Clinical Drug Investigation最新文献

{"title":"Single‑Dose Pharmacokinetics and Safety of the Oral Galectin‑3 Inhibitor, Selvigaltin (GB1211), in Participants with Hepatic Impairment.","authors":"Vassilios Aslanis, Michael Gray, Robert J Slack, Fredrik R Zetterberg, Dimitar Tonev, De Phung, Becky Smith, Brian Jacoby, Hans Schambye, Zahari Krastev, Anna-Lena Ungell, Bertil Lindmark","doi":"10.1007/s40261-024-01395-7","DOIUrl":"10.1007/s40261-024-01395-7","url":null,"abstract":"<p><strong>Background and objectives: </strong>Selvigaltin (GB1211), an orally available small molecule galectin-3 inhibitor developed as a treatment for liver fibrosis and cirrhosis, was evaluated to assess the effect of hepatic impairment on its pharmacokinetics and safety to address regulatory requirements.</p><p><strong>Methods: </strong>GULLIVER-2 was a Phase Ib/IIa three-part study. Parts 1 and 3 had single-dose, open-label designs assessing pharmacokinetics (plasma [total and unbound] and urine), safety, and tolerability of 100 mg oral selvigaltin in participants with moderate (Child-Pugh B, Part 1) or severe (Child-Pugh C, Part 3) hepatic impairment, compared with healthy-matched participants (n = 6 each).</p><p><strong>Results: </strong>All participants received selvigaltin and completed the study. No adverse events were reported. The median time to reach maximum total plasma concentration following drug administration was of 3.49 and 4.00 h post-dose for Child-Pugh B and C participants, respectively; comparable with controls. Total plasma exposure was higher for participants with hepatic impairment compared with controls. Whilst maximum plasma concentration (C_max) was unaffected in Child-Pugh B participants, area under the plasma concentration-time curve from time zero to infinity (AUC_∞) increased by ~ 1.7-fold compared with controls, and half-life was prolonged (geometric mean 28.15 vs 16.38 h). In Child-Pugh C participants, C_max increased by ~ 1.3-fold, AUC_∞ increased by ~ 1.5-fold, and half-life was prolonged (21.05 vs 16.14 h). No trend was observed in plasma unbound fractions or urinary excretion of unchanged selvigaltin in either group.</p><p><strong>Conclusion: </strong>Hepatic impairment increased selvigaltin exposure without safety concerns. These data can inform dose recommendations for future clinical programmes.</p><p><strong>Trial registration: </strong>Clinicaltrials.gov NCT05009680.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"773-787"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364688","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":"Correction to: PB006: A Natalizumab Biosimilar.","authors":"Matt Shirley","doi":"10.1007/s40261-024-01388-6","DOIUrl":"10.1007/s40261-024-01388-6","url":null,"abstract":"","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"729"},"PeriodicalIF":2.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119145","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":"The Effect of Placebo on Pruritus in Patients with Chronic Urticaria: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials.","authors":"Peiwen Xue, Haiyan Qin, Di Qin, Yunzhou Shi, Huijing Li, Tian Luo, Caiyun Shi, Yeliu Wang, Zihao Zhao, Wei Cao, Zihao Zou, Qian Yang, Rongjiang Jin, Juan Li, Xianjun Xiao","doi":"10.1007/s40261-024-01389-5","DOIUrl":"10.1007/s40261-024-01389-5","url":null,"abstract":"<p><strong>Background: </strong>The anti-pruritic effect of placebo in patients with chronic urticaria has gained increasing attention in clinical research. However, the extent of placebo effect and its influencing factors in the treatment of chronic urticaria are not well understood.</p><p><strong>Objective: </strong>The objective of this systematic review and meta-analysis was to investigate the effect of placebo on pruritus in patients with chronic urticaria and to explore relevant influencing factors.</p><p><strong>Methods: </strong>PubMed, Embase, Web of Science, Cochrane Library, and PsycINFO were searched from inception to 10 July, 2024. Primary outcome included pruritus scores. The secondary outcomes focused on global symptoms and quality of life. Subgroup analyses and meta-regression analyses were conducted based on drug types, sample size, participants' age, and other variables. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system and a trial sequential analysis were employed to establish the reliability of evidence.