The Journal of Clinical Pharmacology最新文献

{"title":"Population Pharmacokinetics of Valemetostat and Exposure–Response Analyses of Efficacy and Safety in Patients with Relapsed/Refractory Peripheral T–Cell Lymphoma","authors":"Hiroyuki Inoue MS,&nbsp;Xiaoning Wang PhD,&nbsp;Ramon Garcia PhD,&nbsp;Brian Reilly PharmD, PhD,&nbsp;Masaya Tachibana PhD,&nbsp;YoungJun Yoo PharmD,&nbsp;Yvonne Lau PhD,&nbsp;Yang Chen PhD","doi":"10.1002/jcph.70100","DOIUrl":"10.1002/jcph.70100","url":null,"abstract":"<p>Valemetostat is a dual inhibitor of EZH2/1 approved in Japan for the treatment of relapsed/refractory (R/R) adult T–cell lymphoma/leukemia (ATLL) and R/R peripheral T–cell lymphoma (PTCL). It is administered orally once daily (QD) at 200 mg. Here, we present comprehensive population pharmacokinetic (PPK) and exposure–response (ER) analyses of valemetostat. The PPK model included data from six clinical trials in patients with non–Hodgkin lymphoma, including ATLL/PTCL, or healthy participants. ER efficacy analyses were based on data from one phase 2 clinical trial in patients with PTCL; ER safety analyses used data from three trials in patients with ATLL or PTCL. Valemetostat unbound average concentration up to event was used as the exposure metric. ER analyses included overall response rates for efficacy and six safety endpoints (any Grade ≥3 treatment–emergent adverse event [TEAE]; Grade ≥3 thrombocytopenia, anemia, and neutropenia; and dose reduction and interruption due to TEAEs). Valemetostat pharmacokinetics were well described by a three–compartment model, with a sequential linked zero–/first–order absorption, a saturable binding component in the central compartment, and linear elimination of unbound valemetostat from the central compartment. Alpha-1-acid glycoprotein was the only identified covariate significantly affecting total valemetostat exposure but had no impact on unbound exposure. The ER relationship on efficacy was not significant, and positive relationships were identified for multiple safety endpoints. Safety simulations across different doses suggested an acceptable safety profile for 200 mg QD. Overall, these analyses support the favorable benefit–risk profile of valemetostat at 200 mg QD in patients with R/R PTCL.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 12","pages":"1699-1711"},"PeriodicalIF":0.0,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70100","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006685","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 Randomized Study: Garadacimab Pharmacokinetics, Safety, and Tolerability After Administration via Autoinjector/Pre-Filled Pen Versus Pre-Filled Syringe in Healthy Participants","authors":"Fiona Glassman PhD,&nbsp;John-Philip Lawo PhD,&nbsp;Mihai Alexandru Bica MD, MPH,&nbsp;Anthony Roberts PhD,&nbsp;David Kormann DPM,&nbsp;Ligia Chialda MD,&nbsp;Soeren Miethke MSc,&nbsp;Iwona Dziadowiec MSc,&nbsp;Stephen Caltabiano PhD,&nbsp;Thomas Puchalski PharmD","doi":"10.1002/jcph.70099","DOIUrl":"10.1002/jcph.70099","url":null,"abstract":"<p>Garadacimab is a novel, fully human, anti-activated factor XII monoclonal antibody approved for long-term prophylaxis of patients with hereditary angioedema. This open-label, parallel-group, Phase 1, single-center, bridging study in healthy adults (18–55 years of age) characterized the pharmacokinetics and safety of a single 200 mg subcutaneous injection of garadacimab administered via autoinjector/pre-filled pen (AI/PFP) compared with the pre-filled syringe (PFS) used in previous studies. The aim of the study was to bridge the understanding of the PK and safety of garadacimab between PFS and AI/PFP modes of administration. Participants (N = 132) were stratified by body weight, randomized evenly in six groups by device (AI/PFP or PFS) and injection site (abdomen, thigh, or upper arm). The primary endpoint comprised pharmacokinetic parameter comparison between devices. Safety/tolerability were secondary endpoints. The geometric mean ratio (GMR) for C_max and AUC_0–inf comparing administration by PFS and AI/PFP was close to 1 with 90% confidence intervals within a range of 0.8–1.25, meeting bioequivalence criteria; GMR (90%) was 0.92 (0.81, 1.05) for C_max and 0.96 (0.87, 1.07) for AUC_0–inf. No participants in this study had anti-drug antibodies against garadacimab. Treatment-related emergent adverse events were reported in 9/66 (13.6%) participants in the PFS group and 11/66 (16.7%) participants in the AI/PFP group. Garadacimab 200 mg administered as a single subcutaneous dose via AI/PFP had a consistent safety and tolerability profile to that administered via PFS. These findings support administration of garadacimab via AI/PFP, providing at-home convenience for patients and physicians.