The Journal of Clinical Pharmacology最新文献

{"title":"Fly Me to the Moon and Beyond—Making Life and Medicine Multiplanetary","authors":"Gilbert Koch PhD, John van den Anker MD, PhD, FCP, FAAP","doi":"10.1002/jcph.70251","DOIUrl":"https://doi.org/10.1002/jcph.70251","url":null,"abstract":"<p>The history of spaceflights demonstrates that mathematical modeling is a fundamental prerequisite for operating in extreme environments. For example, the prediction and control of spacecraft trajectories rely on ordinary differential equations (ODEs) derived from physical laws. Such ODE systems, that is, consisting of a spacecraft and different gravity sources, describe time-dependent dynamics that must be solved numerically.<span><sup>1</sup></span> Therefore, without mathematical models and numerical solutions of these ODEs, NASA could not have planned, guided, and verified the trajectories needed, for example, for the Apollo 11 mission to reach the Moon, land, and return safely to Earth.</p><p>At a fundamental level, challenges encountered in systems characterizing spacecraft trajectories are closely related to those emerging in studying the pharmacokinetics (PK) of drugs. In both domains one seeks to characterize the evolution of a system state over time, for example, position and velocity in the former, and drug concentration in the human body in the latter.</p><p>The study led by Mampre et al.<span><sup>2</sup></span> is a significant advancement in the field of space medicine by providing the first PK data during orbital spaceflight using blood-based measurements. In a research domain that is heavily constrained by logistical limitations, including challenges related to sample acquisition and storage, this work introduces both methodological innovation and clinical insights.</p><p>At its core, the study addresses a fundamental question for making life multiplanetary. How does microgravity environment alter the PK of commonly used drugs? Previous investigations have yielded inconsistent findings and relied primarily on saliva sampling, an indirect measure of systemic drug exposure. In contrast, the implementation of volumetric absorptive microsampling using the Mitra device enables reliable, minimally invasive collection of capillary blood samples during a spaceflight. This technological advancement overcomes many of the longstanding barriers for conducting rigorous pharmacological research in space.</p><p>The findings derived by a non-compartmental analysis reveal major changes in the PK of acetaminophen during spaceflight. Notably, the observed increases in maximum plasma concentration (Cmax) and overall drug exposure (AUC), both more than four times higher, demonstrate significant differences in acetaminophen dynamics. Such supratherapeutic plasma concentrations observed in space demonstrate the need for re-evaluation of terrestrial dosing regimens in spaceflight. As human space exploration will extend toward longer-duration missions beyond low Earth orbit, such considerations become critical for safeguarding crew health and mission success.</p><p>Observed changes in the PK of acetaminophen during spaceflight are linked by the authors to physiological adaptations to microgravity, including altered gastrointestinal motility and fluid b","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70251","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148616833","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":"Innovative Clinical Pharmacology, Modeling, and Simulation Strategies for Accelerating Rare Disease Drug Development","authors":"Rajneet K. Oberoi PhD,&nbsp;Cody J. Peer PhD, FCP,&nbsp;Ashutosh Tripathi PhD,&nbsp;Afroz S. Mohammad PhD,&nbsp;Yajing Sun PhD,&nbsp;Kenneth Der BS,&nbsp;Yang Song PhD,&nbsp;Jiayin Huang PhD,&nbsp;Vijay V. Upreti PhD, FCP","doi":"10.1002/jcph.70246","DOIUrl":"https://doi.org/10.1002/jcph.70246","url":null,"abstract":"<p>Clinical drug development for rare diseases continues to face significant challenges due to disease heterogeneity, fewer available patients, and incomplete understanding of pathogenesis, resulting in trials with limited clinical data, thus constraining traditional development pathways. Clinical pharmacology, modeling, and simulation-based approaches can help address these challenges by informing decision-making, mitigating uncertainty, and guiding optimal dose and regimen selection for the appropriate patient population. These approaches help streamline trial designs by reducing the scope and number of clinical trial evaluations, using exposure–response analyses to optimize dosing, the use of mechanistic-physiologically based pharmacokinetics (M-PBPK)-based approaches for biopharmaceutical and formulation optimization, evaluations of drug–drug interactions, and organ impairment. These strategies increase development