Clinical therapeutics最新文献

{"title":"Toxic Epidermal Necrolysis Observed in a Patient With the HLA-B*1502 Treated With Levofloxacin.","authors":"Xiufang Wang, Gangying Cheng, Xiaofang Liang, Junhui Yang, Aiping Deng, Dan Chen, Chao Liu, Ying Gao, Juyi Li","doi":"10.1016/j.clinthera.2024.09.014","DOIUrl":"https://doi.org/10.1016/j.clinthera.2024.09.014","url":null,"abstract":"<p><strong>Purpose: </strong>To determine the relationship between HLA-B gene mutations and levofloxacin-induced toxic epidermal necrolysis (TEN).</p><p><strong>Methods: </strong>A 71-year-old Chinese woman developed TEN after oral administration of solifenacin (5 mg) and levofloxacin (0.5 g) for cystitis. HLA-B*5801 and HLA-B*1502 alleles were detected using real-time PCR.</p><p><strong>Findings: </strong>After supportive therapy (antiallergic treatments, plasma exchange, etc) and withdrawal of the culprit medication levofloxacin, the patient was discharged with re-epithelialization of the exfoliated skin. The patient was HLA-B*1502 allele positive and HLA-B*5801 allele negative.</p><p><strong>Implications: </strong>This is the first report of levofloxacin-induced TEN suspected to be caused by mutations in the HLA-B*1502 allele.</p>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364682","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":"Impact of Preliminary Bronchodilator Dose in Chronic Obstructive Pulmonary Disease Patients With Suboptimal Peak Inspiratory Flow.","authors":"Mohamed Ismail Hassan, Nabila Ibrahim Laz, Yasmin M Madney, Mohamed E A Abdelrahim, Hadeer S Harb","doi":"10.1016/j.clinthera.2024.09.016","DOIUrl":"https://doi.org/10.1016/j.clinthera.2024.09.016","url":null,"abstract":"<p><strong>Purpose: </strong>Suboptimal peak inspiratory flow rate (PIFR) is highly prevalent in patients with chronic obstructive pulmonary disease (COPD) owing to the mismatch of their PIFR with the corresponding inhaler-device resistance. This study aimed to investigate the impact of a preliminary dose of pressurized metered dose inhalers (pMDIs) on patients with COPD with suboptimal PIFR using Diskus dry powder inhalers (DPIs).</p><p><strong>Methods: </strong>A prospective, randomized, case-control study included 24 patients with COPD. PIFR was measured using the In-Check Dial G16 with low-to-medium resistance. Spirodoc was used to measure baseline spirometric data and compare it before and 30 minutes after the administration of Diskus DPI. On a different day, the study dose was given to each suboptimal patient by the same aerosol generator with preceded 2 puffs of salbutamol pMDI and re-evaluated for spirometric parameters 30 minutes after the study dose.</p><p><strong>Findings: </strong>There was a significant difference between the optimal and suboptimal groups in peak expiratory flow (2.38 ± 1.20 vs 1.49 ± 1.06 L/s, P = 0.050). PIFR showed a statistically significant difference between the optimal and suboptimal groups (71.66 ± 6.15 vs 41.25 ± 9.79 L/min, P < 0.0001). There was a significant difference in forced vital capacity (ΔFVC) between optimal and suboptimal groups without a preliminary dose (0.42 ± 0.21 vs 0.16 ± 0.11 L, P = 0.002), forced expiratory volume in 6 seconds (ΔFEV₆) (0.53 ± 0.49 vs 0.17 ± 0.11 L, P = 0.022), forced expiratory volume in 3 seconds (ΔFEV₃) (0.41 ± 0.38 vs 0.1 ± 0.16 L, P = 0.013), forced expiratory volume in 1 second (ΔFEV₁)/FVC (-2.38 ± 8.41 vs 2.96% ± 2.95%, P = 0.033), and ΔFEV₁/FEV₆ (-4.32 ± 11.23 vs 2.91% ± 4.35%, P = 0.015). There was a significant difference in ΔFVC between optimal and suboptimal groups with a preliminary dose (0.42 ± 0.21 vs 0.23 ± 0.18 L, P = 0.046), ΔFEV₁/FVC (-2.38 ± 8.41 vs 5.67% ± 6.53%, P = 0.009), ΔFEV₁/FEV₆ (-4.32 ± 11.23 vs 5.16% ± 4.99%, P = 0.008), and forced expiratory time (ΔFET) (0.28 ± 0.45 vs -0.31 ± 0.70 seconds, P = 0.022). The only parameter that showed a significant difference between suboptimal groups without and with a preliminary dose is Δ peak expiratory flow (0.24 ± 0.59 vs 0.65 ± 0.68 L/s, P = 0.004).</p><p><strong>Implications: </strong>Administering a preliminary dose of pMDI can minimally enhance the effectiveness of DPIs in patients with COPD with suboptimal PIFR and health outcomes.