The Journal of Clinical Pharmacology最新文献

{"title":"Physiologically Based Pharmacokinetic Modeling of Caffeine in Preterm Neonates: Influence of Renal Function and Impairment on Dosing","authors":"Nolan Thomas BS,&nbsp;Matthew W. Harer MD,&nbsp;Sin Yin Lim PharmD, MS","doi":"10.1002/jcph.70135","DOIUrl":"10.1002/jcph.70135","url":null,"abstract":"<p>Currently, the same weight-based caffeine citrate dosing regimen is applied to all neonates. However, due to differences in growth trajectories by gestational age (GA) and altered caffeine elimination in neonates with renal injury, optimal dosing regimens may differ. In this study, we refined the existing physiologically based pharmacokinetic (PBPK) model for caffeine in preterm neonates (GA 25–32 weeks) using Simcyp to evaluate dosing across varying ages and renal function. Real-world data were used to generate weight-for-age growth curves and create virtual preterm populations. CYP1A2 ontogeny model was updated to better reflect the reduced metabolic activity of caffeine in preterm neonates. A 13.7-fold increase in glomerular filtration rate-adjusted renal clearance was needed to match observed data. Additionally, a higher volume of distribution (0.96 L/kg) was required to account for increased body water. The final model was verified using clinical pharmacokinetic data and used to simulate plasma concentration–time profiles. Our simulations showed that more premature neonates (≤28 weeks GA) may require lower weight-based maintenance dosing (8 mg/kg) compared with those with higher GA (10 mg/kg), and may also require an increase in doses after 4–6 weeks of therapy to maintain therapeutic levels. Neonates with significantly reduced renal function (25% of normal) may need a two- to threefold dose reduction. Future studies should aim to define optimal therapeutic targets, as caffeine use continues to expand.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12715538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145641704","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":"Model Informed Precision Dosing of Tacrolimus in Children Following Heart Transplant","authors":"Jadon S. Wagstaff MS,&nbsp;Shaun S. Kumar PhD, DABCP,&nbsp;Kimberly M. Molina MD,&nbsp;Joseph E. Rower PhD, DABCP","doi":"10.1002/jcph.70122","DOIUrl":"10.1002/jcph.70122","url":null,"abstract":"<p>Tacrolimus is a first-line immunosuppressant used after solid organ transplantation that suffers from extensive intra- and inter-patient variability and a narrow therapeutic window. Its critical role in a fragile population, coupled with the difficulties identifying and maintaining an appropriate dose within a given patient, make it an ideal candidate for population pharmacokinetic (popPK)-guided individualized dosing approaches (i.e., model informed precision dosing, MIPD). We previously published a tacrolimus popPK model in pediatric heart transplant recipients that showed promise in its ability to predict future concentrations within an individual. Using that model, we developed a Bayesian forecasting decision support tool (DST) clinical use to more rapidly attain appropriate tacrolimus dosing in this population. After rigorous in silico testing of the DST's mathematical fidelity to the popPK model, we implemented the DST within a clinical trial (NCT04380311). Fifteen children between 6 months and 17 years of age had their tacrolimus doses guided by the DST to determine the time to stable therapeutic tacrolimus dosing (defined by three consecutive concentrations within the targeted therapeutic range). DST-guided dosing achieved stable tacrolimus dosing ∼3 days faster (6.9 days, <i>P</i> = .03) as compared to a historical cohort (9.8 days). This was despite the poor performance of the DST in two children treated with continuous renal replacement therapy. These results demonstrate the clinical utility and benefit of the described DST, which is the first targeted to the pediatric heart transplant population. Rapid attainment of stable therapeutic tacrolimus dosing has benefits for the patient, clinician, and the healthcare system.