The Journal of Clinical Pharmacology最新文献

{"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":"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":"Population Pharmacokinetic and Pharmacodynamic of Atorvastatin in Chinese Lung Transplant Recipients","authors":"Dan Zhang PhD,&nbsp;Wenwen Du PhD,&nbsp;Wei Qin PhD,&nbsp;Wenqian Chen PhD,&nbsp;Pengmei Li MS,&nbsp;Xiaoxing Wang PhD","doi":"10.1002/jcph.6146","DOIUrl":"10.1002/jcph.6146","url":null,"abstract":"<p>Atorvastatin is a widely prescribed cholesterol-lowering drug that inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase to reduce lipid levels. This study aimed to establish a population pharmacokinetic and pharmacodynamic model for atorvastatin in Chinese lung transplant recipients (LTRs), particularly those using voriconazole (VOR) and with different genotypes. It evaluated precise dosing regimens and analyzed the correlation between atorvastatin exposure and clinical outcomes. A nonlinear mixed-effects model was used for the population pharmacokinetic/pharmacodynamic (PK/PD) analysis. A one-compartment population PK model was developed, incorporating VOR, <i>SLCO2A1</i> rs76906503, and <i>SLC22A8</i> rs2187383 to assess apparent clearance and volume of distribution. LDL-C was modeled as a biomarker to evaluate atorvastatin efficacy. A Monte Carlo simulation was conducted to assess various dosing schemes and the effects of different covariates on achieving the target LDL concentration. The correlation between atorvastatin exposure and clinical outcomes was also evaluated. Results indicated that the average probability of target attainment for optimal dosing regimens across various covariate results exceeded 45.8%. Dosages of 10, 20, and 40 mg were deemed suitable for LTRs. A lower dose was recommended for LTRs taking VOR or with mutant-type genotypes to avoid overexposure and adverse reactions. The population PK/PD model offers valuable guidance for evaluating atorvastatin dosing regimens in clinical settings, particularly for LTRs using VOR and those with different genotypes.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 2","pages":"242-252"},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478455","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":"Pharmacodynamic Exposure–Response Analysis of Fracture Count Data Following Treatment with Burosumab in Patients with XLH","authors":"Krina Mehta PhD,&nbsp;Jose Storopoli PhD,&nbsp;Nikita Ramwani MSc,&nbsp;Emilia Quattrocchi MD,&nbsp;Joga Gobburu PhD,&nbsp;Thomas Weber MD,&nbsp;Matthew W. Hruska PhD,&nbsp;Douglas Marsteller PhD","doi":"10.1002/jcph.6140","DOIUrl":"10.1002/jcph.6140","url":null,"abstract":"<p>X-linked hypophosphatemia (XLH) is a rare genetic disorder caused by excessive fibroblast growth factor 23 (FGF23), leading to low serum phosphate levels resulting in increased risk of fractures and pseudofractures. Burosumab is indicated for the treatment of XLH. In this work, we aimed to understand the quantitative relationship between burosumab-treatment-induced improvements in serum phosphate and reduction in fracture and pseudofracture counts in adults with XLH. Burosumab pharmacokinetic pharmacodynamic data from nine clinical studies were first utilized to update a prior population pharmacokinetic pharmacodynamic (PPKPD) model. The updated PPKPD model predictions for serum phosphate exposures along with other factors (i.e., time and treatment) were utilized to evaluate the relationship on fracture counts using Poisson model. The updated PPKPD model suggested that burosumab concentrations required for 50% of maximal effect decreased with increasing baseline serum phosphate levels. A Poisson model with time from baseline, average serum phosphate, and burosumab treatment described the time-varying fracture and pseudofracture count data appropriately. The model suggested a baseline rate of fracture and pseudofracture of 1.87 counts. The model predicted that fracture counts decrease by 1% each week, and by 23% with each unit increase (1.0 mg/dL) in average serum phosphate from lower limit of normal (2.5 mg/dL). An additional 1% decrease in fracture count each week was attributed to burosumab treatment that could not be explained by improvements in serum phosphate. Overall, the model quantified the relationship between burosumab-treatment-induced serum phosphate improvements and reduction in fracture and pseudofracture counts in patients with XLH over time.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 2","pages":"253-260"},"PeriodicalIF":0.