</p>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364679","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 Randomized Placebo-Controlled Trial of Leronlimab in Mild-To-Moderate COVID-19.","authors":"Harish Seethamraju, Otto O Yang, Richard Loftus, Onyema Ogbuagu, Daniel Sammartino, Ali Mansour, Jonah B Sacha, Sohita Ojha, Scott G Hansen, Arvin Cyrus Arman, Jacob P Lalezari","doi":"10.1016/j.clinthera.2024.08.019","DOIUrl":"https://doi.org/10.1016/j.clinthera.2024.08.019","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Purpose: &lt;/strong&gt;Early in the course of the SARS-CoV-2 pandemic it was hypothesised that host genetics played a role in the pathophysiology of COVID-19 including a suggestion that the CCR5-Δ32 mutation may be protective in SARS-CoV-2 infection. Leronlimab is an investigational CCR5-specific humanized IgG4 monoclonal antibody currently in development for HIV-1 infection. We aimed to explore the impact of leronlimab on the severity of disease symptoms among participants with mild-to-moderate COVID-19.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The TEMPEST trial was a randomized, double-blind, placebo-controlled study in participants with mild-to-moderate COVID-19. Participants were randomly assigned in a 2:1 ratio to receive subcutaneous leronlimab (700 mg) or placebo on days 0 and 7. The primary efficacy endpoint was assessed by change in total symptom score based on fever, myalgia, dyspnea, and cough, at end of treatment (day 14).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Overall, 84 participants were randomized and treated with leronlimab (n = 56) or placebo (n = 28). No difference was observed in change in total symptom score (P = 0.8184) or other pre-specified secondary endpoints between treatments. However, in a post hoc analysis, 50.0% of participants treated with leronlimab demonstrated improvements from baseline in National Early Warning Score 2 (NEWS2) at day 14, compared with 20·8% of participants in the placebo group (post hoc; p = 0.0223). Among participants in this trial with mild-to-moderate COVID-19 adverse events rates were numerically but not statistically significantly lower in leronlimab participants (33.9%) compared with placebo participants (50.0%).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Implications: &lt;/strong&gt;At the time the TEMPEST trial was designed although CCR5 was known to be implicated in COVID-19 disease severity the exact pathophysiology of SARS-CoV-2 infection was poorly understood. Today it is well accepted that SARS-CoV-2 infection in asymptomatic-to-mild cases is primarily characterized by viral replication, with a heightened immune response, accompanied by diminished viral replication in moderate-to-severe disease and a peak in inflammatory responses with excessive production of pro-inflammatory cytokines in critical disease. It is therefore perhaps not surprising that no differences between treatments were observed in the primary endpoint or in pre-specified secondary endpoints among participants with mild-to-moderate COVID-19. However, the results of the exploratory post hoc analysis showing that participants in the leronlimab group had greater improvement in NEWS2 assessment compared to placebo provided a suggestion that leronlimab may be associated with a lower likelihood of people with mild-to-moderate COVID-19 progressing to more severe disease and needs to be confirmed in other appropriately designed clinical trials.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Clinicaltrials: &lt;/strong&gt;gov number, NCT04343651 https://classic.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Clinicaltrials: &lt;/strong&gt;gov/","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364678","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":"Response to Letter Regarding Article, \"Pancreatitis and Pancreatic Cancer Risk Among Patients with Type 2 Diabetes Receiving Dipeptidyl Peptidase 4 Inhibitors: An Updated Meta-Analysis of Randomized Controlled Trials\".","authors":"Adili Tuersun, Munire Mohetaer, Munire Tuerhong, Guanxin Hou, Gang Cheng","doi":"10.1016/j.clinthera.2024.09.002","DOIUrl":"https://doi.org/10.1016/j.clinthera.2024.09.002","url":null,"abstract":"","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343083","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 Retrospective Cross-Sectional Analysis of the Humanistic and Economic Burden of Bipolar I Disorder.","authors":"Larry Culpepper, Ashley Martin, Amanda Harrington, Sally W Wade, Mousam Parikh","doi":"10.1016/j.clinthera.2024.08.003","DOIUrl":"https://doi.org/10.1016/j.clinthera.2024.08.003","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Purpose: &lt;/strong&gt;This study quantified the burdens of bipolar I disorder (BP-I) by examining patient characteristics, health-related quality of life (HRQoL), health care resource utilization (HCRU), and costs of patients with versus without BP-I. Additionally, these outcomes were assessed across BP-I severity levels.