Clinical Drug Investigation最新文献

{"title":"Recommendations on Drug Selection and Dose Adjustment for Patients with Liver Cirrhosis: Results from a Multidisciplinary Expert Panel.","authors":"Katharina Karsten Dafonte, Philipp Lutz, Christian Jansen, Marika Busse, Peter Dietrich, Katrin Farker, Hans-Peter Lipp, Jacob Nattermann, Tilman Sauerbruch, Sven Schmiedl, Dorothea Strobach, Jonel Trebicka, Dario Zocholl, Gunther Hartmann, Ulrich Jaehde, Martin Coenen","doi":"10.1007/s40261-026-01536-0","DOIUrl":"10.1007/s40261-026-01536-0","url":null,"abstract":"<p><strong>Background and objectives: </strong>Liver cirrhosis profoundly alters pharmacokinetics and is frequently associated with medication-related problems. Stage-specific dosing guidance remains inconsistent, and prescribing information often lacks clarity. As a result, treatment decisions rely on individual clinical judgement and may differ between professional groups. This study assessed drug-selection and dose-adjustment practices among hepatologists, clinical pharmacologists, and clinical pharmacists, quantified consensus across Child-Pugh stages, and evaluated alignment with prescribing information as a basis for harmonised dosing guidance.</p><p><strong>Methods: </strong>Twelve experts from hepatology, clinical pharmacology, and clinical pharmacy evaluated prioritised drugs for patients with liver cirrhosis across Child-Pugh stages A-C in a structured survey. For each drug, experts indicated whether they would apply no dose adjustment, modify the dose, or avoid administration. Consensus was defined as at least 75% agreement, and interrater agreement was assessed by pairwise percentage agreement. Consensus recommendations were compared with the dosing information provided in each drug's Summary of Product Characteristics.</p><p><strong>Results: </strong>Consensus or strong consensus was achieved for only 20% of 177 recommendations, mainly for no dose adjustment or avoidance. Agreement decreased with disease severity (Child-Pugh A 83%; B 47%; C 41%). Of 36 consensus recommendations, 18 matched the summary of product characteristics, while six diverged from it. Pharmacists and clinical pharmacologists more often recommended dose adjustments, especially in Child-Pugh B and C, whereas hepatologists preferred standard dosing or avoidance.</p><p><strong>Conclusions: </strong>Expert recommendations for dosing in cirrhosis showed marked variability and limited concordance with prescribing information, underscoring the need for harmonised interdisciplinary guidance integrating pharmacokinetic evidence and clinical feasibility.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"377-390"},"PeriodicalIF":3.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12999791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147431300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preventing Contrast-Induced Acute Kidney Injury in Egyptian Patients Undergoing Coronary Angiography: A Randomized Controlled Trial.","authors":"Sarah Sabry, Mai K Ammar, Mahmoud Taeima, Noha Nassar, Azza ElFiky, Ayman Saleh","doi":"10.1007/s40261-026-01524-4","DOIUrl":"10.1007/s40261-026-01524-4","url":null,"abstract":"<p><strong>Background and objectives: </strong>Contrast-induced acute kidney injury (CI-AKI) observed after coronary angiography (CAG) requires preventive strategies guided by clinical judgment. Evidence is still lacking regarding the prevention of CI-AKI in patients undergoing coronary angiography. This study aimed to compare the effect of a high dose of N-acetylcysteine (NAC) plus preprocedural hydration, a high dose of atorvastatin (HDS) plus preprocedural hydration, or preprocedural hydration alone on the prevention of CI-AKI in patients undergoing elective coronary angiography.</p><p><strong>Methods: </strong>A prospective multi-armed randomized comparative study was conducted on elective patients undergoing CAG. Patients were randomly assigned to either control group [n = 40], who received hydration with 0.9% saline started just before contrast media injection and continued for 12 h at a rate 1.0 mL/kg/min after angiography; NAC group [n = 40], who received oral NAC 1200 mg daily started 5 days before angiography and good hydration; or HDS group [n = 40], receiving one oral dose of atorvastatin 80 mg 24 h before angiography and good hydration. CI-AKI was defined as an increase in serum creatinine of > 25% of baseline or an absolute increase of 0.5 mg/dL above baseline after 48 h. Incidence of CI-AKI and incidence of complications were assessed for all groups.</p><p><strong>Results: </strong>The study included 120 patients. The incidence of CI-AKI was [32.5%] in the control group, [20%] in the NAC group, and [12.5%] in the HDS group. The incidence of CI-AKI was significantly lower in the high-dose statin group compared with the control group (risk ratio = 1.658; 95% CI 1.050-2.433). In-hospital clinical outcomes showed no statistical significance among the three groups.