efficiency across all stages of drug development, thereby improving the probability of success. This review highlights case studies that applied innovative clinical and quantitative pharmacology approaches across early and late stages of drug development and regulatory decision-making in rare diseases. The specific examples illustrate the application of pharmacokinetics/pharmacodynamics (PK/PD) and model-informed drug development (MIDD) strategies to support dose and regimen selection, enabling efficient use of direct or adaptive trial designs, facilitating bridging across populations and indications, biopharmaceutics-based transitions, and generating integrated PK/PD evidence to support labeling. Examples include drug repurposing, characterizing PK/PD in early phase to inform late-phase development, population PK analysis to guide trial dosing and label recommendations, using phenotype-targeted study design to address disease heterogeneity, expanding dosing regimen across indications using MIDD, quantitatively evaluating immunogenicity to support mitigation strategies, biomarker bridging, and applying M-PBPK to predict clinical PK in organ impairment populations.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148616829","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":"An Open-Label, 2-Period, Fixed Sequence Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Single Doses of STS101 (Dihydroergotamine Nasal Powder), with and without Concomitant Itraconazole in Healthy Adult Subjects","authors":"Detlef Albrecht MD,&nbsp;Elizabeth Hussey PharmD,&nbsp;Richard B. Lipton MD","doi":"10.1002/jcph.70239","DOIUrl":"https://doi.org/10.1002/jcph.70239","url":null,"abstract":"<p>Dihydroergotamine (DHE) prescribing information contains a boxed warning regarding the possibility of serious and/or life-threatening peripheral ischemia with co-administration of strong cytochrome P450 3A4 (CYP3A4) inhibitors. The effects of the strong CYP3A4 inhibitor itraconazole on the pharmacokinetics and safety of nasally administered STS101 (DHE) were evaluated in this open-label, 2-period, fixed sequence study in 31 healthy participants. Following a single dose of 5.2 mg STS101, DHE exposure when co-administered with itraconazole was 119% and 114% of that when administered alone, for the area under the plasma concentration–time curve from time 0 to infinity (AUC_0–inf), and maximum observed plasma concentration (C_max), respectively. Co-administration of STS101 with itraconazole was not associated with an increase in the frequency of treatment emergent adverse events compared with STS101 alone. No clinically significant findings of a single dose of 5.2 mg STS101 alone or with itraconazole were observed on nasal examinations, safety laboratory values, vital signs, or safety electrocardiograms. In this study, no clinically meaningful drug–drug interactions were seen when STS101 was co-administered with a strong CYP3A4 inhibiting drug.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70239","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148616836","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 Pharmacokinetics and Pharmacodynamics of Depemokimab in People with Asthma and Chronic Rhinosinusitis with Nasal Polyps","authors":"Anders Thorsted PhD,&nbsp;Lénaïg Tanneau PhD,&nbsp;Alexandra Lavalley-Morelle PhD,&nbsp;Richard Follows BSc,&nbsp;Loretta Jacques PhD,&nbsp;Nicholas Bird MSc,&nbsp;Philippe Gevaert MD,&nbsp;Ian Pavord DM,&nbsp;Jakob Ribbing PhD,&nbsp;Anubha Gupta PhD,&nbsp;Peter Howarth DM,&nbsp;Stein Schalkwijk PhD","doi":"10.1002/jcph.70187","DOIUrl":"https://doi.org/10.1002/jcph.70187","url":null,"abstract":"<p>Depemokimab is the first ultra-long-acting biologic with enhanced interleukin-5 (IL-5) binding affinity, high potency, and extended half-life, enabling twice-yearly dosing. Depemokimab has demonstrated efficacy and safety in patients with asthma and chronic rhinosinusitis with nasal polyps. These analyses aimed to characterize the pharmacokinetic/pharmacodynamic (PK/PD) profile of depemokimab. Data from three Phase I studies (NCT03287310/NCT05140200/NCT05602025) and four Phase III studies (SWIFT-1/-2: NCT04719832/NCT04718103; ANCHOR-1/-2: NCT05274750/NCT05281523) were used to develop a PK model for depemokimab and PK/PD model for blood eosinophil count (BEC) reduction, a key biomarker of type 2 inflammation. Participants received subcutaneous depemokimab or placebo (one dose in Phase I [2-300 mg in NCT03287310; 100 mg or 300 mg in NCT05140200/NCT05602025] and two 100 mg doses in Phase III) and ≥1 post-first-dose PK/PD (BEC) observation. PK analysis included 961 participants and PK/PD analysis included 1324 participants. Predicted geometric mean half-life was 47 days, with negligible accumulation in PK. Depemokimab 100 mg rapidly reduced BEC to &lt;25% of baseline, with a small increase observed at the end of the 26-week dosing interval. No clinically relevant covariates were identified for either model. All participants had trough depemokimab concentrations above the half maximal effective concentration (EC₅₀) at the end of the dosing interval (90% above the EC₉₀ level). PK/PD modeling showed that single-dose depemokimab 100 mg provides durable BEC reduction throughout a 26-week dosing interval, suggesting sustained suppression of IL-5 activity. These data support twice-yearly recommended dosing for depemokimab 100 mg, with no dose adjustments required based on intrinsic or extrinsic factors.