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330510","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":"Time Course of Reversal of Fentanyl-Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene and Intramuscular and Intranasal Naloxone","authors":"Alessandra Cipriano MSHS,&nbsp;Glen Apseloff MD,&nbsp;Ram P. Kapil PhD,&nbsp;Ellie He PhD,&nbsp;Manjunath Shet PhD,&nbsp;Stephen C. Harris MD","doi":"10.1002/jcph.6132","DOIUrl":"10.1002/jcph.6132","url":null,"abstract":"<p>The increase in opioid overdose deaths, particularly involving potent, long-acting synthetic opioids, has led to calls for stronger, longer-acting opioid-overdose-reversal agents. Using an opioid-induced respiratory depression model, we investigated the onset and time course of action of naloxone and a long-acting opioid antagonist, nalmefene, in reversing the effects of an ongoing intravenous fentanyl infusion over a period of up to 100 min. Healthy, moderately experienced opioid users received intramuscular (IM) nalmefene 1 mg, IM naloxone 2 mg, or intranasal (IN) naloxone 4 mg after fentanyl-induced respiratory depression was established based on reduction in respiratory minute volume (MV). Each participant received each opioid antagonist twice per a randomized crossover schedule. Reversal of respiratory depression, pharmacokinetics, and safety were investigated. Participants showed rapid increases in plasma opioid antagonist concentrations, and meaningful reversal of depressed MV tended to occur earlier with IM nalmefene and IM naloxone than with IN naloxone. Compared to naloxone, nalmefene provided extended exposure, and mean MV was maintained at a higher level. All participants experienced treatment-related adverse events, but none were severe, serious, or led to study drug discontinuation. This study provides evidence that IM nalmefene 1 mg achieves reversal of fentanyl-induced respiratory depression similar to or better than that achieved with standard-of-care naloxone treatments. No new safety concerns were raised for IM nalmefene at the tested dose. The pharmacokinetic and pharmacodynamic properties of IM nalmefene position it as an important treatment option in opioid overdose reversal, particularly given the increasing prevalence of overdoses involving potent, long-acting synthetic opioids.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 2","pages":"206-216"},"PeriodicalIF":0.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330512","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 of Ganaplacide and Lumefantrine in Adults, Adolescents, and Children with Plasmodium falciparum Malaria Treated with Ganaplacide Plus Lumefantrine Solid Dispersion Formulation: Analysis of Data from a Multinational Phase 2 Study","authors":"Ramachandra Sangana PhD,&nbsp;Bernhards Ogutu MD,&nbsp;Adoke Yeka PhD,&nbsp;Sylvia Kusemererwa MPH,&nbsp;Halidou Tinto PhD,&nbsp;Andre Offianan Toure MD,&nbsp;Afizi Kibuuka MMED,&nbsp;Moussa Lingani MD,&nbsp;Carlos Lourenço MD,&nbsp;Ghyslain Mombo-Ngoma MD,&nbsp;Videlis Nduba MD,&nbsp;Tiacoh Landry N'Guessan MD,&nbsp;Guétawendé Job Wilfried Nassa MD,&nbsp;Mary Nyantaro MMed,&nbsp;Lucas Otieno Tina MD,&nbsp;Anup Anvikar MD,&nbsp;Abhinav Sinha MDPhD,&nbsp;Grace Kaguthi MD,&nbsp;Bakary Fofana MD,&nbsp;Martin Peter Grobusch FRCP,&nbsp;Myriam El Gaaloul PharmD,&nbsp;Anne Claire Marrast MD,&nbsp;Rashidkhan Pathan MSc,&nbsp;Havana Chikoto PhD,&nbsp;Katalin Csermak MD,&nbsp;Celine Risterucci PhD,&nbsp;Guoqin Su PhD,&nbsp;Cornelis Winnips MD,&nbsp;Jie Zhang PhD,&nbsp;Julia Zack PharmD","doi":"10.1002/jcph.6138","DOIUrl":"10.1002/jcph.6138","url":null,"abstract":"<p>The novel antimalarial ganaplacide combined with lumefantrine solid dispersion formulation (LUM-SDF) was effective and well tolerated in the treatment of uncomplicated falciparum malaria in adults, adolescents, and children in a multinational, prospective, randomized, active-controlled Phase II study conducted between August 2017 and June 2021 (EudraCT 2020-003284-25, Clinicaltrials.gov NCT03167242). Pharmacokinetic data from that study are reported here.</p><p>The trial comprised three parts: a run-in part in 12 adult/adolescent patients treated with a single dose of ganaplacide 200 mg plus LUM-SDF 960 mg assessed potential pharmacokinetic (PK) interactions between ganaplacide and lumefantrine; in Part A, adult/adolescent patients received one of the six ganaplacide-LUM-SDF regimens or artemether-lumefantrine; and in Part B, three dose regimens identified in Part A, and artemether-lumefantrine, were assessed in children aged 2 to &lt;12 years, with body weight ≥10 kg. A rich blood sampling schedule was used for all 12 patients in the PK run-in part and a subset of patients (N = 32) in Part A, with sparse sampling for remaining patients in Parts A (N = 275) and B (N = 159). Drug concentrations were determined by a validated protein precipitation and reverse phase liquid chromatography with tandem mass spectrometry detection method. Parameters including AUC_inf, AUC_last, AUC_0-t, <i>C</i>_max, and t_max were reported where possible, using non-compartmental analysis.</p><p>In the PK run-in part, there was no notable increase in ganaplacide or lumefantrine exposure when co-administered. In Parts A and B, ganaplacide exposures increased with dose, but lumefantrine exposure was numerically under dose-proportional. Lumefantrine exposure was higher with ganaplacide-LUM-SDF than with artemether-lumefantrine, although high variability was observed. Ganaplacide and lumefantrine exposures (<i>C</i>_max and AUC_{0-24 h}) were comparable across age and body weight groups. Drug exposures needed for efficacy were achieved using the dose regimen 400 mg ganaplacide plus lumefantrine 960 mg once daily for 3 days under fasted conditions.