The Journal of Clinical Pharmacology最新文献

{"title":"Evaluation of Vancomycin Dosing Practices in Critically Ill Patients Receiving Accelerated Venovenous Hemofiltration","authors":"Nihad Medar PharmD,&nbsp;Lydia R. Ware PharmD,&nbsp;Jeremy R. DeGrado PharmD,&nbsp;Kenneth E. Lupi PharmD,&nbsp;Jeffrey C. Pearson PharmD,&nbsp;David W. Kubiak PharmD","doi":"10.1002/jcph.70176","DOIUrl":"10.1002/jcph.70176","url":null,"abstract":"<p>Accelerated venovenous hemofiltration (AVVH) is a hybrid renal replacement therapy (RRT) offering higher hemofiltration rates and improved hemodynamic stability, but can alter pharmacokinetics and pharmacodynamics of numerous antibiotics, creating uncertainty in efficacy and toxicity. The purpose of this study was to describe vancomycin dosing practices in patients receiving AVVH, with the potential to model vancomycin dosing and monitoring strategies. This was a single-center retrospective analysis of vancomycin dosing strategies utilized in critically ill adult patients receiving AVVH. Patients were included if they received vancomycin while undergoing AVVH and had a vancomycin concentration measured within the first 24 h of initiating concomitant vancomycin and AVVH. Major endpoint of this study was the incidence of in-range vancomycin concentrations (10–20 mcg/mL) in patients undergoing AVVH. There were 52 patients included in the analysis, with 79 unique AVVH sessions with an associated vancomycin concentration assessed. Median dose of vancomycin was 1250 mg (1000–1500), or 14.5 mg/kg (12.7–16.6), per AVVH session. Incidence of in-range vancomycin concentrations was 68.4%, with a median vancomycin concentration of 17.1 mcg/mL (14.0–21.5). Median duration of vancomycin therapy with concomitant AVVH was 2 days (1–7) and the median time from AVVH completion to vancomycin concentration obtainment was 2.8 h (0.3–5.7). The majority of vancomycin concentrations collected were in range, using a median vancomycin dose of 14.5 mg/kg and achieving a median vancomycin concentration of 17.6 mcg/mL. This suggests most patients achieved in-range concentrations, but additional prospective pharmacokinetic studies are needed to understand vancomycin exposure and dosing requirements in patients undergoing AVVH.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057729","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":"Response to Letter to the Editor from Madhuri Tribhuvan and Shashikant N. Phatke","authors":"Kevin. V. Tobin PhD,&nbsp;Addison Leabo MS,&nbsp;J. Steven Leeder PharmD, PhD,&nbsp;Joga Gobburu PhD,&nbsp;Allison Dunn PharmD","doi":"10.1002/jcph.70212","DOIUrl":"10.1002/jcph.70212","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;We thank Madhuri Tribhuvan and Shashikant N. Phatke for their thoughtful evaluation of our work and for highlighting important considerations regarding the clinical interpretation and methodological framework of our population pharmacokinetic analysis of atomoxetine in children and adolescents with ADHD.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; We appreciate the opportunity to clarify key aspects of our approach.&lt;/p&gt;&lt;p&gt;We agree that the rationale for the target plasma concentration of 400 ng/mL was not sufficiently articulated. This target is based on Michelson et al., who evaluated efficacy data from 589 pediatric patients with CYP2D6 genotype information and 294 placebo-treated patients.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Their exposure–response analysis demonstrated a plateau in clinical benefit, with no further improvement in ADHD-RS-IV total score beyond peak concentrations of approximately 400 ng/mL. We agree that explicitly referencing this relationship strengthens clinical justification for the selected target.&lt;/p&gt;&lt;p&gt;We acknowledge the limitations of using a two-stage framework, particularly the inability to distinguish between-subject and between-occasion variability. However, the dataset imposed constraints: most individuals contributed only a single occasion, and within-individual data were insufficient to support stable estimation of between-occasion variability or transient factors such as gastrointestinal physiology or circadian influences. Under these conditions, full population modeling resulted in instability and systematic overprediction at lower concentrations. Treating each subject–occasion as independent allowed estimation of occasion-level parameters without unsupported structural assumptions. While this approach may conflate variability sources, it achieved low shrinkage (&lt;16%) and improved stability. With richer multiple-occasion data, a hierarchical framework would be preferable.