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70187","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148616838","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":"Accelerating Pediatric Oncology Drug Development: Advances in Clinical Pharmacology, Trial Design, Non-Clinical Evidence, and Regulatory Science","authors":"Ya-Feng Wen PharmD, PhD,&nbsp;Xiaoning Wang PhD,&nbsp;Sarandeep Boyanapalli PhD,&nbsp;Lee Anderson PhD,&nbsp;Thao Dang MD,&nbsp;Guan Xing PhD,&nbsp;Marianna Calvet PharmD,&nbsp;Tiffany Hart PharmD,&nbsp;Sreeneeranj Kasichayanula PhD,&nbsp;Xiaochen Zhao PhD","doi":"10.1002/jcph.70242","DOIUrl":"10.1002/jcph.70242","url":null,"abstract":"<p>Pediatric oncology drug development remains uniquely challenging due to the rarity and biological heterogeneity of childhood cancers, ethical considerations in trial conduct, and the limited feasibility of large, randomized studies. Despite these barriers, recent years have seen a notable acceleration in the approval of oncology therapies for pediatric populations, driven by advances in molecularly targeted treatments, evolving regulatory requirements, and innovation in trial design. Reducing nonclinical data requirements and increasing the adaptation of model‑informed drug development approaches are also contributing to advances in pediatric oncology treatment by supporting dose selection, optimizing study design, and reducing unnecessary patient burden. In this review, recent regulatory requirements from the United States, the EU, and other key regions on pediatric oncology drug development are discussed. Thirty-three drugs with oncology indications in pediatric populations approved by the US FDA between 2018 and 2025 are reviewed. These approvals provide examples of how nonclinical and clinical data were generated with a focus on strategies for dose-finding and justification. Common challenges and considerations related to clinical operations and formulation development in pediatric populations and the emerging use of real-world data, external controls, and artificial intelligence/machine learning are also discussed.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148580777","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 Modeling for the Iminosugar Lucerastat Supports Dose Adaptation in Patients With Fabry Disease and Moderate to Severe Renal Function Impairment","authors":"Janneke M. Brussee PhD,&nbsp;Jasper Dingemanse PhD, FCP,&nbsp;Dominik Lott PhD,&nbsp;Benjamin Berger PhD,&nbsp;Aline Frey PharmD,&nbsp;Andreas Krause PhD","doi":"10.1002/jcph.70247","DOIUrl":"10.1002/jcph.70247","url":null,"abstract":"<p>Lucerastat is an iminosugar with the potential to provide substrate reduction therapy for the treatment of Fabry disease (FD), an inherited X-linked lysosomal storage disorder. The aims of this study were to develop a population pharmacokinetic (PK) model describing lucerastat plasma concentration over time, to investigate the relationships between subject-specific characteristics and model parameters, and to assess the influence of these differences between subjects on lucerastat exposure via model-based simulations. Longitudinal nonlinear mixed effects modeling was applied to develop a model based on data from 250 participants in six Phase 1 and two Phase 3 studies. Lucerastat pharmacokinetics were described by a two-compartment model with linear first-order absorption and elimination, including allometric scaling of body weight on clearance and volume parameters. Lucerastat clearance was reduced in subjects with lower estimated glomerular filtration rate (eGFR). Disease status (with/without FD) was found to impact clearance and volumes of distribution to a limited extent. The model described the data well across the dose range from 100 to 4000 mg. Body weight, disease status, and renal function were shown to influence exposure, with dose adaptation only required in patients with renal function impairment, as body weight and disease status had limited impact. Dose adaptation as applied in Phase 3 (i.e., eGFR [mL/min/1.73 m²] ≥60: 1000 mg; ≥45 and &lt;60: 750 mg; ≥30 and &lt;45: 500 mg; ≥15 and &lt;30: 250 mg b.i.d.) resulted in achieving similar exposure in study participants with FD with different levels of renal function impairment.