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12859392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318691","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 1 Study of the Pharmacokinetics, Safety, and Tolerability of Posdinemab (JNJ-63733657) in Healthy Chinese Adults","authors":"Fangfang Wang PhD,&nbsp;Juanfang Liu MD,&nbsp;Daisy Bai MAS,&nbsp;Lingjue Li PhD,&nbsp;Maggie Fedgchin PharmD,&nbsp;David Henley MD,&nbsp;Haiyan Li MD,&nbsp;Fan Zhang PhD","doi":"10.1002/jcph.70116","DOIUrl":"10.1002/jcph.70116","url":null,"abstract":"<p>Posdinemab, a humanized immunoglobulin G1/κ monoclonal antibody, binds with high affinity to phosphorylated tau protein which is associated with Alzheimer's disease (AD) pathophysiology. Posdinemab reduced tau seeding in murine models and was well tolerated in Phase-1 clinical studies. This open-label, single-arm, Phase-1 study examined the effects of posdinemab with single intravenous dose (60 mg/kg) in healthy adults from China. The main objectives were to assess posdinemab serum pharmacokinetics (PK, primary), safety and tolerability (secondary), and presence of anti-drug antibodies (ADAs; secondary). Results were compared with Phase-1 European first-in-human (NCT03375697) and Japanese (NCT03689153) studies. Healthy Chinese participants (N = 10), mean age 60.0 (SD 3.80) years and 60% female, received posdinemab. Mean posdinemab serum C_max was 1401 µg/mL, median t_max was 0.08 days, mean AUC_inf was 18162 µg·day/mL, mean CL was 3.36 mL/day/kg, and mean elimination t_1/2 was 17.5 days. Most participants (n = 8; 80%) experienced ≥1 treatment-emergent adverse event (TEAEs), most common (20%) of which were arthralgia and back pain. Four participants (40.0%) were positive for posdinemab ADAs post-dose with peak titers of 1:22.5 (n = 3) and 1:360 (n = 1). Serum posdinemab concentrations in ADA-positive and ADA-negative participants were generally comparable. In conclusion, PK profile of posdinemab in healthy participants from China was in the expected range and comparable to previous Phase-1 studies in Europe and Japan. There were no new safety concerns. These results support further global development of posdinemab in AD.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12859175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281521","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":"Post-Marketing Safety Assessment for Glucagon-Like Peptide-1 and Dual Incretin Therapies in Diabetes and Obesity","authors":"Chien-Hsiang Weng MD, MPH,&nbsp;Charles L. Bennett MD, PhD, MPP,&nbsp;Joseph Magagnoli PhD,&nbsp;Caroline Richardson MD","doi":"10.1002/jcph.70119","DOIUrl":"10.1002/jcph.70119","url":null,"abstract":"&lt;p&gt;Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped the treatment landscape for type 2 diabetes and obesity. Introduction of dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, such as tirzepatide, has further expanded therapeutic possibilities. However, interpreting potentially unreported adverse drug reaction (ADR) signals and long-term complication risks for these novel therapies requires careful methodological consideration.&lt;/p&gt;&lt;p&gt;Accurately characterizing novel side effect profiles remains a challenge. Historically, financial conflicts of interest may limit clinicians reporting of novel serious ADRs. Clinicians with high prescribing rates of drugs of potential interest are often key opinion leaders for the relevant drugs and also clinicians most likely to identify first cases of novel ADRs. Second, reliance on voluntary reporting systems populated by reports from clinicians, pharmacists, attorneys, patients, attorneys, and pharmacovigilance programs of pharmaceutical manufacturers has contributed to widespread reporting of incomplete side effect data, as observed in prior medication classes such as opioids and in a report from a large-scale National Institute-funded pharmacovigilance program.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Furthermore, aggregation of data by therapeutic class makes it difficult to distinguish individual drug-specific versus class-specific risks among agents sharing presumed therapeutic mechanisms, as was the case with thienopyridine-associated thrombocytopenic purpura caused by ticlopidine (antibody-mediated) and clopidogrel (vascular toxicity);&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; pure-red cell aplasia caused by Johnson and Johnson-manufactured epoetin, but not by Amgen-manufactured or Roche-manufactured epoetin.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Without drug-specific post-marketing evidence, clinicians face uncertainty when counseling patients about potential drug-related versus class-related side effects and risk profiles.&lt;/p&gt;&lt;p&gt;Unlike liraglutide and semaglutide, which are pure GLP-1RAs, tirzepatide's dual agonist mechanism, engaging both GLP-1 and GIP receptors, interacts with distinct physiological pathways. GIP co-activation may mitigate gastrointestinal and potentially metabolic events typically seen with GLP-1RAs.