&lt;/p&gt;&lt;p&gt;Relative bioavailability was not prioritized over clearance in explaining phenotype effects. Covariates were evaluated stepwise. Incorporating CYP2D6 phenotype on clearance resolved most η–covariate relationships for clearance, but residual associations remained for apparent volume. As CYP2D6 is not expected to influence volume directly, a relative bioavailability term was introduced, explaining the variability of both apparent clearance and volume. An additional clearance effect was required for poor metabolizers. We emphasize that the sequence of covariate testing does not influence the final model selection or parameter estimates. Final model selection was based on goodness-of-fit, reduction in unexplained variability, and biological plausibility.&lt;/p&gt;&lt;p&gt;We acknowledge the limited representation of low-frequency metabolizer phenotypes, particularly CYP2D6 and CYP2C19 poor metabolizers. Their low prevalence (∼5%)&lt;sup&gt;2&lt;/sup&gt; presents challenges for enrollment, highlighting the need for targeted studies to improve parameter precision and sup","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70212","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057756","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":"Hepatic CYP1A2 Activity in Adolescents with and without Obesity Assessed by the Urinary Paraxanthine-to-Caffeine Metabolic Ratio: A Pharmacokinetic Study","authors":"Christina Gade MD, PhD,&nbsp;Shahid Ullah PhD,&nbsp;Kim Dalhoff MD, DMSc,&nbsp;Jon Trærup Andersen MD, PhD,&nbsp;Troels Riis MSN,&nbsp;Jens Christian Holm MD, PhD,&nbsp;Ulrik Lausten-Thomsen MD, PhD","doi":"10.1002/jcph.70219","DOIUrl":"10.1002/jcph.70219","url":null,"abstract":"<p>Obesity-related metabolic and hepatic alterations may influence drug metabolism via cytochrome P450 enzymes. While adult studies suggest altered CYP1A2 activity in obesity, data in pediatric populations remain limited and inconclusive. The objective was to assess the in vivo CYP1A2 phenotype in adolescents aged 11-18 years with and without obesity, and to explore sex-based differences in enzyme activity within this age group. In this open-label pharmacokinetic study, which is a part of the CYTONOX study, 65 adolescents aged 11–18 years were included, comprising 30 individuals with obesity and 35 without obesity, recruited based on feasibility. The CYP1A2 phenotype was assessed using urinary paraxanthine/caffeine metabolic ratios following caffeine exposure. Hepatic fat content was measured via magnetic resonance spectroscopy. The study received approval from the Danish Health Authorities (EudraCT: 2014-004554-34) and the Regional Ethical Committee of Zealand (SJ-455). Despite metabolic differences and increased hepatic fat in the obese group, the CYP1A2 phenotype did not differ significantly between obese and non-obese adolescents (mean log10 urinary metabolic ratio: 0.82 vs 0.80; <i>P</i> = .93). No sex-based differences were observed. Obesity in adolescents does not appear to significantly impact CYP1A2 phenotype assessed by urinary metabolic ratio, in contrast to selected studies in adults. These findings suggest preserved CYP1A2 function during adolescence despite metabolic and hepatic changes. Further longitudinal studies are needed to elucidate the age-related progression of hepatic enzyme activity in context of obesity.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057809","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":"Partial Differential Equation (PDE)-Based Spatial Pharmacometrics in NONMEM: Method of Lines (MOL) Implementation with AI-Assisted Model Development","authors":"Yiming Cheng PhD,&nbsp;Yan Li PhD","doi":"10.1002/jcph.70215","DOIUrl":"10.1002/jcph.70215","url":null,"abstract":"<p>Spatial heterogeneity in drug distribution, particularly within solid tumors, compromises target engagement, yet is rarely represented in population pharmacokinetic analyses. Standard “well-stirred” models fail to capture intratumoral gradients. Reaction–diffusion partial differential equations (PDEs) mechanistically represent penetration and washout, but routine implementation in nonlinear mixed-effects modeling (NONMEM) is limited by operational complexity. Native numerical templates remain cumbersome, and manual method of lines (MOL) coding is labor-intensive and error-prone. This work presents a streamlined workflow to implement spatial PDEs in NONMEM using AI tools. We utilized AI-assisted code generation to systematically translate continuous spatial models into coupled ordinary differential equation systems directly executable in NONMEM, maintaining transparent $DES block implementations. We illustrate this approach with one-dimensional, spherical, and two-dimensional reaction–diffusion models, providing guidance for iterative refinement via prompt engineering. Although AI does not resolve numerical stiffness or identifiability limitations, it substantially reduces the engineering burden of large MOL systems. Coupled with disciplined verification, AI-assisted code generation makes PDE-based spatial pharmacometrics in NONMEM practical and maintainable, supporting wider adoption to interrogate target-site exposure and penetration-driven efficacy.