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70099","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006668","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 Novel Maturation Equation for Hepatic Clearance Across Preterm, Term Neonates, Children, and Adults: Application to Paracetamol and Its Metabolite","authors":"Yunjiao Wu MS,&nbsp;Swantje Völler PhD,&nbsp;Sebastiaan C. Goulooze PhD,&nbsp;Karel Allegaert MD, PhD,&nbsp;Catherine M. T. Sherwin PhD,&nbsp;Anne van Rongen PhD,&nbsp;Daniëlla W. E. Roofthooft PhD,&nbsp;Sinno H. P. Simons MD, PhD,&nbsp;Dick Tibboel PhD,&nbsp;Robert B. Flint PhD,&nbsp;John N. van den Anker MD, PhD,&nbsp;Catherijne A. J. Knibbe PhD","doi":"10.1002/jcph.70080","DOIUrl":"10.1002/jcph.70080","url":null,"abstract":"<p>A preterm and term neonate to adult (PTNA) maturation equation was introduced recently to describe the glomerular filtration rate maturation from birth to adulthood for neonates of varying gestational age. This study aims to evaluate the newly developed PTNA equation against common maturation approaches like allometric scaling (AS0.75), the AS0.75 plus postmenstrual age (PMA)-based E_max (AS0.75 + PMA) equation, and the bodyweight dependent exponent equation (BDE) for the maturation of three hepatic pathways of paracetamol (PCM) from preterm and term neonates up to adults. A population pharmacokinetic analysis was conducted with pooled plasma and urine data of PCM, PCM-glucuronide (PCM-GLU), PCM-sulfate (PCM-SULF), and PCM-oxidative metabolites (PCM-OXI) (number of observations:6428) from 298 subjects, including preterm and term neonates, infants, children, and adults. PTNA, AS0.75, AS0.75 + PMA, and BDE were evaluated separately to describe the formation clearance of each PCM metabolite. Results indicated that the PTNA equation best described the formation clearance of PCM-GLU, outperforming the BDE and AS0.75 + PMA equations in both statistical and graphical evaluation metrics and inter-individual variability reduction. For PCM-SULF and PCM-OXI, the PTNA equation also had the best performance, but the improvements were smaller. The final model described the PK of PCM and its metabolites adequately among subpopulations as indicated by diagnostic plots. In conclusion, the PTNA maturation equation best describes the maturation of all hepatic elimination pathways of PCM. It can, as such, be potentially applied to other drugs and pathways when data from both preterm and term neonates and older children are part of the PK analysis.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 12","pages":"1829-1843"},"PeriodicalIF":0.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145001743","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":"From Genotype to Therapeutic Monitoring: Enhancing Tamoxifen Efficacy in Breast Cancer Treatment","authors":"Ana Flávia Mendes Batista BSc,&nbsp;Letícia Penteado Petrolli BSc,&nbsp;Maria Paula Marques Pereira PhD,&nbsp;Adriana Rocha PhD,&nbsp;Jurandyr Moreira de Andrade PhD,&nbsp;Vera Lucia Lanchote PhD,&nbsp;João Paulo Bianchi Ximenez PhD","doi":"10.1002/jcph.70103","DOIUrl":"10.1002/jcph.70103","url":null,"abstract":"<p>Endoxifen is the most active metabolite of tamoxifen and plays a central role in its therapeutic efficacy. However, significant interindividual variability in endoxifen plasma concentrations, driven by both genetic and non-genetic factors, may result in subtherapeutic exposure for a substantial subset of patients. This study evaluated the influence of CYP2D6 phenotype and age on endoxifen steady-state concentrations and explored the clinical utility of therapeutic drug monitoring (TDM) to guide tamoxifen therapy. A total of 63 breast cancer patients receiving tamoxifen 20 mg daily for at least 3 months