</p><p><strong>Conclusions: </strong>Both NAC and high-dose statins may reduce CI-AKI incidence in patients undergoing CAG, with statins showing more promising results. These findings support prophylactic strategies for CI-AKI prevention in high-risk patients undergoing CAG. In-hospital outcomes were comparable.</p><p><strong>Clinical trial registration: </strong>Clinical-Trials.gov (ID; NCT06139952, Date; December 2023).</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"467-477"},"PeriodicalIF":3.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12999647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146212310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of Baricitinib on Nail Alopecia Areata: A 48-Week Single-Center Retrospective Study.","authors":"Michela Starace, Francesca Pampaloni, Federico Quadrelli, Giulia Olivoni, Stephano Cedirian, Luca Rapparini, Francesca Bruni, Bianca Maria Piraccini","doi":"10.1007/s40261-026-01533-3","DOIUrl":"10.1007/s40261-026-01533-3","url":null,"abstract":"<p><strong>Background: </strong>Alopecia areata (AA) is a chronic autoimmune disorder characterized by non-scarring hair loss, which may extend to total scalp (AA totalis) or whole-body hair loss (AA universalis). Nail involvement, though often underestimated, occurs in up to 66% of cases, especially in severe forms and in children.</p><p><strong>Objective: </strong>This retrospective study evaluated the efficacy of baricitinib 4 mg/day, a Janus kinase 1/2 inhibitor, in treating nail manifestations associated with severe AA.</p><p><strong>Methods: </strong>Thirty-seven patients with very severe AA (Severity of Alopecia Tool [SALT] score > 50) and nail involvement were treated with baricitinib for 48 weeks. Nail changes assessed included trachyonichia, pitting, leukonychia, and others. Clinical assessments were performed at baseline and at 12, 24, 36, and 48 weeks using the SALT score, onychoscopy, and the Clinician Reported Outcome (ClinRO) for nail appearance.</p><p><strong>Results: </strong>A significant improvement in both hair regrowth and nail abnormalities has been shown. The mean SALT score decreased from 100 to 16.3, and the average number of affected nails reduced from 6.4 to 2.1 (p < 0.001). ClinRO scores also significantly improved (p < 0.001). However, the correlation between hair and nail improvement was weak and not statistically significant (r = 0.15, p = 0.6). This suggests differential responsiveness of hair and nail units.</p><p><strong>Conclusions: </strong>The findings support baricitinib as a promising treatment for nail involvement in AA, highlighting the need for routine nail assessment and development of more refined evaluation tools. Limitations include small sample size and lack of long-term data.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"447-453"},"PeriodicalIF":3.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147282481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of the Safety Profile of the Triple Monoamine Reuptake Inhibitor Dasotraline Based on Clinical Trial Data and Disproportionality Analyses of Four Related Pharmacological Classes Using Real-World Data from the FDA Adverse Event Reporting System.","authors":"Solomiya Gumenyuk, Ajay Ogirala, Steven T Szabo, Kenneth Koblan, Seth C Hopkins, Mike Ufer","doi":"10.1007/s40261-026-01525-3","DOIUrl":"10.1007/s40261-026-01525-3","url":null,"abstract":"<p><strong>Background and objectives: </strong>The safety profile of single or dual monoamine reuptake inhibitors (MRIs) is based on longstanding post-marketing experience but remains to be established for triple MRIs that may exhibit favorable efficacy as treatment of psychiatric disorders. Here, we characterized the safety profile of the triple MRI dasotraline based on disproportionality analyses and clinical trial data.</p><p><strong>Methods: </strong>The Food and Drug Administration Adverse Event Reporting System was queried for adverse events of commonly prescribed selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine reuptake inhibitors (NRIs), and norepinephrine-dopamine reuptake inhibitors (NDRIs). Bayesian disproportionality analyses were conducted to determine the Empirical Bayes Geometric Mean (EBGM) for each Medical Dictionary for Regulatory Activities (MedDRA^®) preferred term (PT) within each drug class. Five randomized, double-blind, placebo-controlled Phase 2/3 studies with dasotraline were utilized to determine the pooled incidence of disproportionally reported PTs (EBGM ≥3) on dasotraline and placebo.</p><p><strong>Results: </strong>A total of 1087, 940, 409, and 714 PTs with an EBGM ≥3 were identified for SSRIs, SNRIs, NRIs, and NDRIs, respectively. The cumulative pooled incidence of these class-related PTs was approximately 2- to 2.5-fold higher for dasotraline than placebo (SSRIs: 24.7%/9.6%; SNRIs: 50.7%/26.3%; NRIs: 56.5%/32.2%; NDRIs: 35.2%/18.2%).