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A retrospective, cross-sectional analysis of the 2020 National Health and Wellness Survey was conducted. Adults who self-reported a physician diagnosis of BP-I were assigned to the BP-I cohort, with severity-specific subgroups (mild, moderate, severe) created for analysis. A separate cohort of participants without BP-I or MDD was used for comparison. Exclusion criteria included a schizophrenia diagnosis. Bivariate analyses compared demographic and socioeconomic characteristics between cohorts. HRQoL (Short Form-36v2 Health Survey [SF36v2] mental and physical component scores, EuroQol Five-Dimension Visual Analogue Scale [EQ-5D VAS]), HCRU (health care provider visits, emergency department visits, hospitalizations), and annualized costs (direct and indirect) were evaluated for participants with versus without BP-I as well as across BP-I severity subgroups using multivariate analyses adjusted for key baseline differences. Because BP-I is often misdiagnosed as MDD, outcomes were evaluated in a subgroup of participants with MDD who according to the Mood Disorder Questionnaire screened as having probable BP-I (ie, potentially misdiagnosed BP-I) and were compared with the BP-I severity subgroups.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Cohorts included 818 participants with BP-I (mild = 336, moderate = 285, severe = 197) and 53,021 participants without BP-I. Participants with BP-I reported significantly lower HRQoL scores on the SF-36v2 and EQ-5D VAS (all measures, P &lt; 0.001), and increasing BP-I severity was predictive of declining HRQoL. Participants with BP-I had significantly greater HCRU (all measures, P &lt; 0.05) than participants without BP-I and increasing BP-I severity was associated with greater HCRU versus the mild BP-I cohort (all measures, P &lt; 0.05). Participants with BP-I incurred significantly greater total direct (P &lt; 0.01) and indirect (P &lt; 0.001) costs versus participants without BP-I. Direct costs were incrementally higher across BP-I severity, while indirect costs were high across all groups but did not differ significantly. Participants with potentially misdiagnosed BP-I (n = 302) had similar HRQoL to those with mild-to-moderate BP-I and similar HCRU and direct costs to those with mild BP-I.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Implications: &lt;/strong&gt;These results demonstrate the substantial clinical and economic burdens associated with BP-I, and these negative impacts generally increase with BP-I severity. The study also suggests that despite not having the diagnosis of BP-I, burdens of potentially misdiagnosed patients are similar to those with mild-to-moderate BP-I. Together, these results reveal substan","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343081","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":"Comment on \"Pancreatitis and Pancreatic Cancer Risk Among Patients With Type 2 Diabetes Receiving Dipeptidyl Peptidase 4 Inhibitors: An Updated Meta-Analysis of Randomized Controlled Trials\".","authors":"Yuki Nakano, Kazuki Adachi, Kazumasa Kotake","doi":"10.1016/j.clinthera.2024.08.021","DOIUrl":"https://doi.org/10.1016/j.clinthera.2024.08.021","url":null,"abstract":"","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343082","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":"Oncology Dose Selection in Subsequent Indications: What Can We Learn From FDA-approved Oncology Drugs?","authors":"Huy X Ngo, Elise Oh, Chunze Li, Jiajie Yu","doi":"10.1016/j.clinthera.2024.08.020","DOIUrl":"https://doi.org/10.1016/j.clinthera.2024.08.020","url":null,"abstract":"<p><strong>Purpose: </strong>The modern oncology drug development landscape has shifted away from traditional cytotoxic chemotherapies. Following their initial approvals, many oncology drugs have been approved in subsequent indications either as monotherapy or in combination to benefit a broader patient population. To date, dose selection strategies for subsequent indications have not been systematically reviewed. This review examines how approved dosing regimens were selected in subsequent indications for FDA-approved oncology drugs.</p><p><strong>Methods: </strong>The Drugs@FDA database was used to identify FDA-approved new molecular entities (NMEs) between 2010 and 2023. NMEs with more than 1 approved indication were included in the analysis. In total, the dosing regimens for 67 novel oncology drugs that obtained FDA approvals for multiple indications were evaluated.