The Journal of Clinical Pharmacology最新文献

{"title":"Sentinel Dosing—Time for a Risk-Based Approach?","authors":"Peter L. Bonate PhD, FCP, FAAPS, FISoP, Mark Rogge PhD, FCP, Jean-Michel Gries PharmD, PhD, FCP, Alexander J. Prokopienko PharmD, PhD, Sudhakar M. Pai PhD, FCP, ACCP Public Policy Committee","doi":"10.1002/jcph.6167","DOIUrl":"10.1002/jcph.6167","url":null,"abstract":"","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 3","pages":"267-271"},"PeriodicalIF":0.0,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142711631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Training the Next Generation of Pediatric Clinical Pharmacologists: Insights and Trainee Perspectives Over 10 Years","authors":"Rachel L. Randell MD, MSCR,&nbsp;Rose Gelineau-Morel MD,&nbsp;Sydney Thomas PhD,&nbsp;Daniel Gonzalez PharmD, PhD,&nbsp;J. Steven Leeder PharmD, PhD,&nbsp;Christoph P. Hornik MD, PhD, MPH","doi":"10.1002/jcph.6155","DOIUrl":"10.1002/jcph.6155","url":null,"abstract":"<p>The limited number of researchers with expertise necessary toaddress treatment gaps for children presents an ongoing challenge. The NationalInstitutes of Health established a national Pediatric Clinical Pharmacology T32Training Program in 2012 to train a multidisciplinary, collaborative pediatricclinical pharmacology workforce. We surveyed all current T32 trainees andgraduates since inception to identify strengths and opportunities to enhanceworkforce development. A total of 85 out of 155 (55%) responded, with themajority of respondents being female gender (61%), white race (75%), andworking in academia (75%). Nearly all (97%) reported using clinicalpharmacology in their current position, with 88% planning to remain in clinicalpharmacology in the long term, reinforcing current training efforts. Lifestylefactors and student debt appeared to influence career decisions. Mentors werecritical for introduction and future success in the field. Time and fundinglimitations were perceived as barriers to successful training. There was also apressing need to improve diversity. For workforce development, we suggestsupporting: (1) trainees' lifestyle, by offsetting financial pressures ofresearch training and expanding the geographic footprint of pediatric clinicalpharmacology training; (2) mentorship, by identifying mentors in the field andproviding dedicated support for mentorship; (3) efficiency, by evaluatingcurrent training activities and focusing on activities that maximizeopportunities for future funding; and (4) diversity, by examining barriers todiversity in the workforce in general and expanding early enrichmentopportunities.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 3","pages":"389-395"},"PeriodicalIF":0.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6155","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure–Response Analysis of Tofacitinib in Active Psoriatic Arthritis: Results from Two Phase 3 Studies","authors":"Sujatha Menon PhD,&nbsp;Satoshi Shoji PhD,&nbsp;Shinichi Tsuchiwata MS,&nbsp;Lara Fallon PhD,&nbsp;Keith Kanik MD","doi":"10.1002/jcph.6147","DOIUrl":"10.1002/jcph.6147","url":null,"abstract":"<p>Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). These post hoc exposure–response (E–R) analyses of pooled data from two Phase 3 studies (NCT01877668 and NCT01882439) characterized the relationships between tofacitinib exposure and efficacy (American College of Rheumatology [ACR] criteria), and changes in hemoglobin (Hgb) in patients with PsA. Efficacy data for the proportion of patients receiving tofacitinib 5 or 10 mg twice daily, or placebo, achieving ACR ≥20%, ≥50%, or ≥70% response criteria (ACR20, ACR50, and ACR70, respectively) at Month 3, were modeled jointly using a four-category ordered categorical exposure–response model (ACR20 non-responder, ACR20 responder but not ACR50 responder, ACR50 responder but not ACR70 responder, and ACR70 responder). A maximum drug effect (E_max) model (using average concentrations of tofacitinib at steady state [C_avg]) adequately described the exposure–ACR response rate relationship. Model-predicted response rates for tofacitinib 5 and 10 mg twice daily were 51% and 58%, respectively, for ACR20; 29% and 36% for ACR50; and 15% and 20% for ACR70. The E–R relationship between tofacitinib exposure and changes in Hgb was assessed using an indirect response model, which generally predicted Hgb concentration–time profiles across treatments well. The proportions of patients experiencing a decrease in Hgb of &gt;2 g/dL were similar with tofacitinib 5 mg twice daily or placebo. These results were generally consistent with previous analyses in rheumatoid arthritis and psoriasis, and support the use of tofacitinib 5 mg twice daily for active PsA.