</p><p><strong>Conclusions: </strong>The safety profile of the triple MRI dasotraline was not distinct from pharmacologically related classes indicated by a consistently higher incidence of class-related adverse events compared to placebo in randomized, controlled clinical trials. Bayesian disproportionality analyses utilizing post-marketing data from established drug classes can provide meaningful information for qualitative safety evaluation of drugs in clinical development.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov identifiers: </strong>NCT01692782, NCT02428088, NCT02276209, NCT02564588, NCT03107026.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"455-465"},"PeriodicalIF":3.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146200264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics, Safety Profile, and Tolerability of MN-08 Tablets after Single and Multiple Ascending Doses in Healthy Chinese Volunteers.","authors":"Enyue Yang, Mingxin Chen, Mingji Wu, Qi Dong, Jinhua Li, Honglan Xu, Baoju Qu, Huazi Zhang, Zhehu Jin, Guantong Li, Mei Jing, Zaijun Zhang, Gaoxiao Zhang, Hongxin Piao","doi":"10.1007/s40261-026-01522-6","DOIUrl":"10.1007/s40261-026-01522-6","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objective: &lt;/strong&gt;Pulmonary arterial hypertension is a rare, progressive pulmonary vascular disease with limited therapeutic options. MN-08, a nitrate derivative of memantine, is under development for pulmonary arterial hypertension. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of MN-08 in healthy Chinese volunteers following single- and multiple-dose administration.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A phase I, single-center, randomized, double-blind, placebo-controlled study was conducted using dose-escalation designs for both single ascending doses (6-132 mg, n = 69) and multiple ascending doses (12-36 mg twice daily for 7 days, n = 30), and a crossover design for the food effect evaluation (24 mg, n = 18), with an 8-day wash-out interval between periods. Healthy Chinese volunteers aged 18-45 years were enrolled. Safety was monitored continuously from screening through to the end of the study, with adverse events recorded throughout. The study endpoints were the pharmacokinetic parameters of MN-08 following single-dose, multiple-dose, and high-fat/high-calorie breakfast administration. All pharmacokinetic parameters were performed using a non-compartmental analysis with Phoenix WinNonlin&lt;sup&gt;®&lt;/sup&gt; Version 8.2 (Certara USA, Inc., Princeton, NJ, USA).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;After a single dose of MN-08, the median time to maximum plasma concentration was 3.0-6.1 h and the mean half-life was 20.8-30.9 h. The mean maximum plasma concentration was 3.5-95.0 ng/mL. The mean area under the concentration-time curve (AUC) from the time of dosing to the last quantifiable concentration was 84-3428 h·ng/mL and the AUC from zero to infinity was 114-3618 h·ng/mL across all doses. In the multiple ascending dose study, the median time to maximum plasma concentration was 4.6-5.8 h and the half-life was 26.9-31.7 h. The mean maximum plasma concentration was 31.6-132.9 ng/mL. The mean AUC from the time of dosing to the last quantifiable concentration was 1291-5770 h·ng/mL and the AUC from zero to infinity was 1371-6237 h·ng/mL. Consumption of a high-fat and high-calorie meal had a minor effect on the peak concentration of MN-08. Drug accumulation was observed in the multiple ascending dose study and the mean accumulation index ranged from 3.76 to 4.33. There was no significant trend indicative of a sex effect. MN-08 was well tolerated in these healthy subjects. All adverse events were mild or moderate and no drug-related serious adverse events were reported.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;MN-08 exhibited favorable pharmacokinetic characteristics and a good safety and tolerability profile in healthy Chinese subjects across the evaluated dose range. These findings support the progression of MN-08 to phase II studies for the treatment of pulmonary arterial hypertension in Chinese patients.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Clinical trial registration: &lt;/strong&gt;ChiCTR.org.cn identifier number ChiCTR2000","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"391-406"},"PeriodicalIF":3.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147282597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Over-the-Counter Product Use Among Individuals with Vitiligo: A Cross-Sectional International Survey.","authors":"N O Enwereji, O C Opaigbeogu, A Geisler, M S Ceresnie, N C Ezekwe, N Elbuluk, Richard H Huggins","doi":"10.1007/s40261-026-01531-5","DOIUrl":"10.1007/s40261-026-01531-5","url":null,"abstract":"<p><strong>Background and objectives: </strong>Vitiligo is challenging to treat and may have a substantial impact on quality of life. Despite the exponential growth in the development of new \"traditional\" vitiligo treatments, many vitiligo patients choose to employ medical products and practices that are used with or instead of standard medical care (complementary and alternative medicine or CAM). In this study, CAMs and camouflage were discussed together and referred to as over-the-counter products (OTCs). Using an observational cross-sectional study, we aimed to investigate the motivations and demographic factors of individuals with vitiligo who use OTCs, to identify the most utilized OTCs in this population, and to assess side effects and perceived efficacy of the utilized OTCs.