</p><p><strong>Findings: </strong>Overall, in subsequent indications, 72% of NMEs used the same or clinically equivalent alternative dosing regimens to those approved in the initial indications. Amongst the 28% of NMEs that used different dosing regimens, safety/tolerability was the leading cause of a dosing regimen changes in both monotherapy and combination therapy settings. Other factors leading to changes in dosing regimens include differences in tumor biology, disease burden, pharmacokinetics, and overall benefit-risk profiles obtained from dose-finding studies.</p><p><strong>Implications: </strong>Our analysis highlighted the importance of selecting a safe, tolerable, and yet efficacious dosing regimen for the initial indication as a suboptimal initially approved regimen could lead to dosing regimen changes in later indications. Preclinical and clinical data could be leveraged to understand the pharmacology, pharmacokinetic, and pharmacodynamic differences between indications and thus support dose selection in subsequent indications.</p>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281582","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":"Differences in Drug Poisonings Among Those Who Identify as Transgender Compared to Cisgender: An Analysis of the Toxicology Investigators Consortium (ToxIC) Core Registry, United States 2017-2021.","authors":"Kristine Magnusson, Emily Glidden, Desiree Mustaquim, Laura E Welder, Erin K Stokes, Gillian A Beauchamp, Marna R Greenberg, Kim Aldy, Richard J Mazzaccaro, Beth A Careyva, Judith N Sabino, Derek J Fikse, Katelyn McLain, Alexandra M Amaducci","doi":"10.1016/j.clinthera.2024.08.018","DOIUrl":"https://doi.org/10.1016/j.clinthera.2024.08.018","url":null,"abstract":"<p><strong>Purpose: </strong>In this manuscript, the abbreviation TG is defined as persons who identify as transgender, GNC is defined as persons who identify as gender nonconforming, and CG is defined as persons who identify as cisgender. TG and GNC (e.g., nonbinary), are those whose gender identity and sex assigned at birth do not align, as opposed to CG. This study describes drug poisonings among TG, GNC, and CG captured in the Toxicology Investigators Consortium (ToxIC) Core Registry during 2017-2021.</p><p><strong>Methods: </strong>Authors conducted a secondary data analysis of medical toxicology physician consultations involving intentional exposures (i.e., use with the knowledge of the exposed person) within the ToxIC Core Registry from 2017 through 2021. Demographic characteristics, exposure intent, and reported drug classes are reported by gender identity and sex assigned at birth.</p><p><strong>Findings: </strong>From a total of 15,800 medical toxicology consultations, 213 (1.3%) involved both TG (n = 187, 1.2%) and GNC (n = 26, 0.2%), and 15,587 (98.7%) involved CG. Among TG, 128 (68.8%) were transgender men, 58 (31.2%) transgender women. Sixty-two percent of TG/GNC (n = 132) and 34.8% of CG (n = 5,428) were aged ≤18 years. Reported intent for exposure (i.e., self-harm and misuse/harmful use) differed proportionally across both sexes assigned at birth and gender identity among transgender men and cisgender men.</p><p><strong>Implications: </strong>In the ToxIC Core Registry, the consultations varied proportionally by age group across TG/GNC and CG, with more than half of TG/GNC aged ≤18 years. The proportion of consultations also varied by intent across TG/GNC and CG. Further research to delineate differences between TG/GNC and CG could increase knowledge in prevention, assessment, and treatment of drug poisonings in this population.</p>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281581","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":"The Totality of Evidence for SDZ-deno: A Biosimilar to Reference Denosumab.","authors":"Barbara Vogg, Johann Poetzl, Arnd Schwebig, Susmit Sekhar, Alan Kivitz, Natalia Krivtsova, Oliver Renner, Jean-Jacques Body, Richard Eastell","doi":"10.1016/j.clinthera.2024.08.007","DOIUrl":"https://doi.org/10.1016/j.clinthera.2024.08.007","url":null,"abstract":"<p><strong>Purpose: </strong>Sandoz biosimilar denosumab (GP2411 [SDZ-deno]; Jubbonti/Wyost) is approved by the US FDA, EMA and Health Canada for all indications of reference denosumab (REF-deno; Prolia/Xgeva), a fully human IgG2κ monoclonal antibody that binds with high affinity and specificity to receptor activator of nuclear factor kappa-B ligand (RANKL). Denosumab blocks RANKL, preventing bone resorption and loss of bone density/architecture in conditions characterized by excessive bone loss such as osteoporosis in postmenopausal women and metastatic bone disease, among others.</p><p><strong>Methods: </strong>This narrative review summarizes the totality of evidence (ToE) for SDZ-deno that supported its approval as Jubbonti/Wyost in the EU and US.