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 3","pages":"369-377"},"PeriodicalIF":0.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6147","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure-Efficacy Analysis and Dopamine D2 Receptor Occupancy in Adults with Schizophrenia after Treatment with the Monthly Intramuscular Injectable Risperidone ISM","authors":"Andreas Lindauer PhD,&nbsp;Eric Snoeck PhD,&nbsp;Christian Laveille PharmD,&nbsp;Ignacio Ayani MD,&nbsp;Lourdes Ochoa Díaz de Monasterioguren PhD,&nbsp;Marcos Almendros PhD,&nbsp;Javier Martínez-González MD,&nbsp;Lourdes Anta PhD,&nbsp;Ibón Gutierro PhD","doi":"10.1002/jcph.6152","DOIUrl":"10.1002/jcph.6152","url":null,"abstract":"<p>Dopamine D2 receptor occupancy (D2RO) significantly influences the clinical effectiveness and safety of many antipsychotic drugs. Maintaining a D2RO range of 65%-80% provides the best antipsychotic effects while minimizing adverse reactions. Data from a Phase III trial were used to establish an exposure–response relationship for monthly intramuscular Risperidone ISM (75 and 100 mg) or placebo administered to adults with schizophrenia. Pharmacodynamic analysis was based on an E_max model for Positive and Negative Syndrome Scale (PANSS) developed in NONMEM. Plasma concentrations of the active moiety were derived using a previously developed population pharmacokinetic model, which was used for D2RO simulations in conjunction with a published E_max model. The optimal D2RO range (65%-80%) was reached for the median within hours following the first injection of both Risperidone ISM doses. At steady state, median D2RO for both doses remained above 65% throughout the 28-day dosing period and demonstrated lower variability than oral risperidone. PANSS response did not differ significantly between dose groups, most likely because active moiety concentrations had already reached the plateau of the concentration–response relationship. The pharmacokinetic/pharmacodynamic analysis showed a profound placebo effect (−11.7%), and an additional maximal drug effect (−6.6%) resulting in a total PANSS improvement over time of −18.3%. Pharmacokinetic/pharmacodynamic modeling quantified a PANSS improvement over time after Risperidone ISM administration. The response was not significantly different in either dose group, likely because D2RO was already above the proposed efficacy threshold (65%) within 1 h after the first Risperidone ISM injection and remained above this level following repeated administrations.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 3","pages":"350-360"},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6152","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and Safety of SGLT-2 Inhibitors in Acute Myocardial Infarction: A Systematic Review and Meta-Analysis","authors":"Hila Asham PharmD,&nbsp;Samad Ghaffari MD,&nbsp;Mohammadreza Taban-Sadeghi MD,&nbsp;Taher Entezari-Maleki PharmD","doi":"10.1002/jcph.6149","DOIUrl":"10.1002/jcph.6149","url":null,"abstract":"<p>Since there is no specific recommendation of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in acute myocardial infarction (MI), this systematic review and meta-analysis was performed to address this lack of evidence. Scopus, Embase, PubMed, Web of Sciences, and Cochrane Library were searched from inception until May 30, 2024. We used both random and fixed-effects models for data analyses. Odds ratio (OR) and standard means difference (SMD) were performed for binary and continuous variables, respectively. Nine studies including five randomized clinical trials (RCTs) and four observational studies including 15,595 individuals with acute MI were entered. Overall, SGLT-2 inhibitors are significantly associated with a reduction of hospitalization for heart failure (OR, 0.78; 95% CI, 0.63 to 0.97; <i>P</i> =  .02; I² = 0%) and all-cause mortality (OR, 0.55; 95% CI, 0.38 to 0.81; <i>P</i> =  .002; I² = 0%) based on the RCTs and observational studies, respectively. SGLT-2 inhibitors also significantly improved the left ventricular ejection fraction (SMD, 0.36; 95% CI, 0.02 to 0.70; <i>P</i> =  .04; I² = 62%) among RCTs. Further evaluation of these drugs also revealed an acceptable safety profile without any major adverse events. In conclusion, although SGLT-2 inhibitors may have some clinical benefits among acute MI individuals, further RCTs are still needed to provide robust evidence regarding the use of SGLT-2 inhibitors in this setting.