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148521270","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":"Evaluating the Impact of Enfortumab Vedotin Dose Modifications on Clinical Efficacy Using Tumor Growth Inhibition Modeling in Patients With Advanced Urothelial Cancer","authors":"Vaishali L. Chudasama PhD,&nbsp;Gabriela Patilea-Vrana PhD,&nbsp;Hong Mu MSc (MS),&nbsp;Salaheldin Hamed PhD,&nbsp;Srinivasu Poondru PhD,&nbsp;Amit Garg PhD,&nbsp;Yen Lin Chia PhD","doi":"10.1002/jcph.70241","DOIUrl":"https://doi.org/10.1002/jcph.70241","url":null,"abstract":"<p>Enfortumab vedotin (EV) is approved for previously treated locally advanced or metastatic urothelial cancer (mUC), based on results from pivotal trials (phase 2, EV-201; phase 3, EV-301) evaluating EV monotherapy at 1.25 mg/kg 3Q4W (Days 1, 8, and 15 of a 28-day cycle). Adverse events (AEs) were managed by protocol-recommended dose modifications, with 35.5%–51.7% patients requiring dose reductions and most patients in EV-301 maintaining the 1.25 mg/kg dose through Cycle 7. Dose modifications appeared to have a limited impact on long-term efficacy in patients who achieved a response. Given that target lesion shrinkage is predictive of progression-free survival (PFS) and overall survival (OS) in patients with mUC in EV-301, we aimed to quantify the impact of EV starting dose and dose modifications on response onset and durability, hence the impact on PFS and OS, by characterizing tumor dynamics via a tumor growth inhibition (TGI) model. A population pharmacokinetic-TGI model was developed using data from 603 patients with mUC who received EV monotherapy at 0.5–1.25 mg/kg 3Q4W. Various dosing simulations indicated that a 1.25 mg/kg starting dose maximized the likelihood of response, and dose modifications at or after Cycle 3 had limited impact on simulated response duration. However, unwarranted treatment modifications in earlier treatment cycles (&lt;3 cycles) or premature discontinuations may compromise efficacy. In conclusion, higher EV dose intensity, particularly in early cycles, is likely to maximize response probability. Dose modifications appear to be effective in managing AEs, thus allowing patients to continue receiving long-term EV benefits with minimal impact on efficacy.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70241","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467567","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":"Extrapolating Efficacy of Cariprazine to Pediatric Schizophrenia and Bipolar Mania Through Population Pharmacokinetic Analysis","authors":"Shams Ismaeil PharmD,&nbsp;Lucia Siovitz MS,&nbsp;Rahul K. Goyal PhD,&nbsp;Doerthe Eckert MS,&nbsp;Sven Stodtmann PhD,&nbsp;Hao Xiong PhD","doi":"10.1002/jcph.70243","DOIUrl":"10.1002/jcph.70243","url":null,"abstract":"<p>The US FDA recently accepted efficacy extrapolation from adult to pediatric patients for atypical antipsychotics in the treatment of schizophrenia (SCZ) and bipolar mania (BPM), considering the similarity in both disease and exposure-response relationships for this class of drugs. Under this pharmacokinetic (PK)-based efficacy extrapolation framework, pediatric population PK (popPK) models for cariprazine and its two active metabolites (desmethyl cariprazine [DCAR], didesmethyl cariprazine [DDCAR]) were developed by modifying previously validated adult popPK models and using pediatric PK data from two phase I trials. Covariate effects on PK parameters in legacy adult models were retained in the pediatric models, except that body weight effect on apparent elimination clearance and apparent volume of distribution of the central compartment were re-estimated for all analytes. The final pediatric popPK models adequately described observed plasma concentrations of all three analytes with no significant bias over age or body weight in pediatric patients. Simulated total cariprazine (sum of cariprazine, DCAR and DDCAR) exposure at 1.5-4.5 mg once daily (QD) in adolescents (13-17 years) with SCZ and 3.0-4.5 mg QD in children (10-12 years) and adolescents with BPM resulted in predicted total cariprazine exposures within established efficacious ranges in adults with these conditions. Body weight did not meaningfully affect total cariprazine exposure and analyses did not support weight-based dosing in 10-12 year olds. This PK analysis supported the FDA approvals of cariprazine for the treatment of SCZ and BPM in pediatric patients by identifying efficacious doses for each indication based on efficacy extrapolation.