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 2","pages":"179-189"},"PeriodicalIF":0.0,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330511","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":"Determination of Vatiquinone Drug-Drug Interactions, as CYP450 Perpetrator and Victim, Using Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation","authors":"Lucy Lee PharmD, FCP,&nbsp;Noriko Okudaira PhD,&nbsp;Katsuyuki Murase PhD,&nbsp;Ronald Kong PhD,&nbsp;Hannah M. Jones PhD","doi":"10.1002/jcph.6133","DOIUrl":"10.1002/jcph.6133","url":null,"abstract":"<p>Vatiquinone, a 15-lipoxygenase inhibitor, is in development for patients with Friedreich's ataxia. Physiologically based pharmacokinetic (PBPK) modeling addressed drug-drug interaction gaps without additional studies. A PBPK model (Simcyp Simulator version 21, full model) was developed using parameters obtained from in vitro studies, in silico estimation and optimization, and two clinical studies. A venous blood dosing model best characterized vatiquinone lymphatic absorption. Apparent oral clearance (CL/F) was used to optimize intrinsic clearance (CL_int). Intestinal availability (F_g) was estimated using the hybrid flow term (Q_gut), unbound fraction in the enterocytes (fu_gut), and gut intrinsic metabolic clearance (CLu_G,int). Renal clearance (CL_R) was set to zero. Assuming an F_a of 1, CYP3A4 contribution (fm_CYP3A4) was further optimized. The PBPK model was verified with two clinical studies and demonstrated that it adequately characterized vatiquinone PK. As a perpetrator, the model predicted no risk for vatiquinone to significantly alter the drug exposures of CYP3A4 and CYP1A2 substrates as evident bynegligible reduction in both midazolam and caffeine area under the curve (AUC)_inf and C_max. As a victim, the model predicted that vatiquinone exposures are weakly influenced by moderate CYP3A4 inhibitors and inducers. With fluconazole coadministration, vatiquinone AUC_inf and C_max increased by nearly 50% and 25%, respectively. With efavirenz coadministration, vatiquinone AUC_inf and C_max decreased by approximately 20% and 10%, respectively. Results suggested that vatiquinone does not significantly impact CYP3A4 and CYP1A2 substrates and that moderate CYP3A4 inhibitors and inducers weakly impact vatiquinone AUC.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 2","pages":"160-169"},"PeriodicalIF":0.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142299274","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":"Association of Gene Polymorphisms and Serum Levels of ALAS1 with the Risk of Anti-Tuberculosis Drug-Induced Liver Injury","authors":"Bing Han MSc,&nbsp;Yiwen He MSc,&nbsp;Min Zhu MSc,&nbsp;Meiling Zhang BSc,&nbsp;Lihuan Lu MSc,&nbsp;Xiaoyan Xu MSc,&nbsp;Xiaomin He MSc,&nbsp;Honggang Yi PhD,&nbsp;Shaowen Tang PhD","doi":"10.1002/jcph.6137","DOIUrl":"10.1002/jcph.6137","url":null,"abstract":"<p>The accumulation of protoporphyrin IX in the liver caused by isoniazid and rifampicin through the disorder of heme biosynthesis was considered an important mechanism of anti-tuberculosis drug-induced liver injury (ATLI). Alanine synthase 1 (ALAS1) is a rate-limiting enzyme in the process of heme synthesis. This study aimed to investigate the association between ALAS1 gene polymorphism, serum ALAS1 level, and the risk of ATLI. This study was a case-control study including 58 ATLI cases and 192 controls. Four single nucleotide polymorphisms (SNPs) of the ALAS1 gene were selected for genotyping and serum ALAS1 concentrations were detected using ELISA kits. There was no significant difference in the genotype distribution of four SNPs between the ATLI cases and the controls under different genetic models. Patients carrying the GG genotype of SNP rs352163 in controls had higher baseline ALAS1 levels than those in ATLI cases (243.6 vs 290.2 ng/L, <i>P</i> = .034), and patients with baseline ALAS1 &lt; 337.85 ng/L had a higher risk of ATLI than those with ALAS1 ≥ 337.85 ng/L (HR = 2.679, 95% CI: 1.360-5.278, <i>P</i> = .004). Our findings indicated that the serum ALAS1 concentrations in the ATLI cases were lower than those in the controls, and the lower baseline ALAS1 levels can be associated with higher ATLI risk.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 2","pages":"197-205"},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251348","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":"Ensuring the Appropriate Use of Glucagon-Like Peptide-1 Receptor Agonists","authors":"Kenneth Todd Moore DBE, MS, FAHA, FCP,&nbsp;Aman Gupta MD,&nbsp;Jinshan Shen PhD,&nbsp;Parag Kumar PharmD","doi":"10.1002/jcph.6136","DOIUrl":"10.1002/jcph.6136","url":null,"abstract":"","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 2","pages":"153-159"},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142299275","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}