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Therefore, grouping tirzepatide with pure GLP-1RAs in pharmacovigilance analyses risks obscuring crucial mechanistic differences, particularly regarding potentially unrecognized toxicities. While mechanism-aware pharmacovigilance can guide hypothesis generation about expected toxicities, mechanism-agnostic approaches are equally crucial. The inherent complexity of human biochemistry—characterized by redundant, interconnected, and often unpredictable signaling pathways—means that unanticipated adverse events may emerge outside of expected pharmacologic models.&lt;/p&gt;&lt;p&gt;Formulation differences further complicate safety interpretation within the GLP-1RA class. For","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70119","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276368","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":"Risks and Benefits for Sirolimus in Aging Prevention","authors":"Mallikaarjun S. PhD, FCP,&nbsp;Kirstein M. N. PharmD,&nbsp;Gupta A. K. MD,&nbsp;Shukla S. PhD,&nbsp;Gromme A. N. MD,&nbsp;the ACCP Public Policy Committee","doi":"10.1002/jcph.70112","DOIUrl":"10.1002/jcph.70112","url":null,"abstract":"<p>There is keen interest amongst the general population in preventing aging and age-related infirmities. Sirolimus is approved for preventing organ rejection in kidney transplant patients, has immune-modulating and growth-inhibitory properties, and is one of the therapies currently being used off-label for this purpose. There is a lack of formal guidance, such as a policy statement or position paper, on the appropriate dosing and administration of sirolimus for aging prevention. The American College of Clinical Pharmacology strongly recommends that clinicians prescribing sirolimus weigh the benefits and risks of sirolimus for off-label use in aging prevention, ensuring patients understand that such prescriptions lack any regulatory approval and rigorous supporting evidence. Health care providers are also encouraged to inform patients of the available clinical evidence and ongoing clinical trials in age-related conditions to build a stronger foundation of safety, efficacy, and optimal dosing for sirolimus in aging prevention.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253313","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":"Quantitative Comparison of the Predictive Accuracy of Warfarin Pharmacogenetic Dosing Algorithms Derived From Population Data of Different Ethnicities in the Chinese Population","authors":"Dongyun Nan BSC,&nbsp;Shaoke Li MD,&nbsp;Yi Wang MD,&nbsp;Yiqun Cai MD,&nbsp;Bo Liu MD,&nbsp;Jialing Peng MS,&nbsp;Jiexin Deng PhD","doi":"10.1002/jcph.70118","DOIUrl":"10.1002/jcph.70118","url":null,"abstract":"<p>This study systematically evaluated the predictive performance of 10 international warfarin dosing algorithms (originating from the United States, China, Singapore, Thailand, India, United Kingdom, Japan, and South Korea) in 87 Chinese patients, aiming to identify optimal algorithms for warfarin dose optimization. Clinical and genetic data were analyzed using mean dose error (MDE) and ideal dose prediction (IDP) rate metrics, with sensitivity analysis stratifying patients into low-dose (≤14 mg/week, n = 21), medium-dose (14–21 mg/week, n = 43), and high-dose (≥21 mg/week, n = 23) groups based on actual weekly maintenance dose (mean: 18.9 ± 8.8 mg/week). Results revealed significant variation in MDEs (−6.6 to 11.3 mg/week) across algorithms. The Chinese-developed Huang algorithm and Thai-developed Sangviroon algorithm demonstrated superior overall accuracy, both achieving MDEs &lt;1 mg/week and IDPs &gt;40%. In medium-dose patients, their performance was particularly robust (Huang IDP: 65.1%; Sangviroon IDP: 74.4%). However, both algorithms showed limitations at dose extremes: they overestimated doses in 90.48% of low-dose patients and underestimated doses in 60.9%–65.2% of high-dose patients. This evidence indicates that region-specific algorithms (Huang and Sangviroon) outperform internationally recommended models (e.g., IWPC/Gage endorsed by CPIC) for warfarin dosing in Chinese populations. Locally derived algorithms may thus offer greater clinical utility despite current international guidelines.