were enrolled. Patients were genotyped for CYP2D6 using TaqMan assays and classified as normal metabolizers (NMs, n = 49), intermediate metabolizers (IMs, n = 13), or ultrarapid metabolizers (UMs, n = 1). Plasma concentrations of tamoxifen and its metabolites were quantified by LC-MS/MS at steady state. Endoxifen levels were significantly lower in IMs (7.13 ng/mL; 95% CI: 3.38-15.08) compared to NMs (22.66 ng/mL; 95% CI: 18.57-27.66; <i>P</i> &lt; .001). Subtherapeutic endoxifen concentrations (&lt;6 ng/mL) were observed in 23.1% of IMs and 4.1% of NMs. These results support the combined use of CYP2D6 genotyping and TDM as the optimal strategy for personalizing tamoxifen therapy and minimizing the risk of subtherapeutic endoxifen exposure.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 12","pages":"1712-1718"},"PeriodicalIF":0.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70103","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145001736","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":"Clinical Pharmacology Characterization of the First-In-Class Oncolytic Viral Therapy T-VEC in Adults and Pediatric Subjects","authors":"Xinwen Zhang PhD,&nbsp;Bhavya Balu PhD,&nbsp;Po-Wei Chen PhD,&nbsp;Khamir Mehta PhD,&nbsp;Chuang Li MD,&nbsp;Vijay V. Upreti PhD, FCP","doi":"10.1002/jcph.70102","DOIUrl":"10.1002/jcph.70102","url":null,"abstract":"<p>Oncolytic viruses are an emerging class of immunotherapies for cancer treatment. Talimogene laherparepvec (T-VEC) is a first-in-class oncolytic virus approved globally for advanced melanoma. Herein, we describe the quantitative clinical pharmacology aspects of T-VEC that supported the development of this unique therapy. As a live therapy, the exposure characteristics of T-VEC are vastly different from the pharmacokinetics (PK) of traditional small molecules or therapeutic proteins and were characterized as tumor site oncolytic viral kinetics. Relatively flat relationships between T-VEC dose, lesion exposures, and efficacy were identified based on dose–exposure–response (D-E-R) analyses of 60 adult subjects, indicating that optimal drug effect was achieved over the studied dose range (10⁶-10⁸ plaque forming unit [PFU]/mL); hence, efficacy was not sensitive to dose variations within the range. The relatively flat D-E-R relationship for T-VEC was also beneficial for biopharmaceutic aspects unique for live viruses, including bridging small variations in viral infectivity observed from batch to batch during manufacturing. Additionally, the exposures in pediatric subjects (N = 15) were within the range, although generally lower in medians than adults (N = 60). The primary safety concern of T-VEC-related herpetic infection was evaluated using a mechanistic PK-PD model which indicated minimal infection risk over the up to 5 years follow-up duration. Overall, T-VEC demonstrated favorable PK-PD profiles and was well tolerated in adults and pediatric subjects at the approved dosing regimen. Quantitative clinical pharmacology analyses have supported the optimal development of T-VEC and are poised to accelerate the development of these promising therapeutic oncolytic viruses.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145001704","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":"Correction to “Physiologically Based Pharmacokinetic Modeling of Vancomycin and its Comparison with Population Pharmacokinetic Model in Neonates”","authors":"","doi":"10.1002/jcph.70098","DOIUrl":"10.1002/jcph.70098","url":null,"abstract":"<p>Cao A, Li Q, Han M, et al. Physiologically based pharmacokinetic modeling of vancomycin and its comparison with population pharmacokinetic model in neonates. J Clin Pharm. 2025;65:87-95. https://doi.org/10.1002/jcph.6126</p><p>In the article cited above, Yanping Guan was listed as the corresponding author due to an administrative error. The correct corresponding author is Lu Tan and the contact information is listed below.</p><p>Lu Tan</p><p>Department of Pharmacy, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China</p><p>[email protected]</p><p>We apologize for this error.