</p><p><strong>Methods: </strong>We performed an international observational cross-sectional study between July 2021 and June 2022. An anonymous digital questionnaire was distributed to adults (aged ≥ 18 years) who had been diagnosed with vitiligo by a healthcare provider via e-mails from the Global Vitiligo Foundation to vitiligo support groups and through postings on the MyVitiligoTeam social media network. Participants were presented with a predefined list of OTC products and an open-ended option was also provided.</p><p><strong>Results: </strong>Of the 224 respondents, half were aged 45-64, most were female (69.6%), and the majority were White (56.3%). A total of 41.1% of participants used OTCs, either exclusively (19.2%) or with prescribed therapies (22%), while 58.9% used only prescribed therapies. The top reasons for using OTCs were dissatisfaction with conventional therapy, concerns about side effects, inconvenience, and cost. The most commonly used OTCs were camouflage, Vitamin B12, Vitamin D, zinc, ginkgo biloba, and vitamin C. Camouflage was reported as the most helpful OTC. Mild side effects were reported by 6.3% of users.</p><p><strong>Conclusion: </strong>This study highlights the widespread use of OTCs in managing vitiligo, emphasizing the need for healthcare providers to be familiar with commonly used OTCs. Patients using OTCs raised concerns about conventional treatments, which should be considered in management discussions and drug development. Camouflage was the most beneficial OTC in this study, and it should be included in management plans. A better understanding of OTCs could improve treatment strategies and patient satisfaction.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"407-414"},"PeriodicalIF":3.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discrete Choice Experiment (DCE) as a Tool to Elicit Patient Preferences in a Complex Benefit-Risk Evaluation: A Case Study.","authors":"Jian-Yu E, Shahrul Mt-Isa, Kimberley Hockley, Kexin Zhu, Stephanie Tcherny-Lessenot, Juhaeri Juhaeri","doi":"10.1007/s40261-025-01519-7","DOIUrl":"10.1007/s40261-025-01519-7","url":null,"abstract":"<p><strong>Background and objectives: </strong>Discrete choice experiment (DCE) is increasingly recognized for its utility to elicit patient preferences in benefit-risk (BR) evaluation, particularly when options entail complex tradeoffs. This rimonabant case study focused on the methodology and versatility of DCE to elicit patient preferences for anti-obesity drugs. This study aimed to demonstrate the application of DCE as a tool to capture patient preferences concerning the BR profile of rimonabant, focusing on attribute-based choices, preference elicitation, experimental design, quantitative analysis, and practical application.</p><p><strong>Methods: </strong>A DCE was conducted involving standard steps: identifying attributes and levels, constructing choice sets, designing the questionnaire, and analyzing responses. Two benefit and three risk attributes important to the BR profile of anti-obesity drugs were selected based on their significance to patients from published literature. Responses were analyzed using probit regression to quantify the preference for each attribute. Preference weights, derived from DCE, were combined with efficacy and safety data from clinical trials to estimate the utility function and probability of treatment selection. Lastly, the generated marginal rates of substitution (MRS) were used to present the extent to which patients were willing to trade off benefits to avoid risks.</p><p><strong>Results: </strong>The coefficients from the probit model indicated that psychiatric conditions (i.e., mild anxiety to severe depression) significantly impacted treatment preference, followed by cardiovascular conditions, weight loss, and gastrointestinal conditions. On average, rimonabant was preferred over placebo 67% of the time. On the basis of MRS, to avoid a 1% increase of psychiatric condition, patients would be willing to forgo a 3.9% reduction in number of people achieving 10% weight loss, or a 0.44 level of improvement in high-density lipoprotein cholesterol, which elucidates how patients value benefits and risks when deciding on a treatment.</p><p><strong>Conclusions: </strong>This case study reaffirmed the utility of DCE as a valuable tool for BR evaluations, which aligned with what patients deemed important. The case study demonstrated essential attributes for anti-obesity medications. The methodological rigor and flexibility of DCE provided a robust framework for understanding, quantifying and analyzing preferences. The integration of elicited patient preferences, utility functions, and relevant clinical data offered quantitative insights into the structured BR assessment for regulatory decision-making and beyond.