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057731","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":"Population Pharmacokinetics of Oral Gecacitinib in Healthy Subjects and Patients with Autoimmune and Inflammatory Diseases","authors":"Qingheng Meng MS,&nbsp;Yuansheng Zhao PhD,&nbsp;Wenyang Chen MS,&nbsp;Lingxiao Zhang MS,&nbsp;Ling Xu PhD,&nbsp;Lujin Li PhD","doi":"10.1002/jcph.70214","DOIUrl":"10.1002/jcph.70214","url":null,"abstract":"<p>Gecacitinib is a novel, broad-spectrum Janus kinase (JAK) inhibitor being developed for the treatment of myelofibrosis, severe alopecia areata, ankylosing spondylitis, and atopic dermatitis. This study aimed to develop population pharmacokinetic (PopPK) models for gecacitinib and its metabolites ZG0244 and ZG0245 to evaluate influential factors. Data from healthy subjects and patients across nine clinical trials were pooled. PopPK models were developed using NONMEM, and covariates of interest were tested. The PopPK structure for gecacitinib was a two-compartment model with first-order absorption and linear elimination. The metabolite ZG0244 was best described by a two-compartment model with Michaelis–Menten formation and linear elimination, while for metabolite ZG0245, it was a one-compartment model with Michaelis–Menten formation and linear elimination. Statistically significant factors affecting pharmacokinetic parameters included sex, age, indication, and co-administration with a strong CYP3A inducer or inhibitor. The effects of sex, age, and strong CYP3A inducer on exposure were limited, requiring no dose adjustment. A strong CYP3A inhibitor increased exposure by approximately 1.3-fold. The median time to reach 95% of steady-state concentration was approximately 3 days for gecacitinib and ZG0244, and approximately 7 days for ZG0245. This study developed population pharmacokinetic models for gecacitinib and its metabolites, and quantified the effects of covariates.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057751","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":"Population Pharmacokinetics and Exposure-Response Analyses for Ubrogepant Efficacy and Safety in the Acute Treatment of Migraine: Analysis of Phase 1–3 Studies","authors":"Sven Stodtmann PhD,&nbsp;Lucia Siovitz MSc,&nbsp;Heiko Babel PhD,&nbsp;Ramesh R. Boinpally PhD","doi":"10.1002/jcph.70175","DOIUrl":"10.1002/jcph.70175","url":null,"abstract":"<p>A population pharmacokinetic (popPK) model was developed for ubrogepant using data from 10 Phase 1, 1 Phase 2, and 2 Phase 3 studies. The data were described by a 2-compartment model with linear elimination and transit compartment absorption. Formulation, food intake, race, gender, and hepatic impairment had a statistically significant impact on ubrogepant PK. Significant exposure-response relationships were found for 2 h pain relief and pain freedom, and 24 h sustained pain relief and sustained pain freedom. Ubrogepant significantly improved the symptoms of phonophobia and photophobia, and the most bothersome migraine symptom, with a modest trend with ubrogepant dose. A Phase 3 study evaluating ubrogepant use during the prodrome was incorporated into the popPK model, and the mean transit time and inter-individual variability were re-estimated. Exposure-response analysis across multiple endpoints in the prodrome study (including absence of moderate/severe headache within 24 or 48 h, absence of headache of any intensity within 24 h, and ability to function normally within 24 h) showed a treatment effect with improved outcomes after receiving ubrogepant.