The Journal of Clinical Pharmacology最新文献

{"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":"A Phase I Study of the Pharmacokinetics, Pharmacodynamics, and Safety of Liposomal Bupivacaine for Sciatic Nerve Block in the Popliteal Fossa for Bunionectomy","authors":"Daniel I. Sessler MD,&nbsp;Xiaodong Bao MD, PhD,&nbsp;David Leiman MD,&nbsp;Jia Song MS,&nbsp;Jason Chittenden PhD,&nbsp;Alexander Voelkner PhD,&nbsp;Alparslan Turan MD,&nbsp;Jeffrey Gadsden MD","doi":"10.1002/jcph.6159","DOIUrl":"10.1002/jcph.6159","url":null,"abstract":"<p>This trial assessed the pharmacokinetics, pharmacodynamics, and safety of liposomal bupivacaine given via ultrasound-guided popliteal sciatic nerve block with or without immediate-release bupivacaine hydrochloride in adults having bunionectomies. Forty-five adults were enrolled into four sequential cohorts: (1) liposomal bupivacaine 266 mg with bupivacaine hydrochloride 50 mg; (2) liposomal bupivacaine 133 mg with bupivacaine hydrochloride 50 mg; (3) liposomal bupivacaine 266 mg; or (4) bupivacaine hydrochloride 100 mg. Outcomes included pharmacokinetics (e.g., bupivacaine maximum plasma concentration [C_max]), onset and duration of motor and sensory nerve block, and safety. Liposomal bupivacaine admixed with bupivacaine hydrochloride produced biphasic bupivacaine plasma disposition profiles with two distinct peaks. Geometric mean C_max of the early peak ranged from 235 to 421 ng/mL and the geometric mean of the late C_max was ∼30%-50% lower than the early peak. Median time to sensory block onset was 18 to 29 min in all cohorts. Sensory blocks lasted about twice as long with liposomal bupivacaine (median, 119-167 h) than with bupivacaine hydrochloride alone (median, 67 h). There were no serious adverse events. In conclusion, liposomal bupivacaine provided prolonged sensory nerve block when given as popliteal sciatic nerve blocks with or without bupivacaine hydrochloride, and bupivacaine plasma concentrations were well below the lower bound of the toxicity threshold of 2000 ng/mL for all cohorts.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"441-451"},"PeriodicalIF":0.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6159","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142630720","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":"Pharmacometric Analysis to Describe Pharmacokinetics and Exposure-Efficacy Response of Ivermectin in Adolescents Infected with Trichuris trichiura","authors":"David T. Ajayi PhD,&nbsp;Ochuko M. Orherhe MPhil,&nbsp;Goonaseelan (Colin) Pillai PhD,&nbsp;Samer Mouksassi PhD,&nbsp;Britta Steffens PhD,&nbsp;Dominic Bräm PhD,&nbsp;Viviane Sprecher MSc,&nbsp;Daniela Hofmann PhD,&nbsp;Michael Buettcher MD,&nbsp;Jean T. Coulibaly PhD,&nbsp;Said M. Ali MSc,&nbsp;Jennifer Keiser PhD,&nbsp;Marc Pfister PhD","doi":"10.1002/jcph.6158","DOIUrl":"10.1002/jcph.6158","url":null,"abstract":"<p>The efficacy of the combination therapy of albendazole and ivermectin against <i>Trichuris trichiura</i> infection is higher in Tanzania than in Côte d'Ivoire. This study therefore aimed to investigate the difference between the population pharmacokinetics (PK) at these study sites and to determine if an exposure-response analysis could explain the low efficacy of the combination therapy in Côte d'Ivoire. Twenty-four participants (aged 12-19 years) receiving single doses of ivermectin (200 µg/kg) and albendazole (400 mg) were included in the population PK modeling. A regression analysis was performed to investigate the relationship between the reduction of fecal whipworm eggs and different exposure metrics (peak concentration, area under the plasma drug concentration-time curve [AUC], and time above a certain threshold). The PK profile of ivermectin was best described by a one-compartment model, first-order absorption, and no delay in absorption, with the absorption rate constant estimated as 0.26 per h, an apparent volume of distribution of 162.43 L, and an apparent clearance of 7.82 L/h. In Tanzania, all patients showed a very high reduction in egg count independent of exposure. In Côte d'Ivoire, a relationship was found between higher ivermectin exposure and egg reduction, although not statistically significant. There was no significant difference between the PK profiles at both study sites, despite a difference in clinical outcome. Model-based simulations indicate that higher ivermectin doses such as 400 and 600 µg/kg may be associated with reduced egg count. Larger clinical studies are warranted to explore further the exposure-efficacy response relationship at 200 µg/kg and higher ivermectin doses in adults and children.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"433-440"},"PeriodicalIF":0.0,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591409","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 Pain Medications in Modulating Peripheral Nerve Injury Recovery","authors":"JuliAnne E. Allgood BS,&nbsp;Logan Whitney BS,&nbsp;Jeffrey Goodwin BA,&nbsp;Brian S. H. Chong MS,&nbsp;Amanda Brooks PhD,&nbsp;Jessica Pullan PhD","doi":"10.1002/jcph.6156","DOIUrl":"10.1002/jcph.6156","url":null,"abstract":"<p>Peripheral nerve injuries (PNIs) are common, costly, and cause significant pain. Effective management of PNIs involves tailoring medications to the injury type as well as understanding the pharmacokinetics/pharmacodynamics to support nerve regeneration and reduce pain. Opioids act on opioid receptors to significantly reduce pain for many patients, but there are significant addiction risks and side effects. In addition, opioids may exacerbate pain sensitivity and affect nerve regeneration. Non-steroidal anti-inflammatory drugs or acetaminophen act on cyclooxygenase enzymes and are commonly used for nerve pain, with 34.7% of people using them for neuropathic pain. While effective for mild pain, they are often combined with opioids, gamma-aminobutyric acid (GABA) analogs, lidocaine, or corticosteroids for more severe pain. Corticosteroids, mimicking adrenal hormones like cortisol, treat