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"343-352"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12950029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, Tolerability, and Pharmacokinetics of Subcutaneous Extended-Release Injectable Olanzapine in Patients with Schizophrenia and Schizoaffective Disorder.","authors":"Irina Cherniakov, Avia Merenlender Wagner, Roy Eshet, Ryan Tiver, David Bibi, Itay Perlstein, Attila Kalmanczhelyi, Nir Sharon, Gadi Cohen, Kristina Ferderber, James Roberts, Anna Elgart, Dikla Gutman, Laura Rabinovich-Guilatt","doi":"10.1007/s40261-025-01507-x","DOIUrl":"10.1007/s40261-025-01507-x","url":null,"abstract":"<p><strong>Background and objective: </strong>This study evaluated the pharmacokinetics (PK), safety, and tolerability of TV-44749 in patients with schizophrenia or schizoaffective disorder. TV-44749 is a novel, long-acting, subcutaneous (SC) olanzapine injection designed to leverage the benefits of long-acting injectable treatment, reduce the risk for post-injection delirium/sedation syndrome (PDSS), and maintain the efficacy of olanzapine.</p><p><strong>Methods: </strong>In this open-label phase I study, patients completed an oral olanzapine treatment period followed by administration of TV-44749 single doses (SD cohort; 318 mg, 425 mg, or 531 mg) or multiple doses (MD cohort; three consecutive monthly doses of 283 mg or 566 mg). For the SD cohort, the follow-up period was up to 84 days (i.e., day 85) after TV-44749 administration. Patients in the MD cohort received TV-44749 on days 1, 29, and 57 over an 84-day treatment period and were followed until the end of the study. Evaluations included PK, adverse events (AEs), clinical assessments, and injection-site pain.</p><p><strong>Results: </strong>A total of 71 (SD, 42; MD, 29) patients each received ≥ 1 dose of TV-44749. Both cohorts had overall similar baseline characteristics. Following subcutaneous administration, TV-44749 reached clinically relevant plasma concentrations (≥ 10 ng/mL) within 1-2 days, with a maximum observed plasma drug concentration (Cmax) within 11-14 days, followed by a sustained release profile over the dosing period of 1 month. The mean beta half-life values ranged from 5 to 10 days, and the mean apparent terminal half-life range was 11-17 days. The systemic exposure (Cmax and area under the plasma concentration-time curve (AUC)) of olanzapine and its two major metabolites, 10N‑glucuronide and N-desmethyl olanzapine, increased in an approximate dose-proportional manner over the clinically relevant dose range of 283 mg through 566 mg. The relative bioavailability of TV-44749 SD and MD compared with oral olanzapine after single or multiple doses was 112% (90% confidence interval (CI) 97, 129%) and 95% (90% CI 86, 106%), respectively. There were no grade ≥3 adverse events, no serious treatment-related adverse events, no suspected or confirmed post-injection delirium/sedation syndrome events, and no deaths.</p><p><strong>Conclusion: </strong>TV-44749 administration resulted in a sustained release profile and comparable exposure to daily therapeutic doses of oral olanzapine over a monthly dosing interval. The TV-44749 systemic safety profile was consistent with approved oral olanzapine. The local tolerability was acceptable, and there were no PDSS events. These results contributed to the dose selection of TV-44749 in a phase III study evaluating its efficacy and safety in adults with schizophrenia (SOLARIS; NCT05693935).</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"307-320"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12950048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cost-Consequences Analysis of Biologic Treatments for Moderate-to-Severe Crohn's Disease Using Real-World Transition Probability and Cost Data in Thailand.","authors":"Thanaboon Chaemsupaphan, Onuma Sattayalertyanyong, Khachen Kongpakwattana, Nichcha Subdee, Pritsana Chuenprapai, Julajak Limsrivilai","doi":"10.1007/s40261-026-01526-2","DOIUrl":"10.1007/s40261-026-01526-2","url":null,"abstract":"<p><strong>Background and objectives: </strong>The treatment goal for patients with Crohn's disease (CD) is sustained clinical, biochemical, and endoscopic remission, with biologic therapy often necessary in moderate-to-severe cases. This study aimed to evaluate the value of biologic agents in moderate-to-severe CD in Thailand by assessing cost consequences using real-world transition probabilities and cost data.