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70098","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975508","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 of Nifedipine in High-Altitude and Plain Patients with Hypertension","authors":"Yu Li MM,&nbsp;Shouhua Mu MM,&nbsp;Qin Huang MM,&nbsp;Jingyan Jin MM,&nbsp;Yinlian Tong MM,&nbsp;Rong Wang PhD,&nbsp;Wenbin Li PhD","doi":"10.1002/jcph.70087","DOIUrl":"10.1002/jcph.70087","url":null,"abstract":"<p>The pharmacokinetic characteristics of drugs are altered under high-altitude hypoxia. We aim to describe the population pharmacokinetics of nifedipine to investigate the effects of high-altitude hypoxia on the pharmacokinetics of nifedipine in hypertensive patients. A total of 206 plasma concentrations were collected from 50 patients with hypertension in plateau areas and 53 in plain areas. The PK of nifedipine in hypertensive patients in the plateau and plain area of China was described using nonlinear mixed-effects modeling. The patient's blood pressure was recorded to evaluate the antihypertensive effect of nifedipine. The pharmacokinetics of nifedipine were described by a one-compartment model with zero-order absorption and first-order elimination. The estimated apparent clearance was 18.74 L/h with 31.91% interindividual variability, and the apparent volume of distribution was 103.88 L with 22.44% interindividual variability. Plateau versus plains were identified as a significant covariate affecting nifedipine pharmacokinetics, particularly in inter-individual clearance rates. The interindividual variability of CL was reduced from 36.26% to 31.91%, and the CL of patients in the plateau area was about 1.35 times higher than that in the plain area. This study may contribute to the rational use of nifedipine in the plateau area.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 12","pages":"1757-1766"},"PeriodicalIF":0.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975485","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":"Application of Lactation Physiologically Based Pharmacokinetic Modeling to Predict Milk Exposure of Passively Diffused Drugs","authors":"Ruhul Kayesh PhD,&nbsp;Michelle Pressly PhD,&nbsp;Daphne Guinn PhD,&nbsp;Zhoumeng Lin PhD,&nbsp;Stephan Schmidt PhD, FCP,&nbsp;Kiara Fairman PhD,&nbsp;Carrie Ceresa PharmD, MPH,&nbsp;Elimika Pfuma Fletcher PharmD, PhD, FCP","doi":"10.1002/jcph.70093","DOIUrl":"10.1002/jcph.70093","url":null,"abstract":"<p>Physiologically based pharmacokinetic (PBPK) models have gained interest as a tool for predicting drug transfer to human milk and assessing the exposure levels in infants. Our group previously developed an integrated lactation PBPK model framework to understand the transfer of drugs into milk and the resulting exposure in infants. As a part of the framework, the current paper focuses on performance of lactation PBPK models to predict maternal plasma and milk concentrations for drugs that are not substrates of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) transporters—atenolol, escitalopram, and alprazolam. PBPK models for healthy adult subjects were developed for atenolol and escitalopram in Simcyp v23 and verified against clinical data. For alprazolam, the Simcyp library model was used. The built-in lactation compartment in Simcyp was utilized for the three drugs. Atenolol and escitalopram adult healthy PBPK models showed agreement of plasma concentration–time profiles with respective clinical data. The lactation PBPK models predicted milk concentration profiles with reasonable agreement for all three drugs as well. The predicted milk concentration–time profile, milk pharmacokinetic parameters and milk-to-plasma (M/P) ratio of atenolol, alprazolam, and escitalopram were within 2-fold of the reported values, suggesting agreement between simulation and clinical data. The current work shows the potential of lactation PBPK models to predict drug exposure in human milk for drugs that are not P-gp or BCRP substrates. The approach will be further evaluated for drugs that are substrates for these active transporters known to be present in mammary tissues.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 12","pages":"1637-1649"},"PeriodicalIF":0.