PNI-related inflammation and pain. Their pharmacokinetics are complex, often requiring local injections in order to minimize systemic risks while effectively treating PNIs. Lidocaine, a common local anesthetic, blocks ion channels in the central nervous system (CNS) and peripheral nerves, providing strong analgesic and anti-inflammatory effects. If used improperly, lidocaine can cause neuronal toxicity instead of anesthetic effect. GABA acts as an inhibitory neurotransmitter in the CNS and its drug analogs like pregabalin and gabapentin can alleviate neuropathic pain by binding to voltage-gated Ca²⁺ channels, inhibiting neurotransmitter release. These pain medications are commonly prescribed for PNIs despite a limited guidance on their effects on nerve regeneration. This review will discuss these drug's mechanisms of action, pharmacokinetics/pharmacodynamics, and their clinical application to highlight their effect on the PNI recovery.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"411-423"},"PeriodicalIF":0.0,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569957","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":"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":"Efficacy of Bile Acid Sequestrants in the Treatment of Bile Acid Diarrhea: A Meta-Analysis of Randomized Controlled Trials","authors":"Giulia Almiron R. Soares Medical Student,&nbsp;Amanda Godoi BSc (Hons), Medical Student,&nbsp;Patricia Marcolin MD,&nbsp;Gabriel Piredda Medical Student,&nbsp;Estella Laia Medical Student,&nbsp;Airton Zogaib Rodrigues MD","doi":"10.1002/jcph.6154","DOIUrl":"10.1002/jcph.6154","url":null,"abstract":"<p>Bile acid sequestrants (BASs) have often been used for bile acid diarrhea (BAD) but carry a high risk of adverse events. New generations of BASs show promising results; however, their efficacy remains unclear. This systematic review and meta-analysis was conducted using PubMed, Cochrane, and Embase to assess randomized controlled trials (RCTs) published up to November 2023 to retrieve studies that measured the parameters before and after the administration of BASs. The outcomes assessed were cessation or improvement in diarrhea, fecal consistency, abdominal cramping, frequency of diarrhea, and adverse events. Risk ratios (RRs) and mean differences with 95% confidence intervals (CIs) were pooled using a random-effects model. Statistical analyses were conducted using RStudio version 4.1.2. The protocol was prospectively registered with PROSPERO (CRD42023445444). Seven RCTs with a total of 311 patients were included, of which 168 (54%) were randomized to BASs. Among BAS-treated patients, 101 (60.1%) received colesevelam, 40 (23.8%) received chenodeoxycholate, 18 (10.7%) received cholestyramine, and 9 (5.3%) received colestid. BASs were associated with a significant improvement in the cessation of diarrhea (RR 3.27; 95% CI 2.08 to 5.15; <i>P</i> ≤ .05) and liquid stool to normal fecal consistency (RR 2.69; 95% CI 1.56 to 4.65; <i>P</i> ≤ .05), as well as an increase in abdominal cramps (RR 5.27; 95% CI 1.21 to 22.93; <i>P</i> ≤ .05). There were no differences in urgency, adverse events, or nausea between groups. These findings indicate that BASs are effective in the treatment of BAD, as indicated by the improvement or cessation of diarrhea episodes.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"478-485"},"PeriodicalIF":0.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478413","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":"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":"Population Pharmacokinetic Simulations for Dose Optimization of Tenofovir Disoproxil Fumarate in HIV-Infected Patients with Moderate-to-Severe Renal Impairment","authors":"Apinya Boonpeng PhD,&nbsp;Noppaket Singkham PhD,&nbsp;Chanadda Wutthikul PhD,&nbsp;Thanawan Rattanakul PharmD,&nbsp;Pinmanee Weeket PharmD,&nbsp;Chananan Saengpraphanan PharmD,&nbsp;Rungrawin Plaengnok PharmD","doi":"10.1002/jcph.6153","DOIUrl":"10.1002/jcph.6153","url":null,"abstract":"<p>Tenofovir disoproxil fumarate (TDF) requires dosage adjustments from the standard 300 mg once daily to every 48-96 h for moderate-to-severe renal impairment to avoid excessive exposure. However, this extended interval can lead to variable drug exposure and inconvenience. This study aimed to utilize the population pharmacokinetic (PPK) models to optimize TDF dosing regimens for HIV-infected patients with renal impairment. A systematic literature search was conducted across PubMed, Cochrane Library, and Scopus databases to identify relevant PPK studies of TDF in HIV-infected patients. From the included studies, the PPK models and associated parameters were extracted. Monte Carlo simulations (n = 2000) were performed to generate concentration–time profiles and derive PK parameters compared against reference ranges. For moderate renal impairment, the TDF 150 mg once-daily regimen achieved cumulative exposure comparable to the approved 300 mg every-other-day regimen. In severe renal impairment, TDF 75-100 mg administered once daily provided similar cumulative exposure as 300 mg every 72-96 h regimen while maintaining daily exposure comparable to the standard dose in patients with normal renal function. The approved extended dosing intervals of 72-96 h exhibited high drug exposure variability, initially resulting in supratherapeutic levels followed by suboptimal levels preceding the subsequent dose administration. In conclusion, administering smaller once-daily doses of TDF maintains consistent daily drug exposure comparable to the standard dose in patients with normal renal function while reducing variability in drug exposure, potentially mitigating the risk of nephrotoxicity. However, additional clinical studies are required to confirm these findings.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 4","pages":"424-432"},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478456","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":"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}