study of neonates hospitalized from January 2018 to March 2023 in the Department of Neonatology of the First Affiliated Hospital of Zhengzhou University who received intravitreal injection of anti-vascular endothelial growth factor owing to type 1 prethreshold ROP, threshold ROP, or aggressive posterior ROP. Clinical data were collected to record the cure, recurrence, number of injections, and side effects of ROP.</div></div><div><h3>Findings</h3><div>A total of 224 neonates (444 eyes) were enrolled in this study, of which 121 (241 eyes) received IVA and 103 (203 eyes) received IVR. There were no significant differences in the general characteristics of infants between the two groups (<em>P</em> &gt; 0.05). The corrected gestational age of the first injection was 37.27 ± 3.07 weeks in the IVA group and 37.20 ± 4.89 weeks in the IVR group (<em>P</em> = 0.582). The recurrence rate was 15.8% in the IVA group and 14.9% in the IVR group (<em>P</em> = 0.841). For relapsed infants, the postmenstrual age (PMA) was 34.89 ± 3.49 weeks in the IVA group and 35.28 ± 4.43 weeks in the IVR group at the first treatment. The PMA was 43.69 ± 4.57 and 40.96 ± 4.98 weeks at the second treatment in the IVA and IVR groups, respectively (<em>P</em> = 0.185). There were two children in the IVA group that required a third treatment, with PMAs of 58.71 and 57.29 weeks at the time of surgery, and one child in the IVR group, with a PMA of 43.14 weeks at the time of injection (<em>P</em> = 0.221). No complications were recorded in either group.</div></div><div><h3>Implications</h3><div>The efficacies of aflibercept and ranibizumab in treating ROP are similar, and the safety of the medications was good. Further research should be conducted in large-scale, prospective clinical trials, providing ophthalmologists with new options for the treatment of ROP.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 10","pages":"Pages 773-777"},"PeriodicalIF":3.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379232","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":"Venetoclax Clinical Pharmacokinetics After Administration of Crushed, Ground or Whole Tablets","authors":"","doi":"10.1016/j.clinthera.2024.03.012","DOIUrl":"10.1016/j.clinthera.2024.03.012","url":null,"abstract":"<div><h3>Purpose</h3><div>Venetoclax is a potent, orally bioavailable BCL-2 inhibitor used in the treatment of some hematological malignancies. Crushing tablets may be necessary to help with the administration of venetoclax to patients with swallowing difficulties or patients requiring nasogastric tube feeding. The study was conducted to assess the bioavailability of crushed and finely ground venetoclax tablets relative to whole tablets.</div></div><div><h3>Methods</h3><div>An open-label, randomized, 3-way, crossover study in 15 healthy adult females was conducted. Venetoclax tablets were administered orally in a crushed, ground or intact form on Day 1 of each period with water following a high-fat breakfast. Pharmacokinetic samples were collected up to 72 hours postdosing.</div></div><div><h3>Findings</h3><div>The crushed and ground tablets met the bioequivalence criteria (0.80–1.25) relative to the intact tablets with respect to area under the concentration-time curve to time of the last measurable concentration (AUC_t) and to infinite time (AUC_inf) but exhibited a slightly lower maximum plasma concentration (C_max). This was not considered clinically significant as only venetoclax overall exposure (AUC) has been shown to correlate with clinical efficacy. There was no change in the physical appearance and the evaluated physicochemical properties of crushed and ground venetoclax tablets after 72 hours of storage at 25°C/60% relative humidity.</div></div><div><h3>Implications</h3><div>Crushing or grinding venetoclax tablets before administration could be considered as a viable alternative method of administration for patients who have difficulty swallowing whole venetoclax tablets or patients requiring nasogastric tube feeding.</div></div><div><h3>ClinicalTrials.gov identifiers</h3><div>NCT05909553, registered June 12, 2023.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 10","pages":"Pages 752-758"},"PeriodicalIF":3.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086989","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":"Effect of Raloxifene Treatment on Apolipoproteins and Lipoprotein(a) Concentrations in Postmenopausal Women: A Meta-Analysis of Randomized Controlled Trials","authors":"Xinyi Liao ,&nbsp;Jian Deng ,&nbsp;Lei Du ,&nbsp;Benjamin Hernández-Wolters ,&nbsp;Kousalya Prabahar ,&nbsp;Hamed Kord-Varkaneh","doi":"10.1016/j.clinthera.2024.07.008","DOIUrl":"10.1016/j.clinthera.2024.07.008","url":null,"abstract":"<div><h3>Background and Aim</h3><div>Although various randomized controlled trials (RCTs) have evaluated the effect of raloxifene on apolipoproteins and lipoprotein(a) concentrations in postmenopausal women, the results have been inconsistent and inconclusive. Therefore, we conducted this meta-analysis of RCTs to investigate the effect of raloxifene administration on apolipoproteins and lipoprotein(a) [Lp(a)] concentrations in postmenopausal women.