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 3","pages":"303-317"},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and Safety of Intravenous Candidate Biosimilar CT-P47 and Reference Tocilizumab: A Randomized, Double-Blind, Phase 1 Study","authors":"Miwa Haranaka MD,&nbsp;Takashi Eto PhD,&nbsp;Takanori Tanaka MD,&nbsp;Rie Yazawa MD,&nbsp;Gerd Burmester MD,&nbsp;Edward Keystone MD,&nbsp;SungHyun Kim PhD,&nbsp;YunJu Bae MS,&nbsp;JeeHye Suh MS,&nbsp;GoEun Yang BS,&nbsp;YunAh Kim BS,&nbsp;JaeYong Lee MS,&nbsp;Josef S. Smolen MD","doi":"10.1002/jcph.6139","DOIUrl":"10.1002/jcph.6139","url":null,"abstract":"<p>CT-P47 is a candidate biosimilar of tocilizumab. This 12-week, randomized, double-blind, parallel-design, phase 1 study aimed to demonstrate pharmacokinetic (PK) equivalence of CT-P47 and reference tocilizumab. Participants were healthy Japanese adults aged 18-55 years. Participants were randomized (1:1:1) to receive a single intravenous dose (8 mg/kg) of CT-P47, EU-approved tocilizumab (EU-tocilizumab), or US-licensed tocilizumab (US-tocilizumab). Primary PK endpoints were area under the concentration–time curve (AUC) from time zero to infinity, AUC from time zero to the last quantifiable concentration, and maximum serum concentration. Additional PK variables, safety, and immunogenicity were evaluated. The study was conducted from January 20 to May 26, 2023, in three centers in Japan. In total, 133 male participants were randomized (n = 45 to CT-P47, n = 44 to EU-tocilizumab, and n = 44 to US-tocilizumab). For all primary PK variables, 90% confidence intervals of the ratio of geometric least squares means were within the predefined equivalence margin of 0.80-1.25. Secondary PK variables were similar across groups. The most common treatment-emergent adverse event (TEAE) was neutrophil count decreased, occurring in 15 (33.3%), 13 (30.2%), and 12 (27.3%) participants in the CT-P47, EU-tocilizumab, and US-tocilizumab groups, respectively. There were no serious TEAEs, deaths, or study drug discontinuations due to TEAEs. Few participants were anti-drug antibody (ADA)- or neutralizing antibody (NAb)-positive. At the end of study, four (8.9%), one (2.3%), and two (4.5%) participants in the CT-P47, EU-tocilizumab, and US-tocilizumab groups, respectively, were ADA-positive; two (4.4%), zero (0%), and one (2.3%) in the respective groups were NAb-positive. CT-P47 demonstrated PK equivalence and comparable safety to EU- and US-tocilizumab.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 2","pages":"233-241"},"PeriodicalIF":0.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological Management of Sleep–Wake Disturbances in Delirium","authors":"Erik A. Levinsohn MD,&nbsp;Varsha Radhakrishnan MD,&nbsp;Haley Euting MD,&nbsp;Gary B. Kaplan MD","doi":"10.1002/jcph.6151","DOIUrl":"10.1002/jcph.6151","url":null,"abstract":"<p>Delirium is a heterogeneous syndrome primarily characterized by fluctuations in attention and awareness. Sleep–wake disturbances are a common and significant feature of delirium and can manifest as circadian rhythm inversion, sleep fragmentation, and reduced rapid eye movement (REM) and slow-wave sleep. Some literature suggests that the relationship between sleep disruption and delirium is reciprocal wherein the two reinforce one another and may share an underlying etiology. As there are no FDA-approved medications for delirium or delirium-related sleep disturbances, management is primarily focused on addressing underlying medical concerns and promoting physiologic circadian patterns with non-pharmacological behavioral interventions. In practice, however, medications are often used, albeit with limited evidence to support their use. This literature review explores the pharmacology and pharmacokinetics of several medications with literature investigating their use in delirium: melatonin, ramelteon, dual orexin receptor antagonists (DORAs), and dexmedetomidine. Current evidence suggests a possible benefit of ramelteon or melatonin, dexmedetomidine for patients in the ICU setting, and DORAs as therapeutic options for the re-regulation of sleep–wake cycle disruption in delirium. We discuss pertinent pharmacokinetic and pharmacodynamic factors that may influence clinical decision-making regarding these interventions.