The Journal of Clinical Pharmacology最新文献

{"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}

{"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}

{"title":"Exploring the Impact of Developmental Clearance Saturation on Propylene Glycol Exposure in Adults and Term Neonates Using Physiologically Based Pharmacokinetic Modeling","authors":"Olusola Olafuyi PhD,&nbsp;Robin Michelet PhD,&nbsp;Michael Garle PhD,&nbsp;Karel Allegaert PhD","doi":"10.1002/jcph.6150","DOIUrl":"10.1002/jcph.6150","url":null,"abstract":"<p>Propylene glycol (PG) is a pharmaceutical excipient which is generally regarded as safe (GRAS), though clinical toxicity has been reported. PG toxicity has been attributed to accumulation due to saturation of the alcohol dehydrogenase (ADH)-mediated clearance pathway. This study aims to explore the impact of the saturation of ADH-mediated PG metabolism on its developmental clearance in adults and neonates and assess the impact of a range of doses on PG clearance saturation and toxicity. Physiologically based pharmacokinetic (PBPK) models for PG in adults and term neonates were developed using maximum velocity (V_max) and Michaelis–Menten's constant (K_m) of ADH-mediated metabolism determined in vitro in human liver cytosol, published physicochemical, drug-related and ADH ontogeny parameters. The models were validated and used to determine the impact of dosing regimen on PG clearance saturation and toxicity in adults and neonates. The V_max and K_m of PG in human liver cytosol were 1.57 nmol/min/mg protein and 25.1 mM, respectively. The PG PBPK model adequately described PG PK profiles in adults and neonates. The PG dosing regimens associated with saturation and toxicity were dependent on both dose amount and cumulative in standard dosing frequencies. Doses resulting in saturation were higher than those associated with clinically observed toxicity. In individuals without impaired clearance or when PG exposure is through formulations that contain excipients with possible interaction with PG, a total daily dose of 100-200 mg/kg/day in adults and 25-50 mg/kg/day in neonates is unlikely to result in toxic PG levels or PG clearance saturation.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 3","pages":"272-284"},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.6150","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478414","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}