</div></div><div><h3>Methods</h3><div>Two independent researchers systematically searched the scientific literature (including PubMed/Medline, Scopus, Web of Science, and EMBASE) for English-language randomized controlled trials (RCTs) published up to June 2024. We included RCTs reporting the impact of raloxifene on apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), and Lp(a) levels in postmenopausal women. The primary outcome of interest was change in Lp(a), and the secondary outcomes were changes in ApoA-I and ApoB.</div></div><div><h3>Findings</h3><div>The present meta-analysis incorporated 12 publications with 14 RCT arms. The comprehensive outcomes derived from the random-effects model revealed a statistically significant increase in ApoA-I (WMD: 6.06 mg/dL, 95% CI: 4.38, 7.75, <em>P</em> &lt; 0.001) and decrease in ApoB concentrations (WMD: -8.48 mg/dL, 95% CI: -10.60, -6.36, <em>P</em> &lt; 0.001) and Lp(a) (WMD: -3.02 mg/dL, 95% CI: -4.83, -1.21, <em>P</em> &lt; 0.001) following the administration of raloxifene in postmenopausal women. In the subgroup analyses, the increase in ApoA-I and the decrease in ApoB and Lp(a) levels were greater in RCTs with a mean participant age of ≥60 years and a duration of ≤12 weeks.</div></div><div><h3>Implications</h3><div>The current meta-analysis of RCTs demonstrates that treatment with raloxifene reduces ApoB and Lp(a) levels while increasing ApoA-I levels in postmenopausal women. Since these effects on lipid components are associated with a reduced risk of cardiovascular disease (CVD), raloxifene could be a suitable therapy for postmenopausal women who are at an increased risk of CVD and have other medical indications for raloxifene administration.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 10","pages":"Pages 799-807"},"PeriodicalIF":3.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055163","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":"Weight Loss With Once-nightly Sodium Oxybate for the Treatment of Narcolepsy: Analysis From the Phase III Randomized study Evaluating the efficacy and SafeTy of a ONce nightly formulation of sodium oxybate (REST-ON) Trial","authors":"Thomas Roth PhD ,&nbsp;Anne Marie Morse DO ,&nbsp;Richard Bogan MD ,&nbsp;Asim Roy MD ,&nbsp;Jennifer Gudeman PharmD ,&nbsp;Yves Dauvilliers MD, PhD","doi":"10.1016/j.clinthera.2024.07.010","DOIUrl":"10.1016/j.clinthera.2024.07.010","url":null,"abstract":"<div><h3>Purpose</h3><div>Individuals with narcolepsy are more likely to be obese than the general population. Changes in weight-related measures with extended-release, once-nightly sodium oxybate (ON-SXB) and characteristics of participants with ≥5% weight loss were assessed in a Randomized study Evaluating the efficacy and SafeTy of a ONce nightly formulation of sodium oxybate (REST-ON) trial post hoc analysis.</div></div><div><h3>Methods</h3><div>REST-ON (NCT02720744) was a Phase III, double-blind, placebo-controlled, multicenter, randomized clinical trial. Participants aged ≥16 years with narcolepsy type 1 (NT1) or NT2 received ON-SXB or placebo for 13 weeks (week 1, 4.5 g; weeks 2–3, 6 g; weeks 4–8, 7.5 g; and weeks 9–13, 9 g). Weight and body mass index were measured at baseline and study end.</div></div><div><h3>Findings</h3><div>Weights were similar between groups at baseline (mean [SD]; ON-SXB, 81.2 [20.8] kg; N = 107 [NT1, n = 80; NT2, n = 27]; placebo, 82.1 [22.5] kg; N = 105 [NT1, n = 82; NT2, n = 23]). At week 13 (9 g), mean (SD) weight decreased 1.3 (3.6) kg with ON-SXB and increased 0.2 (2.6) kg with placebo; 17.8% (19/107; NT1, n = 14; NT2, n = 5) of participants receiving ON-SXB had ≥5% weight loss versus 3.8% receiving placebo (4/105; NT1, n = 3; NT2, n = 1; <em>P</em> = 0.001). At week 13, least squares mean (SE) body mass index change from baseline was ‒0.51 (0.13) kg/m² with ON-SXB and 0.08 (0.13) kg/m² with placebo (least squares mean difference [95% CI], −0.59 [−0.95 to −0.23] kg/m²; <em>P</em> = 0.001). Excessive daytime sleepiness improved for both groups with ON-SXB, the ≥5% weight-loss subgroup exhibited larger improvement in the Maintenance of Wakefulness Test and Epworth Sleepiness Scale versus the other subgroup (weight loss &lt;5%, no change, or weight gain) (Maintenance of Wakefulness Test, <em>P</em> = 0.019; Epworth Sleepiness Scale score, <em>P</em> &lt; 0.001).</div></div><div><h3>Implications</h3><div>Narcolepsy is often associated with obesity, which may increase cardiometabolic risks. ON-SXB, an effective treatment for excessive daytime sleepiness and cataplexy, may be preferred in overweight or obese individuals to provide a more tailored treatment approach.