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226127","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 Dapoxetine in Healthy Chinese Male Subjects","authors":"Libin Pu BPharm,&nbsp;Tong Wu BPharm,&nbsp;Fuqiang Bai BPharm,&nbsp;Haobo Lu BSc,&nbsp;Yiming Wang BPharm,&nbsp;Yuan Gao MPharm,&nbsp;Wen Qiu PhD","doi":"10.1002/jcph.70117","DOIUrl":"10.1002/jcph.70117","url":null,"abstract":"<p>Dapoxetine is a short-acting selective serotonin reuptake inhibitor used to treat premature ejaculation. However, its clinical effectiveness is challenged by substantial inter-individual variability in pharmacokinetics, as both the drug's therapeutic efficacy and the incidence of adverse reactions are highly dependent on its exposure. This study aims to develop a population pharmacokinetic model for dapoxetine, to investigate the sources of the variability, and to identify demographic and pharmacogenetic factors that influence drug exposure. The pharmacokinetic data for this analysis were obtained from a bioequivalence study conducted in 39 healthy Chinese male subjects. As part of this study, all volunteers were genotyped for the CYP3A4*1G, CYP3A5*3, CYP2D6*10, and CYP2D6*41 allelic variants. Population pharmacokinetic modeling was performed in Monolix. The final model was then used to simulate and compare the effect of different covariate levels on dapoxetine exposure. A two-compartment model with first-order absorption and an absorption lag time best described the pharmacokinetics of dapoxetine. The population parameters for apparent clearance (CL/F), apparent intercompartmental clearance (Q/F), apparent central volume of distribution (Vc/F), apparent peripheral volume of distribution (Vp/F), absorption lag time (Tlag), and absorption rate constant (ka) were 37.8 L/h, 17.2 L/h, 65.6 L, 191.7 L, 0.68 h, and 1.29/h, respectively. CYP2D6*10 and CYP2D6*41 alleles were found to be significant covariates on CL/F. The CYP3A4*1G allele influenced Q/F, while body mass index (BMI) was a significant covariate on Vc/F. Our analysis identified CYP2D6*10 and CYP2D6*41 polymorphisms as the significant factors contributing to inter-individual variability and influencing drug exposure.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201445","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":"Caffeine in Preterm Infants and its Effect on Neonatal Sleep: A Systematic Review","authors":"Kristina Denisova BA, MS, PhD,&nbsp;Nicholas Diamandis BS, MA,&nbsp;Jean Ee Tang BS, MS, PhD,&nbsp;Mia Eng-Kohn BA,&nbsp;Gloria Willson BA, MLIS, MPH,&nbsp;Bikash Shrestha BS,&nbsp;Alyssa DeStefano BS,&nbsp;Jane Lee BS, MA,&nbsp;Jacob Merrin BS, MS, PsyD,&nbsp;Zhichun Lin BS, MS,&nbsp;Neli Kotlyar ,&nbsp;Amanda Kessler BS, MA,&nbsp;Ryan Dosumu-Johnson BS, MD, PhD,&nbsp;Kirwan Walsh BS,&nbsp;Yidan Lou BMed, MPH,&nbsp;Jeremy Payano BS,&nbsp;John N. van den Anker MD, PhD","doi":"10.1002/jcph.70096","DOIUrl":"10.1002/jcph.70096","url":null,"abstract":"<p>The development of good-quality sleep is very important in early life. Sleep promotion programs aim to increase preterm infants’ sleep quality because preterm infants in the neonatal intensive care unit (NICU) have poor sleep. Interestingly, the majority of preterm infants are treated with caffeine, a nervous system stimulant. The primary objective of this systematic review was therefore to appraise the current evidence concerning potentially sleep-disruptive effects of caffeine in preterm infants within the first month of life. We performed a search (PROSPERO protocol CRD42022273596) according to PRISMA guidelines in PubMed, Embase, Scopus, and PsycInfo (as well as CENTRAL). We looked for studies involving preterm infants (&lt;37 weeks of gestational age) treated with caffeine in the NICU, with sleep measures acquired within the first month of life. Eight studies met the eligibility criteria. Underlying effect sizes for main outcomes are represented using albatross plots. Among studies reporting on wakefulness (N = 213), 83.33% detected significant disruptions (<i>P</i> &lt; .05). Among studies reporting on sensorimotor functioning (N = 80), 100% detected significant reductions (<i>P</i> &lt; .05). Moreover, significant reductions (<i>P</i> &lt; .05) in sleep states were detected. Available evidence suggests that caffeine exposure in preterm infants may produce alterations in sleep–wake and sensorimotor functioning, and related processes during the first month of life. The overall evidence is mixed, with some studies reporting no effect of caffeine exposure on neonatal sleep. Additional research is needed to understand how caffeine alters the quality of neonatal sleep in preterm infants and whether the effects may differ among infant subgroups. There is a continued need to investigate and support sleep quality in preterm infants during their NICU stay.