</p><p><strong>Methods: </strong>A published decision tree combined with a Markov model was adapted to estimate 2-year health outcomes, healthcare resource utilization, and cost implications of treatment options (conventional therapy, overall biologic therapies, infliximab, vedolizumab, and ustekinumab) for moderate-to-severe CD. The base-case analysis used a 2-year time horizon. Key input parameters, including transition probabilities and costs, were obtained from real-world data at Siriraj Hospital, a tertiary hospital in Thailand, while efficacy and safety data were sourced from relevant published literature. Uncertainty was assessed through scenario analyses and one-way sensitivity analyses varying input parameters across plausible ranges.</p><p><strong>Results: </strong>Overall, biologics demonstrated superior health outcomes compared to conventional therapy, with a higher remission rate (number needed to treat = 4) and reduced healthcare resource utilization, including lower hospitalization (absolute risk reduction; ARR = 135.3%) and fewer CD-related surgeries (ARR = 40.5%), although with a higher incidence of adverse drug reactions. Among biologic-naïve patients, infliximab was the most effective agent, with a cost-saving of 171,213 Thai baht compared to conventional therapy. Scenario and sensitivity analyses revealed consistent findings, with infliximab consistently dominating in biologic-naïve patients. Cost-effectiveness analyses demonstrated that infliximab dominated conventional therapy among biologic-naïve patients, while conventional therapy remained most cost-effective in biologic-exposed patients.</p><p><strong>Conclusions: </strong>Biologic therapy improved outcomes and reduced healthcare use compared with conventional therapy, but cost considerations remain crucial. Infliximab was most effective and cost-saving in biologic-naïve patients, whereas conventional therapy remained most cost effective in biologic-exposed patients. These real-world findings support treatment decisions for moderate-to-severe CD in Thailand.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"293-305"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ContraIndicator: A Natural Language Processing-Based Approach to Potential Drug-Drug Interaction Detection in Pediatric Intensive Care.","authors":"Pradeep Singh, Akshaya Devadiga, Ridam Pal, Pranam R Betrabet, Jhuma Sankar, Tavpritesh Sethi, Rakesh Lodha","doi":"10.1007/s40261-026-01529-z","DOIUrl":"10.1007/s40261-026-01529-z","url":null,"abstract":"<p><strong>Background and objectives: </strong>The intricate nature of pediatric patients' physiology and the frequent administration of multiple medications in pediatric intensive care units expose hospitalized patients to potential drug-drug interactions. Therefore, this study aimed to examine and characterize clinically relevant drug-drug interactions in pediatric patients admitted to intensive care units, leveraging artificial intelligence to enhance their identification and management.</p><p><strong>Methods: </strong>Prescription data from pediatric intensive care unit admissions were analyzed using ContraIndicator, a natural language processing-based framework developed for the identification of potential drug-drug interactions. Medication information extracted from prescription records was evaluated against the DDInter database, and its clinical relevance was determined using the severity ratings of the database (major, moderate, and minor). Using univariate and multivariate logistic regression, the associations between severity and age, as well as between severity and the number of prescribed medications, were investigated.</p><p><strong>Results: </strong>The examination of 8010 prescriptions for 899 hospitalized patients identified 3884 potential drug-drug interactions. The most frequent interacting drug pairs were midazolam + fluconazole, fluconazole + fentanyl, fentanyl + dexamethasone, and vancomycin + piperacillin. Among the 49.6% (446) of pediatric patients who had at least one interaction (major, moderate, or minor), 38.8% (173) had a major potential drug-drug interaction. In this investigation, a higher number of prescribed drugs was significantly linked with a higher incidence of potential drug-drug interactions (odds ratio: 12.79; 95% confidence interval: 8.26-20.6; p < 0.001).</p><p><strong>Conclusions: </strong>The study suggests that potential drug-drug interactions are frequent in pediatric intensive care units. The majority of these interactions were moderate, followed by major severity. There is a statistically significant association between the quantity of drugs provided and the prevalence of potential drug-drug interactions. The findings of this study could aid in planning and executing future studies, as well as in monitoring and preventing potential drug-drug interactions in patients receiving intensive care. This study introduces ContraIndicator, a graphical user interface that presents empirical findings and promotes awareness regarding potential drug-drug interactions.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"331-341"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146178156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}