</p><p><strong>Results: </strong>A total of 65 eligible publications (including 67 randomized controlled trials) involving 10,704 patients with chronic urticaria were included. The pruritus scores decreased following placebo treatment (moderate evidence). In addition, favorable results were observed in global symptoms (moderate evidence) and quality of life (low evidence) after placebo treatment. Subgroup analyses indicated that the type of active medication in intervention groups was an influencing factor of placebo effect of pruritus. Meta-regression analyses demonstrated that the anti-pruritic effect of placebo was inversely correlated with sample size and positively correlated with participants' age. A trial sequential analysis provided further support for the anti-pruritic effect of placebo.</p><p><strong>Conclusions: </strong>A substantial improvement of pruritus after placebo treatment was observed in patients with chronic urticaria. The anti-pruritic effect of placebo varied with sample size, participants' age, and type of active medication used. Future research should further investigate the effect size of placebo and clarify the potential mechanism.</p><p><strong>Prospero registration: </strong>The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) as CRD42023482608.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"635-654"},"PeriodicalIF":2.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145310","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":"Correction to: AVT04: An Ustekinumab Biosimilar.","authors":"Hannah A Blair","doi":"10.1007/s40261-024-01385-9","DOIUrl":"10.1007/s40261-024-01385-9","url":null,"abstract":"","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"731"},"PeriodicalIF":2.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016509","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":"The Cost Effectiveness of Adjunctive Treatments for Proton Pump Inhibitor-Refractory Gastroesophageal Reflux Disease.","authors":"Ulysses S Rosas, Christopher V Almario, Kyung-Sang Yu, Brennan M R Spiegel","doi":"10.1007/s40261-024-01387-7","DOIUrl":"10.1007/s40261-024-01387-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Half of patients with gastroesophageal reflux disease (GERD) experience persistent symptoms while on proton pump inhibitors (PPIs), thus driving efforts to develop novel adjunctive therapies for PPI-refractory GERD. An economic analysis was performed to establish at what cost and efficacy such potential medications are likely to become cost effective in clinical practice.</p><p><strong>Methods: </strong>A Markov decision model was used to examine a hypothetical cohort of patients being evaluated for PPI-refractory GERD in the USA. The model compared 3 strategies: (1) usual care (i.e., upfront diagnostic testing with upper endoscopy ± ambulatory pH testing); (2) use of a PPI-adjunctive therapy after positive ambulatory pH testing; and (3) empiric use of a PPI-adjunctive therapy (i.e., diagnostic testing only after failing empiric treatment). The primary outcome was incremental cost per quality-adjusted life year (QALY) gained (third-party payer perspective) over a 10-year time horizon using a willingness to pay threshold of $100,000/QALY.</p><p><strong>Results: </strong>In two-way sensitivity analyses varying the cost and effectiveness of the PPI-adjunctive therapy, most combinations revealed that use of the medication after positive pH testing was the most cost-effective approach. Empiric treatment was the preferred strategy only when the therapy was highly efficacious (≥ 87.5% response rate) and low cost (≤ $109/month). Use of PPI-adjunctive treatments were not cost effective when the cost exceeded $1150/month.</p><p><strong>Conclusion: </strong>Use of PPI-adjunctive therapies in those with persistent GERD symptoms may become cost effective when guided by ambulatory pH tests. These data can guide investigators, industry, and payers as they develop, validate, and price new treatments for PPI-refractory GERD.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"703-714"},"PeriodicalIF":2.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145309","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":"Efficacy and Safety of Topical Roflumilast for the Treatment of Psoriasis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.","authors":"Rafaela de Moraes-Souza, Regina Chahine Chater, Izabela Pera Calvi, Yasmin Mesquita, Rubiana Sarto, Izadora Lapenda, Lívia Figueiredo Pereira, Luana Moury, Pedro Herranz-Pinto","doi":"10.1007/s40261-024-01368-w","DOIUrl":"10.1007/s40261-024-01368-w","url":null,"abstract":"<p><strong>Background and objective: </strong>Plaque psoriasis is commonly treated topically with glucocorticoids and vitamin D derivatives. However, potential side effects such as skin atrophy underscore the need for safe and effective alternative topical therapies. Recently, the US Food and Drug Administration (FDA) and Health Canada approved roflumilast 0.3% cream as an option for treating this disease. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to assess the efficacy and safety of topical roflumilast 0.3% compared with vehicle for plaque psoriasis.</p><p><strong>Methods: </strong>PubMed, Embase, ClinicalTrials.gov, and Cochrane databases were searched from inception to 1 May 2024, assessing the outcomes of Investigator's Global Assessment (IGA) or body-IGA success (clear or almost clear status plus an at least 2-grade improvement from baseline), Psoriasis Area and Severity Index (PASI)-50, PASI-75, PASI-90, intertriginous-IGA success (clear or almost clear status on the intertriginous-IGA plus an at least 2-grade improvement from baseline), and adverse events (AEs). Statistical analysis was performed using Review Manager, R software, and RStudio. Heterogeneity was determined using the Cochran Q test and I² statistics.</p><p><strong>Results: </strong>Four RCTs were included, comprising a total of 1403 patients, of whom 885 (63.1%) received topical roflumilast 0.3% and 518 (36.9%) received vehicle. At week 8, the achievement of IGA or body-IGA success was significantly higher among those treated with topical roflumilast than in the vehicle group [relative risk (RR) 5.07; 95% confidence interval (CI) 3.55-7.23; p < 0.01]. Similar findings were observed at week 8 for PASI-50 (RR 2.73; 95% CI 2.27-3.29; p < 0.01), PASI-75 (RR 4.48; 95% CI 2.26-8.89; p < 0.01), and PASI-90 (RR 5.61; 95% CI 2.57-12.25; p < 0.01). Corresponding outcomes were found at weeks 2, 4, and 6. Additionally, a higher percentage of patients treated with topical roflumilast 0.3% once daily achieved intertriginous-IGA success, compared with those receiving vehicle, at week 8 (71.9% versus 20.5%; RR 3.32; 95% CI 2.11-5.22; p < 0.01), with similar findings at weeks 2, 4, and 6. While a significant difference was observed in the overall incidence of AEs between the topical roflumilast and vehicle groups, there was no difference in treatment-related AEs, serious AEs, or AEs leading to study discontinuation.</p><p><strong>Conclusion: </strong>These findings support the superiority of topical roflumilast 0.3% over vehicle and suggest its use as a valuable asset for the treatment of plaque psoriasis.</p><p><strong>Protocol registration: </strong>International Prospective Register of Systematic Reviews (PROSPERO), CRD42023456494.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"655-665"},"PeriodicalIF":2.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016511","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-Effectiveness Analysis of Newborn Screening for Spinal Muscular Atrophy in Italy.","authors":"Gianni Ghetti, Francesco Saverio Mennini, Andrea Marcellusi, Matthias Bischof, Gabriele Maria Pistillo, Marika Pane","doi":"10.1007/s40261-024-01386-8","DOIUrl":"10.1007/s40261-024-01386-8","url":null,"abstract":"<p><p>BACKGROUND AND OBJECTIVE: Untreated spinal muscular atrophy (SMA) is the leading genetic cause of death in children younger than 2 years of age. Early detection through newborn screening allows for presymptomatic diagnosis and treatment of SMA. With effective treatments available and reimbursed by the National Health Service, many regions in Italy are implementing newborn screening for SMA. We evaluated the cost effectiveness of universal newborn screening for SMA in Italy.</p><p><strong>Methods: </strong>A decision-analytic model assessed the cost effectiveness of newborn screening from the National Health Service perspective in 400,000 newborns. Newborn screening enabling early identification and presymptomatic treatment of SMA was compared with no newborn screening, symptomatic diagnosis, and treatment. Transition probabilities between health states were estimated from clinical trial data. Higher-functioning health states were associated with increased survival, higher utility values, and lower costs. Long-term survival and utilities were extrapolated from scientific literature. Health care costs were collected from official Italian sources. A lifetime time horizon was applied, and costs and outcomes were discounted at an annual rate of 3%. Deterministic and probabilistic sensitivity analyses were conducted.</p><p><strong>Results: </strong>Newborn screening followed by presymptomatic treatment yielded 324 incremental life-years, 390 incremental quality-adjusted life-years, and reduced costs by €1,513,375 over a lifetime time horizon compared with no newborn screening. Thus, newborn screening was less costly and more effective than no newborn screening. Newborn screening has a 100% probability of being cost effective, assuming a willingness-to-pay threshold of > €40,000.