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187409","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":"Physiologically Based Pharmacokinetic Modeling of Oxcarbazepine to Characterize Its Disposition in Children with Obesity","authors":"Patricia D. Maglalang PharmD,&nbsp;Jaydeep Sinha PhD,&nbsp;Victόria Etges Helfer PhD,&nbsp;Andrea Edginton PhD,&nbsp;Kanecia Zimmerman MD, PhD, MPH,&nbsp;Chi Dang Hornik PharmD,&nbsp;William J. Muller MD, PhD,&nbsp;Mobeen Rathore MD,&nbsp;Daniel K. Benjamin Jr. MD, PhD, MPH,&nbsp;Jia-Yuh Chen PhD,&nbsp;Ravinder Anand PhD, MS,&nbsp;Daniel Gonzalez PharmD, PhD,&nbsp;the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee","doi":"10.1002/jcph.70107","DOIUrl":"10.1002/jcph.70107","url":null,"abstract":"<p>Oxcarbazepine (OXC) is a second-generation antiseizure medication, effective through its active metabolite, 10-mono-hydroxy derivative (MHD). OXC is used as adjunctive therapy for focal-onset and primary generalized tonic–clonic seizures, with recommended dosing based on age and body weight. This study uses physiologically based pharmacokinetic (PBPK) modeling and leverages pharmacokinetic (PK) data acquired from children enrolled in pragmatic trials to understand dosing and subsequent exposure requirements in children with obesity. Drug concentrations of OXC and MHD (n = 148 each) from children with (n = 31) and without (n = 10) obesity, aged 2-20 years, were collected from two clinical trials (NCT01431326 and NCT02993861) and used for external evaluation of a previously developed PBPK model of OXC using PK-Sim. We used a previously published virtual population that accounts for the obesity-related changes in physiology (e.g., liver size and glomerular filtration rate) in children for PK simulations in children with obesity. Model evaluation showed that ≥80% of MHD concentrations contributed by about two thirds of study subjects (26 out of 41) fell within the 90% prediction interval. The PBPK model showed that children with obesity had lower median (interquartile range) simulated weight-normalized clearance (0.060 L/h/kg [0.048-0.076 L/h/kg]) than children without obesity (0.067 L/h/kg [0.060-0.077 L/h/kg]). Simulations revealed that the recommended pediatric dosing regimen produced comparable MHD exposure between children with and without obesity at steady state, supporting its applicability regardless of obesity status. This PBPK-based dosing aligns with product label recommendations and demonstrates the potential of PBPK modeling for dosing other drugs in children with obesity.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187377","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":"Approval of Upadacitinib in Pediatric Patients with Active Polyarticular Juvenile Idiopathic Arthritis or Active Psoriatic Arthritis: A Regulatory Perspective","authors":"Lei He PhD,&nbsp;Da Zhang PhD,&nbsp;Eric J. Gapud MD, PhD,&nbsp;Suzette Peng MD,&nbsp;Ozlem Belen MD, MPH,&nbsp;Chandrahas Sahajwalla PhD,&nbsp;Suresh Doddapaneni PhD,&nbsp;Youwei Bi PhD,&nbsp;Jianmeng Chen MD, PhD","doi":"10.1002/jcph.70104","DOIUrl":"10.1002/jcph.70104","url":null,"abstract":"<p>On April 26, 2024, FDA approved Rinvoq (upadacitinib, extended-release [ER] tablets) and Rinvoq LQ (1 mg/mL oral solution), a new pediatric immediate-release (IR) formulation, for the treatment of active polyarticular juvenile idiopathic arthritis (pJIA) and active psoriatic arthritis (PsA) in patients 2 years of age and older. The approved dosing regimens include a weight-tiered twice daily (BID) regimen with IR oral solution and a once-daily (QD) regimen with ER tablets. The objective of this article is to summarize the FDA's major review findings and considerations supporting these approvals from a regulatory perspective. This clinical development program included a single study (Study 1) conducted in pediatric subjects aged 2 to less than 18 years with JIA with active polyarthritis to evaluate the pharmacokinetics (PK), safety, and tolerability of multiple doses of upadacitinib. No clinical trials or dedicated PK studies were conducted in pediatric patients with PsA. Efficacy was extrapolated from adults with rheumatoid arthritis (RA) or PsA to pediatric patients with pJIA or PsA, respectively, based on a PK-matching approach considering disease similarity, similar response to treatment, and comparable PK exposure. PK data analysis and simulations showed that the approved upadacitinib pediatric dosing regimen, including a BID regimen with IR oral solution and QD regimen with ER tablet, provide comparable PK exposure (Cmax and AUC) in pediatric subjects with pJIA or PsA as compared to the approved 15 mg ER tablet QD regimen in adults with RA or PsA, respectively, supporting the efficacy extrapolation from adults to pediatric subjects.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182432","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}