</div></div><div><h3>ClinicalTrials.gov identifier</h3><div>NCT02720744.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 10","pages":"Pages 791-798"},"PeriodicalIF":3.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995477","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":"The Effect of Rituximab on the Cognitive Function of Patients with Relapsing-Remitting Multiple Sclerosis","authors":"Masood Najafi Msc ,&nbsp;Ghasem Farahmand MD ,&nbsp;Pargol Balali MD ,&nbsp;Atefeh Behkar MD, MPH ,&nbsp;Mojtaba Shahbazi MD ,&nbsp;Negar Moradian MD ,&nbsp;Sara Pouyanmanouchehri MD ,&nbsp;Mohammad Hossein Harirchian MD ,&nbsp;Sara Ranji MD","doi":"10.1016/j.clinthera.2024.07.011","DOIUrl":"10.1016/j.clinthera.2024.07.011","url":null,"abstract":"<div><h3>Purpose</h3><div>Cognitive impairment can begin in the early stages of multiple sclerosis (MS). No medicine has been approved for treating cognitive impairment in MS patients. There is a lack of data on the role of rituximab in managing cognitive impairment in MS patients. Using minimal assessment of cognitive function in MS (MACFIMS), this study aims to investigate the effect of rituximab on the cognitive status of relapsing-remitting MS (RRMS) patients.</div></div><div><h3>Methods</h3><div>In this pre-post interventional trial, 28 eligible RRMS patients participated. They were administered rituximab for a year. Cognitive tests (MACFIMS), MS neuropsychological questionnaire (MSNQ), and Beck depression inventory-fast screen (BDI-FS) scores were evaluated at baseline, six, and 12 months following rituximab administration.</div></div><div><h3>Findings</h3><div>Eighteen participants with a mean age of 40.5 ± 12.91, 7 men, completed all three follow-ups. There was no statistically significant change in BDI-FS, MSNQ, Paced Auditory Serial Addition Test (<em>P</em>: 0.743), Symbol Digit Modalities Test (<em>P</em>: 0.711), Brief Visual Memory Test (BVMT) (<em>P</em>: 0.426), learning BVMT (<em>P</em>: 0.268), and delayed recall BVMT (<em>P</em>: 0.394) scores. However, the California Verbal Learning Test (CVLT), CVLT learning, and Controlled Oral Word Association Test scores significantly improved by 45.2% (<em>P</em> &lt; 0.001), 12.3% (<em>P</em>: 0.013), and 26.7% (<em>P</em>: 0.011), respectively, 6-month follow-up rituximab treatment. There was a significant improvement in CVLT (+55.7%, <em>P</em> &lt; 0.001), CVLT learning (+15.9%, <em>P</em>: 0.011), and delayed recall CVLT (+28%, <em>P</em>: 0.022) scores 12-month follow-up rituximab treatment.</div></div><div><h3>Implications</h3><div>Rituximab prevents cognitive deterioration and improves some cognitive functions. Further investigations with a larger sample size, longer follow-ups, and inclusion of a placebo or another treatment arm are recommended.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 10","pages":"Pages e1-e5"},"PeriodicalIF":3.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105140","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":"Dosing of Venetoclax in Pediatric Patients with Relapsed Acute Myeloid Leukemia: Analysis of Developmental Pharmacokinetics and Exposure-Response Relationships","authors":"Mohamed Badawi ,&nbsp;Sathej Gopalakrishnan ,&nbsp;Benjamin Engelhardt ,&nbsp;Tammy Palenski ,&nbsp;Seth E. Karol ,&nbsp;Jeffrey E. Rubnitz ,&nbsp;Rajeev Menon ,&nbsp;Ahmed Hamed Salem","doi":"10.1016/j.clinthera.2024.09.008","DOIUrl":"10.1016/j.clinthera.2024.09.008","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;This work aimed to characterize the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) to identify venetoclax doses to be administered to pediatric patients in the phase 3 study.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Data from 121 patients across three phase 1 studies enrolling pediatric patients with R/R malignancies were utilized to develop a population pharmacokinetic model to describe venetoclax pharmacokinetics in pediatric patients. Individual patient average venetoclax plasma concentration up to the event of interest, derived based on the population pharmacokinetics analysis, was used to evaluate the exposure-response relationships to efficacy (complete response) and safety (neutropenia and thrombocytopenia) endpoints for patients with AML who received venetoclax in combination with azacitidine, decitabine, or cytarabine (n = 36). The population pharmacokinetic model was then used to simulate exposures in pediatric age- and weight-based subgroups to identify the venetoclax doses for pediatric patients.