</p><p><strong>Conclusions: </strong>Newborn screening followed by presymptomatic SMA treatment is cost effective from the Italian National Health Service perspective.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"687-701"},"PeriodicalIF":2.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016510","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":"Disability and Adverse Effects of Oral Versus Long-Acting Injectable Antipsychotics in Schizophrenia-Spectrum and Bipolar Disorder: A Comparison Based on Data-Driven Taxonomy.","authors":"Alessandro Rodolico, Sofia Francesca Aprile, Pierfelice Cutrufelli, Gabriele Privitera, Sabrina Castellano, Carmen Concerto, Rosaria Furnari, Claudia Savia Guerrera, Ludovico Mineo, Giuseppe Alessio Platania, Antonino Petralia, Filippo Caraci, Maria Salvina Signorelli","doi":"10.1007/s40261-024-01391-x","DOIUrl":"10.1007/s40261-024-01391-x","url":null,"abstract":"<p><strong>Background: </strong>Patients undergoing antipsychotic treatment for psychiatric disorders may experience challenges in functioning, either stemming from the severity of the illness or from the tolerability issues of prescribed medications.</p><p><strong>Objectives: </strong>The aims of this cross-sectional study are to investigate the impact of adverse effects of antipsychotic drugs on patients' daily life functioning, comparing oral and long-acting injectable (LAI) antipsychotics, and further dividing antipsychotics by receptor-binding profiles based on recently defined data-driven taxonomy.</p><p><strong>Methods: </strong>This study involved patients with schizophrenia and bipolar spectrum disorders taking oral or LAI antipsychotics. Disability and functioning levels were assessed using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS), and the adverse effects of medications were evaluated using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale and its subscales.</p><p><strong>Results: </strong>The total sample consisted of 126 participants with a diagnosis of schizophrenia-spectrum or bipolar disorder, and included 54 males and 72 females ranging from 18 to 78 years of age (mean 45.1, standard deviation 14); 78 patients were taking oral antipsychotics and 48 were taking LAI antipsychotics, with subcategories of muscarinic (31), adrenergic/low dopamine (25), serotonergic/dopaminergic (23), dopaminergic (1), LAI muscarinic (15), LAI adrenergic (6), and LAI serotonergic/dopaminergic (25). The UKU total score for adverse effects showed significant correlations with WHODAS total score (ρ = 0.475; p < 0.001). Compared with oral antipsychotics, LAIs showed significantly lower scores in psychological (p = 0.014), autonomic (p = 0.008), other (p = 0.004), and sexual adverse effects (p = 0.008), as well as the UKU total score (p = 0.002). The Kruskal-Wallis test showed a significant difference in adverse effects between LAI and oral muscarinic subgroups, with LAIs having lower scores compared with antipsychotics binding to muscarinic receptors (p = 0.043).</p><p><strong>Conclusion: </strong>These findings indicate clinically relevant differences in adverse effects among formulations, warranting further investigation for future observational studies.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"715-727"},"PeriodicalIF":2.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281358","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":"Risk of Congenital Anomalies with Dolutegravir-Based Anti-retroviral Regimens: A Systematic Review and Meta-analysis.","authors":"Shuvasree Payra, Divya Harsha, Keshav Kumar, Pramod Kumar Manjhi, Shruti Singh, Rajesh Kumar, Sunil Kumar Singh, Alok Kumar, Vikas Maharshi","doi":"10.1007/s40261-024-01390-y","DOIUrl":"10.1007/s40261-024-01390-y","url":null,"abstract":"<p><strong>Background and objectives: </strong>Dolutegravir has been used as a first-line anti-human immunodeficiency virus drug because of its better efficacy compared with other counterpart medicines. However, making a unanimous decision on its use during pregnancy has become difficult for stakeholders following congenital anomalies reported with its use. The objective of this systematic review and meta-analysis was to study the risk of congenital anomalies in newborns exposed to dolutegravir-based-regimens compared with those exposed to non-dolutegravir-based regimens during the antenatal period.