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 3","pages":"285-302"},"PeriodicalIF":0.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Propofol in Alcohol Withdrawal Syndrome: A Systematic Review","authors":"Logan Shirk BSPS, Pharm.D. Candidate,&nbsp;Justin P. Reinert Pharm.D., MBA, BCCCP","doi":"10.1002/jcph.6135","DOIUrl":"10.1002/jcph.6135","url":null,"abstract":"<p>The objective of this review was to evaluate the efficacy and safety of propofol in the treatment of critically ill patients diagnosed with alcohol withdrawal syndrome (AWS). A review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria, and Embase, MEDLINE (PubMed), Cochrane CENTRAL, and Web of Science were queried for results through June 2024. Studies providing efficacy or safety data associated with propofol with a reported diagnosis of AWS in critically ill patients were included. Studies evaluating pediatric patients, those without quantitative and qualitative outcome data, and those not readily translatable to English were excluded. Five retrospective cohort analyses of 218 patients were included in this systematic review. Patients were found to have both significant and non-significant increases in time to resolution of AWS symptoms when treated with propofol versus the AWS standard of care. Adjunct treatment with propofol was generally associated with reductions in total benzodiazepine use and increases in both ICU length of stay and duration of mechanical ventilation. The results of this systematic review provide the evidence necessary to support the use of propofol as an efficacious and safe medication in the management of severe and refractory AWS. Further investigation is required to determine optimal dosing strategies and durations of therapy. The results of this systematic review demonstrate the clinical utility of propofol as part of the management strategy for severe and refractory AWS.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 2","pages":"170-178"},"PeriodicalIF":0.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiologically Based Pharmacokinetic Modeling to Assess the Impact of Pathophysiological Changes in Neonates: Strengths, Weaknesses, and Next Steps","authors":"Karel Allegaert MD, PhD","doi":"10.1002/jcph.6148","DOIUrl":"10.1002/jcph.6148","url":null,"abstract":"&lt;p&gt;In neonates, there are many unmet needs to assure safe and effective therapeutics for their conditions. This is also reflected in the still commonly used off-label practices in this population. There are several reasons why drug development as well as licensing or labeling remains limited in newborns, even when weighted to other pediatric subpopulations. Among others, these reasons relate to economic sustainability (market size and difficulty in pricing), as well as to efficacy and safety assessment (clinical outcome assessment and endpoints), poorly understood mechanisms of disease, or challenges in trial design (time-dependent physiology, driven by [non]-maturational factors).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Effective and safe pharmacotherapy in neonates necessitates understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs and doses selected to treat their specific diseases. Differences in gestational and postnatal age or weight (birth weight and current weight) are the major drivers of the observed intra- and inter-variability in drug disposition and effects: &lt;i&gt;the key characteristic of neonatal pharmacology and physiology is fast maturation&lt;/i&gt;.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; This variability is further extended due to non-maturational factors, like co-morbidity or disease characteristics.