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Findings&lt;/h3&gt;&lt;div&gt;The pharmacokinetic data were adequately described by the two-compartment population pharmacokinetic model with first-order absorption and elimination. The model accounted for cytochrome P450 3A developmental changes using a maturation function and incorporated allometric scaling to account for growth and body size effect. Weight was identified as a statistically significant covariate on clearance and volume of distribution and retained in the final model. Population pharmacokinetic estimates were comparable to previously reported estimates in adults. Exposure-response analyses suggested that the clinical efficacy of venetoclax in combination with high-dose cytarabine (HDAC) is maximized at 600 mg adult-equivalent, and higher doses are unlikely to enhance clinical efficacy. Venetoclax 600 mg adult-equivalent was selected for further development in combination with HDAC. Additionally, venetoclax 400 mg adult-equivalent was selected for bridging/maintenance therapy in combination with azacitidine. Flat exposure-response relationships were observed with Grade ≥3 neutropenia and thrombocytopenia. Doses were selected based on weight (allometric scaling) for children aged ≥2 years old and based on weight and CYP3A ontogeny for children aged &lt;2 years. The selected age- and weight-based dosing scheme of venetoclax is projected to achieve venetoclax exposures in pediatric subgroups comparable to those observed in adults receiving venetoclax 400 mg or 600 mg.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Implications&lt;/h3&gt;&lt;div&gt;This work characterized the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients and guided the selection of pediatric dosing regimens in support of the venetoclax phase 3 trial in pediatric AML (NCT05183035).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Clinical Studies&lt;/h3&gt;&lt;div&gt;","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 10","pages":"Pages 759-767"},"PeriodicalIF":3.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379230","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":"Lessons Learned From Clinical Studies in Centronuclear Myopathies: The Patient Perspective—A Qualitative Study","authors":"","doi":"10.1016/j.clinthera.2024.03.008","DOIUrl":"10.1016/j.clinthera.2024.03.008","url":null,"abstract":"<div><h3>Background</h3><div>Since 2014, several clinical studies focusing on centronuclear myopathies have been conducted, including a prospective natural history study, a gene transfer clinical trial and a clinical trial using an antisense oligonucleotide. Dedicated patient organizations have played an important role in this process. The experience of members of these organizations, either as a study participant, parent or as a patient organization member communicating with the sponsors are potentially very informative for future trial design.</div></div><div><h3>Methods</h3><div>We investigated the burden of and the lessons learned from the first natural history studies and clinical trials from a patient perspective using a qualitative approach. We arranged 4 focus groups with a total of 37 participants from 3 large international patient organizations: ZNM-ZusammenStark!, the Myotubular Trust, and the MTM-CNM Family Connection. 4 themes, based on a systematic literature search were discussed: Expectations and preparation, Clinical study participation, Communication and Recommendations for future clinical trials. The focus group recordings were transcribed, anonymized, and uploaded to Atlas-ti version 8.1 software. The data were analyzed using a thematic content analysis.</div></div><div><h3>Results</h3><div>Overall, participants were realistic in their expectations, hoping for small improvements of function and quality of life. The realization that trial participation does not equate to a treatment was challenging. Participating in a clinical study had a huge impact on many aspects of daily life, both for patients and their immediate families. First-hand insights into the burden of the design and its possible effect on performance were provided, resulting in numerous compelling recommendations for future clinical studies. Furthermore, participants stressed the importance of clear communication, which was considered to be especially vital in cases of severe adverse events. Finally, while patients were understanding of the importance of adhering to the regulations of good clinical practice, they indicated that they would strongly appreciate a greater understanding and/or acknowledgment of the patient perspective and a reflection of this perspective in future clinical trial design.</div></div><div><h3>Conclusion</h3><div>The acknowledgment and inclusion of patients’ perspectives and efficient and effective communication is expected to improve patient recruitment and retention in future clinical studies, as well as more accurate assessment of the patient performance related to suitable planning of the study visits.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"46 10","pages":"Pages 742-751"},"PeriodicalIF":3.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140763181","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}