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70243","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450042","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":"External Evaluation of Population Pharmacokinetic Models for Factor VIII in Chinese Patients with Hemophilia A","authors":"Jinxia Lu BSc,&nbsp;Zipeng Wei MSc,&nbsp;Baohua Xu MSc,&nbsp;Shuxia Zhang PhD,&nbsp;You Zheng MSc,&nbsp;Qingxia Liu MSc,&nbsp;Chunrong Chen MSc,&nbsp;Yanfang Lin MSc,&nbsp;Zhiqiang Xie MSc,&nbsp;Lihua Zhang MSc,&nbsp;Fenge Yang BSc,&nbsp;Meijuan Huang PhD,&nbsp;Xuemei Wu PhD","doi":"10.1002/jcph.70244","DOIUrl":"10.1002/jcph.70244","url":null,"abstract":"<p>Although numerous population pharmacokinetic (PopPK) models related to factor VIII (FVIII) replacement therapy have been published, the vast majority have not undergone external validation. This study aims to externally validate existing PopPK models of FVIII, derived from both domestic and international sources using independent datasets. PopPK models for FVIII were identified and reconstructed using their respective control files. Data were collected from Chinese patients with hemophilia A who received FVIII therapy. The dataset included essential information such as dosing regimens, blood sampling times, plasma concentrations, and blood group, which were used to generate model input files. The predictive accuracy of each model was assessed through prediction-based diagnostics. A visual predictive check (VPC) was conducted to evaluate the agreement between model predictions and observed concentrations. Model validity was further tested using normalized prediction distribution errors (NPDE). In addition, a Bayesian forecasting approach was employed to explore whether incorporating prior concentration points could enhance the predictive performance of the models. A total of 258 samples were collected from 45 patients to constitute the external validation dataset. Following screening, six models were successfully reconstructed for external validation. Prediction-based diagnostics analysis indicated that Model D showed relatively smaller median prediction error. However, VPC and NPDE analyses both revealed clear deviations from model assumptions, with NPDE indicating systematic model misspecification. Bayesian forecasting analysis further indicated that the model's predictive performance could be improved by incorporating 1–3 prior concentration values.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148399718","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 and Simulation to Support the Regulatory Submission of the Two-Injection Start Regimen with Aripiprazole Once-Monthly Long-Acting Injectable Intramuscular Administration in Japanese Patients with Schizophrenia or Bipolar I Disorder","authors":"Yumiko Yamasaki MSc,&nbsp;Tomohiro Sasaki PhD,&nbsp;Antal Martinecz PhD,&nbsp;Mayumi Hasegawa PhD,&nbsp;Kazuo Kuwahara MSc,&nbsp;Ayaka Soga BS,&nbsp;Kai Yamada MSc,&nbsp;Satoshi Katayama MSc,&nbsp;Kenji Maeda PhD,&nbsp;Takako Ichimura BS,&nbsp;Yosuke Kawai MSc","doi":"10.1002/jcph.70230","DOIUrl":"10.1002/jcph.70230","url":null,"abstract":"<p>To improve medication adherence in Japanese patients with schizophrenia or bipolar I disorder, this population pharmacokinetic (popPK) modeling and simulation was conducted to support the regulatory submission of the two-injection start (TIS; two aripiprazole once-monthly long-acting injectable [LAI; 400 mg each] administered at different sites, along with a single oral dose of aripiprazole [6–15 mg]) regimen by comparing it with the original regimen (single LAI with 2-week concomitant oral dose of aripiprazole [6–15 mg]). Pharmacokinetic data from four Japanese clinical trials in patients with schizophrenia were used to externally validate and update a previously validated popPK model developed from seven non-Japanese trials in healthy subjects or in patients with schizophrenia/schizoaffective disorders. Simulations were conducted assuming two types of patients: with and without prior stabilization on oral aripiprazole. The dataset of 1123 participants (13,985 observations) from clinical trials, including 306 Japanese patients (5699 observations) from Japanese clinical trials, was used as the input in the popPK model. Simulations showed that the plasma concentration–time profiles of the original regimen and the TIS regimen were similar in the Japanese population. In addition, the currently available postmarketing safety data did not show any new safety concerns and/or an incremental safety risk with the TIS regimen compared with the original regimen. The aripiprazole TIS regimen provides a new option by reducing the oral aripiprazole administration period to a single day. This is expected to reduce the medication burden on patients and, consequently, reduce the burden on healthcare professionals and caregivers.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70230","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148399760","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}