&lt;/p&gt;&lt;p&gt;To mitigate these burdens and characteristics, new approaches emerged to support orphan, pediatric, or neonatal drug development. These mitigation strategies include the use of real-world data and evidence, and the development of tools to support extrapolation. When focusing on extrapolation tools, there are obvious strengths, as well as weaknesses and next steps are necessary to further improve the applicability and confidence in these tools.&lt;span&gt;&lt;sup&gt;3-5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Extrapolation to pediatric patients, including to neonates is getting increasingly important. The extrapolation concept is based on a well-characterized source population (like adults or older children, treated for a specific condition) and a well-described target population (like neonates). When the condition is similar between the target and source population, source population-related information can be applied to the target population. For example, if a bacterial infection has similar aspects in adults and neonates, antibiotic efficacy can be “extrapolated” to newborns. Even in a setting of conditions unique to neonates, leveraging prior information available from preclinical or clinical (adult and other pediatric studies) coupled with novel quantitative approaches can be instrumental to predict neonatal doses and optimize trial design.&lt;/p&gt;&lt;p&gt;The International Council for Harmonization (ICH) only very recently (August 21, 2024) adopted a guideline on pediatric extrapolation (E11A), providing a framework, a concept, and a plan on how to apply pediatric extrapolation.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; The ICH hereby clearly mentions that extrapolation to younger pediat","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"64 12","pages":"1606-1609"},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6148","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and Safety of a Novel Extended-Release Microsphere Formulation of Risperidone in Patients with Schizophrenia or Schizoaffective Disorder","authors":"David P. Walling PhD,&nbsp;Ying Dong MD, PhD,&nbsp;Robert Litman MD,&nbsp;Wenyan Wang PhD,&nbsp;Chunli Liu MS,&nbsp;Joe Tai BS,&nbsp;Pinglan Liu MS,&nbsp;Yanan Shi PhD,&nbsp;Wanhui Liu PhD,&nbsp;Fenghua Fu PhD,&nbsp;Kaoxiang Sun PhD","doi":"10.1002/jcph.6143","DOIUrl":"10.1002/jcph.6143","url":null,"abstract":"<p>Risperidone extended-release injectable suspension (R-ERIS; marketed as RYKINDO) is a novel immediate-release version of risperidone formulated as extended-release microspheres for biweekly intramuscular injection to treat schizophrenia in adults. The pharmacokinetics (PK) and safety of R-ERIS were evaluated in a multicenter, randomized, open-label, multiple-dose study in patients with stable schizophrenia or schizoaffective disorder. Eligible patients (N = 108) 18 to 65 years old were randomized (1:1) to receive IM injections of R-ERIS 25 mg or the comparator, a biweekly risperidone long-acting injectable (BW-RLAI; marketed as RISPERDAL CONSTA) 25 mg for a total of 5 injections. The primary objective was to evaluate the relative bioavailability of active moiety (risperidone plus 9-hydroxyrisperidone) at steady state. Blood samples were analyzed for risperidone and 9-hydroxyrisperidone using a validated, specific, and sensitive liquid chromatography with tandem mass spectrometry method. Plasma concentration–time data were analyzed using non-compartmental methods. Pharmacokinetic parameters were calculated based on individual patient PK profiles. Safety was assessed using standard measures. At steady state, mean plasma concentrations of the active moiety were similar for R-ERIS and BW-RLAI. R-ERIS rapidly released risperidone after the injection without apparent lag time. Plasma active moiety levels reached steady state after the second injection of R-ERIS. The elimination of the drug was completed approximately 2 weeks earlier for R-ERIS as compared to that for BW-RLAI. R-ERIS was safe and well tolerated. Overall, R-ERIS exhibited a faster onset and offset than BW-RLAI and statistical analysis of exposure parameters demonstrated bioequivalence at steady state.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 3","pages":"340-349"},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}