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70093","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975496","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":"Clinical Impact of Hepatic Impairment on the Pharmacokinetics of Sotorasib and Its Major Metabolites: Implications for Dose Adjustment","authors":"Mason McComb PhD,&nbsp;Panli Cardona PharmD,&nbsp;Caitlin Sampson MS,&nbsp;Jessica Purkis BS,&nbsp;Christopher A. James PhD,&nbsp;Brett Houk PhD","doi":"10.1002/jcph.70095","DOIUrl":"10.1002/jcph.70095","url":null,"abstract":"<p>Sotorasib is a small molecule KRAS^G12C inhibitor approved for the treatment of KRAS^G12C mutated locally advanced or metastatic non-small cell lung cancer in adult patients. The effect of hepatic impairment on the pharmacokinetics (PK) of sotorasib and major metabolites M10, M18, and M24, safety, and tolerability after a single oral dose of 960 mg was assessed in a phase 1, parallel-arm, multi-center (US), open-label study. Sotorasib AUC_inf ratio for subjects with moderate (n = 7) or severe (n = 4) hepatic impairment relative to normal hepatic function (n = 7) was 0.746 (90% CI: 0.431-1.29) and 1.04 (0.545-1.97), respectively. C_max ratio for moderate and sever hepatic impairment was 0.955 (0.512-1.78) and 1.43 (0.688-2.96), respectively. Mean t_1/2 values for sotorasib were similar in subjects with normal hepatic function and subjects with moderate or severe hepatic impairment. C_max and AUC_inf of M10 and M24 increased, while M18 decreased with increasing severity of hepatic impairment. Treatment-emergent adverse events were mild in severity and no serious adverse events were reported. Overall, moderate or severe hepatic impairment did not considerably affect the exposure of sotorasib, M10, M18, and M24. This data supports that adjustments to sotorasib dosing are not indicated for moderate or severe hepatic impairment.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 12","pages":"1864-1875"},"PeriodicalIF":0.0,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144884143","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":"Recent Utilization of Pediatric Extrapolation and Modeling and Simulation Approaches in Pediatric Drug Development in Japan","authors":"Akinori Nakashima MS,&nbsp;Akihide Tsujimoto MS,&nbsp;Masako Saito PhD,&nbsp;Jun Takeda PhD,&nbsp;Makiko Natori MS,&nbsp;Satoshi Shoji PhD","doi":"10.1002/jcph.70091","DOIUrl":"10.1002/jcph.70091","url":null,"abstract":"<p>In Japan, the percentage of approved drugs with pediatric indications increased to 30% in 2010-2015, but no further increase was observed through 2020. The Ministry of Health, Labor, and Welfare in Japan presented draft future directions to promote pediatric drug development, where the modeling and simulation (M&amp;S) approach was introduced as a tool to support efficacy and safety, utilizing existing data when building a flexible data package for pediatric drug approval. M&amp;S is considered a powerful scientific tool in pediatric drug development using the pediatric extrapolation approach. We examined approval application data packages for pediatric drugs approved in Japan from January 2019 to March 2023, where 95 drug products were identified as pediatric drugs for this survey. Drugs with complete, partial, or no extrapolation accounted for 43.2%, 30.5%, and 26.3% of the total drugs, respectively. M&amp;S was widely used as the major rationale in dose selection for pediatric clinical trials and/or the recommended dosing regimen in drug approval applications for the pediatric population (60.0%). Further use of existing data with extrapolation strategies may lead to the development of flexible and efficient data packages for pediatric drug approval. Since safety profiles may be different between pediatric and adult populations due to age-related factors, pediatric developmental safety should be incorporated into M&amp;S in future assessments. The pharmaceutical industry, regulatory authorities, and academia need to discuss development strategies from an early stage and share lessons learned, thereby facilitating further discussions on efficient pediatric drug development and delivering drugs for children without delay in Japan.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 12","pages":"1889-1899"},"PeriodicalIF":0.0,"publicationDate":"2025-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876348","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}