</p><p><strong>Methods: </strong>An extensive literature search was performed in MEDLINE (through PubMed), EMBASE, Cochrane Database of Systematic Reviews, Google Scholar, and ClinicalTrials.gov until 30 November, 2023. Studies reporting data on congenital anomalies following antenatal use of dolutegravir were included. Risk of bias for randomized controlled trials, non-randomized controlled trials, and observational studies was assessed using RoB2, ROBINS-I, and ROBINS-E tools, respectively. A meta-analysis was performed in 'RevMan 5.4.1' using a random-effects model. Heterogeneity was assessed by the 'Q' statistic and I² value. A sensitivity analysis was performed for higher heterogeneity/high-risk studies. The study protocol was registered in PROSPERO [CRD42023446374] a priori.</p><p><strong>Results: </strong>Of 26 eligible studies, 12 (six randomized controlled trials and six observational studies with a pooled sample of 32,617) were included in a meta-analysis and 14 in a qualitative synthesis only. The meta-analysis does not show a statistically significant difference in the risk of congenital anomalies between newborns exposed antenatally to dolutegravir-based regimen(s) and those exposed to non-dolutegravir-based regimens [risk ratio 1.10; 95% confidence interval 0.79-1.53; p = 0.59]. Heterogeneity was moderate (I² = 47%). Pooled results for randomized controlled trials and observational studies separately and the sensitivity analysis for heterogeneity provided similar results.</p><p><strong>Conclusions: </strong>The risk of congenital anomalies was not significantly different between dolutegravir-based regimens and non-dolutegravir-based-regimens in newborns exposed during their antenatal period.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"667-685"},"PeriodicalIF":2.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281370","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 and Pharmacodynamics of Nipocalimab, a Neonatal Fc Receptor Blocker, in Healthy Japanese Volunteers.","authors":"Nobuko Matsushima, Sayori Shibata, Jocelyn H Leu, An Vermeulen, Jay Duffner, Leona E Ling, Lisa B Schwartz, Hideo Harigae","doi":"10.1007/s40261-024-01380-0","DOIUrl":"10.1007/s40261-024-01380-0","url":null,"abstract":"<p><strong>Background and objectives: </strong>Nipocalimab is a high-affinity, fully human, effectorless immunoglobulin G1 monoclonal antibody targeting the neonatal Fc receptor and is currently under evaluation for the treatment of rare and prevalent immunoglobulin G autoantibody-mediated and alloantibody-mediated diseases. This phase I, randomized, double-blind, placebo-controlled, single-dose escalation study in healthy Japanese volunteers (N = 24) assessed the safety, pharmacokinetics, and effect on the serum immunoglobulin G level of single doses of nipocalimab.</p><p><strong>Methods: </strong>Volunteers were grouped into three cohorts and received intravenous nipocalimab at 10, 30, or 60 mg/kg or placebo. To complement the study, genetic variation in the Fcγ receptor and transporter subunit of the neonatal Fc receptor was analyzed in Japanese and diverse populations.</p><p><strong>Results: </strong>Nipocalimab was generally safe and well tolerated at all dose levels, with three (12.5% [3/24]) volunteers experiencing treatment-emergent adverse events across all nipocalimab doses. Mean serum immunoglobulin G levels decreased in a dose-dependent manner from baseline with nipocalimab treatment compared with placebo. Maximum serum nipocalimab concentrations demonstrated proportional increases with dose, while the area under the concentration-time curve was dose dependent and demonstrated non-linear increases with dose. Mean observed half-life was longer as the dose increased. Analysis of genetic variation in Fcγ receptor and transporter identified no unique Japanese variants or variants that alter amino acid sequences in or near the neonatal Fc receptor immunoglobulin G binding site targeted by nipocalimab.</p><p><strong>Conclusions: </strong>The comparable pharmacokinetic/pharmacodynamic profiles and highly conserved neonatal Fc receptor structure among diverse populations further support the clinical development of nipocalimab for the treatment of various immunoglobulin G autoantibody-mediated and alloantibody-mediated diseases across global sites and populations, including the Japanese population.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":"587-599"},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11339140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787435","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}