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70175","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057770","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":"First-in-Human Dose Selection and Safety, Tolerability, Pharmacokinetics, and Immunogenicity of the Muscle-Specific Kinase Agonist Adimanebart (ARGX-119)","authors":"Tonke van Bragt MSc,&nbsp;Christa Kneip PhD,&nbsp;Sofie Priem MSc,&nbsp;Xinghong Leng MD, PhD,&nbsp;Rachelle Mutch MD,&nbsp;Sonya K. Patel MD,&nbsp;Peter Vanhoenacker PhD,&nbsp;Cristina Vaghi PhD,&nbsp;Sven Hoefman PhD,&nbsp;Rebecca Shilling MD,&nbsp;Roeland Vanhauwaert PhD","doi":"10.1002/jcph.70208","DOIUrl":"10.1002/jcph.70208","url":null,"abstract":"<p>Adimanebart (ARGX-119), a first-in-class, humanized, agonistic monoclonal antibody, specifically targets and activates muscle-specific kinase, stabilizing the neuromuscular junction, increasing muscle strength, and decreasing muscle weakness and fatigability in nonclinical, proof-of-concept studies. Adimanebart may have broad therapeutic potential in neuromuscular junction disorders. This Phase I, first-in-human, double-blinded, placebo-controlled study assessed the safety, tolerability, pharmacokinetics, and immunogenicity of adimanebart in healthy participants. With no pharmacodynamic marker for muscle-specific kinase dimerization by adimanebart, human dose predictions were based on the minimum anticipated biological effect level in nonclinical studies. In this two-part study, 112 healthy participants were randomized to receive adimanebart or placebo in single ascending intravenous doses (0.005-15 mg/kg) or a single subcutaneous dose (5 mg/kg; Part A; n = 76), or weekly multiple ascending intravenous doses (0.3-5 mg/kg; Part B; n = 36). Adimanebart was well tolerated with a favorable safety profile. In single-ascending dose (SAD) cohorts, adimanebart demonstrated nonlinear pharmacokinetics at low concentrations, a dose-proportional increase in maximum concentration (mean range: 0.1-343 µg/mL), and a ≈6-fold increase in area under the concentration–time curve (0 to infinity) following a single intravenous dose, indicating target-mediated drug disposition. Incidence and prevalence of adimanebart anti-drug antibodies were comparable between treatment groups in SAD cohorts (adimanebart: 16.0% and 18.0%, placebo: 16.7% and 22.2%, respectively) and were not detected in multiple-ascending-dose cohorts. There was no apparent impact of anti-drug antibodies on adimanebart pharmacokinetics or safety. This study supports investigation of adimanebart as an agonistic muscle-specific kinase monoclonal antibody treatment for neuromuscular junction disorders.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13185087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147976488","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148085884","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":"Population Pharmacokinetic Modeling of Niraparib to Assess Different Absorption Models","authors":"Anna Gaffney PhD,&nbsp;Yoko Franchetti PhD, PhD,&nbsp;Mathieu Desrosiers MSc,&nbsp;Mirjam N. Trame PharmD, PhD,&nbsp;Roxanne C. Jewell PhD","doi":"10.1002/jcph.70210","DOIUrl":"10.1002/jcph.70210","url":null,"abstract":"<p>Niraparib is a poly(ADP-ribose) polymerase inhibitor approved for maintenance treatment of advanced ovarian cancer. Using data from a previous niraparib population pharmacokinetic (PK) model with data from four studies, this model added phase 1 pharmacokinetic data from two studies. The previous model was a three-compartment model with linear elimination, zero-order drug release into the absorption compartment, lag time, and first-order absorption into the central compartment. With added data, several absorption models, including dual absorption, were explored. Model fit was assessed using standard diagnostics. The resulting updated population PK model had the same three-compartment structure; absorption delays were newly described by three transit compartments. Covariate effects included increase in clearance (CL/F) with increasing baseline albumin (ALB) and creatinine clearance (CrCL); decrease in CL/F with increasing baseline alkaline phosphatase (ALP); increase in relative bioavailability and mean transit time in fed versus fasted/unknown state; increase in central volume of distribution (Vc/F) with increasing ALB and body weight; and increase in first peripheral volume of distribution with increasing ALB. Estimated typical values of CL/F and Vc/F were 15.9 L/h and 450 L. Except for extreme values of ALB, ALP, or CrCL, covariates resulted in minor effects on exposure (≤25% change). A thorough evaluation of additional phase 1 data for absorption established the niraparib reference population PK model. Despite a different absorption structure, estimates of CL/F, total volume of distribution, and covariate effects were similar to the previous model. The niraparib reference population PK model will play a pivotal role for future model-informed drug development.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13185089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147976603","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148085883","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}