</p><p><strong>Findings: </strong>Analytical evaluation indicated that SDZ-deno has high purity and structural homology with REF-deno. SDZ-deno also demonstrated similar binding affinities, size and charge variants, and disulfide isoforms to REF-deno, and did not trigger clinically meaningful antibody-dependent cellular cytotoxicity. In clinical evaluation, SDZ-deno was similar to REF-deno in pharmacokinetics (PK) and pharmacodynamics (PD) in a 39-week Phase I study in 502 healthy male participants, and to REF-deno in a 72-week Phase III study in 527 postmenopausal women with osteoporosis. In both studies, the 90% and 95% confidence intervals (for PK and PD endpoints, respectively) of the geometric mean ratios for AUC_inf, C_max (and AUC_last in the Phase I study; PK endpoints), and area under the effect versus time curve of percent change from baseline in serum carboxy-terminal crosslinked telopeptide of type I collagen (PD endpoint), were fully contained within the prespecified equivalence margins (0.80, 1.25). The Phase III study also demonstrated SDZ-deno is similar in efficacy to REF-deno in postmenopausal women with osteoporosis, as the difference in percent change from baseline in lumbar spine bone mineral density at week 52 between REF-deno and SDZ-deno was fully contained within the prespecified equivalence margins (-1.45, 1.45). SDZ-deno was well tolerated in both studies. As the ToE has established biosimilarity of SDZ-deno and REF-deno, extrapolation to all indications is justified based on the common mechanism of action and the comparable PK, safety, and immunogenicity across all indications.</p><p><strong>Implications: </strong>The ToE for SDZ-deno suggests it will be an effective biosimilar to REF-deno, and its lower unit price is anticipated to increase the number of appropriate patients who will benefit.</p>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and Pharmacodynamics of a Fixed-Dose Combination of Esomeprazole and Magnesium Hydroxide Compared to the Enteric-Coated Esomeprazole.","authors":"Yoonjin Kim, Sungyeun Bae, Inseung Jeon, Jihoon Kwon, Sung Hee Hong, Na Young Kim, Kyung-Sang Yu, In-Jin Jang, SeungHwan Lee","doi":"10.1016/j.clinthera.2024.08.006","DOIUrl":"https://doi.org/10.1016/j.clinthera.2024.08.006","url":null,"abstract":"<p><strong>Purpose: </strong>A fixed-dose combination (FDC) of proton pump inhibitors (PPIs) and antacid salts enables rapid acid suppression through the neutralizing effect of the antacid salt and the rapid absorption of PPIs. This study aimed to compare the pharmacokinetics (PKs) and pharmacodynamics (PDs) of a recently formulated FDC of esomeprazole and magnesium hydroxide to the enteric-coated esomeprazole in healthy subjects.</p><p><strong>Methods: </strong>A randomized, open-label, multiple-dose, two-treatment, two-way crossover design was conducted in healthy subjects. Forty-nine subjects were randomized to one of the two treatment sequences and received either the test drug (esomeprazole/magnesium hydroxide 40/350 mg) or reference drug (enteric-coated esomeprazole 40 mg) for 7 days in the first period and the alternative in the second period with a 14-day washout period. Blood samples were collected for up to 24 hours for PK assessment, and 24-hour gastric pH monitoring was conducted for PD assessment both before and after a single administration, as well as at a steady state after seven consecutive days of administration. The PK and PD parameters were compared between the two drugs.</p><p><strong>Findings: </strong>After multiple administrations, the median value of time to reach maximum concentration was faster in the test drug than in the reference drug, with a difference of 1.68 hours. The overall systemic exposure of the test drug was similar to that of the reference drug, and the PK parameter fell within the equivalence criteria. The test drug demonstrated a shorter time to reach gastric pH ≥ 4 compared to the reference drug (P = 0.0463). A decrease from baseline in integrated gastric acidity over 24 hours, which represents the degree of inhibition of gastric acid secretion, was equivalent between the two drugs.</p><p><strong>Implications: </strong>The fixed-dose combination of esomeprazole and magnesium hydroxide showed rapid absorption and quicker gastric acid suppression than enteric-coated esomeprazole with comparable PK and PD properties.</p><p><strong>Clinicaltrials: </strong>gov identifier: NCT04324905 (https://classic.</p><p><strong>Clinicaltrials: </strong>gov/ct2/show/NCT04324905).</p>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281584","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}