Journal of Clinical Pharmacology最新文献

{"title":"THC Precision Dosing Requires Exposure Provenance and Psychiatric Phenotyping.","authors":"Yu-Yuan Hung, Lien-Chung Wei","doi":"10.1002/jcph.70283","DOIUrl":"10.1002/jcph.70283","url":null,"abstract":"","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"66 9","pages":"e70283"},"PeriodicalIF":2.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148882332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Portability of Surrogate Endpoints.","authors":"Henry Bair","doi":"10.1002/jcph.70286","DOIUrl":"10.1002/jcph.70286","url":null,"abstract":"","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"66 9","pages":"e70286"},"PeriodicalIF":2.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"One Model to Dose Them All: A Population Pharmacokinetic Model for Multiple Aminoglycosides Across the Human Lifespan.","authors":"Dominic M H Tong, Jonathan D Faldasz, Ron J Keizer, Jasmine H Hughes","doi":"10.1002/jcph.70231","DOIUrl":"10.1002/jcph.70231","url":null,"abstract":"<p><p>Aminoglycosides require therapeutic drug monitoring due to substantial pharmacokinetic variability across individuals. While population pharmacokinetic (popPK) models have been developed for individual drugs across age groups, and cross-drug maturation models have been explored, it is unclear whether pooling data across aminoglycosides improves predictive performance. We developed and evaluated a unified multi-aminoglycoside popPK model spanning neonates, children, and adults. De-identified data from 5659 amikacin, gentamicin, and tobramycin patients at 154 US institutions were split into training and testing datasets. Predictive performance in the test dataset was evaluated using mean percent error, normalized root mean square error (nRMSE), and clinical accuracy (trough concentrations correctly classified as below or above 1 mg/L and non-troughs within 20% of observation), and compared with selected published popPK models. To assess generalizability, the final model was refit using single-drug datasets and leave-one-subgroup-out datasets. The unified model achieved the lowest nRMSE across age groups, with absolute reductions of 0.6%-24.8%. Clinical accuracy was highest for the unified model, with a posteriori accuracy in pediatric patients of 56.4% versus 48% in the best published model. Leave-one-out refits yielded similar estimates but reduced precision, while single-drug models demonstrated substantially reduced precision, and one such model was not identifiable. This unified model improved predictive performance across drugs and age groups and demonstrated robustness to exclusion of individual drug-age group combinations. These findings support use of a unified aminoglycoside model for Bayesian model-informed precision dosing and demonstrate the advantages of pooling drugs within a class and across developmental stages.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"66 9","pages":"e70231"},"PeriodicalIF":2.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148882280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population pharmacokinetics for the CTLA-4 modulator gotistobart in patients with advanced solid tumors.","authors":"Tianhong Li, Jiahui Xue, Yang Liu, Jun Yang, Ido D Weiss, Hasan Abu Kharma, Juanjuan Su, Yuye Shen, Tairan Yang, Kumpal Madrasi, Frank Engler, Shuang Liang, Pan Zheng","doi":"10.1002/jcph.70275","DOIUrl":"10.1002/jcph.70275","url":null,"abstract":"<p><p>Gotistobart is an investigational, next-generation, humanized IgG1 monoclonal antibody targeting cytotoxic T-lymphocyte antigen-4. It is engineered to preserve cytotoxic T-lymphocyte antigen-4 through endosomal recycling while enhancing intratumoral regulatory T-cell depletion. A population pharmacokinetic model was developed to characterize gotistobart pharmacokinetics and identify covariates contributing to inter-individual variability in patients with advanced solid tumors. Serum concentration-time data were obtained from 632 patients enrolled in three phase I-III clinical trials. In total, 3406 pharmacokinetic observations across a dose range from 0.1 to 10 mg/kg were collected. A two-compartment model with linear elimination best described the data, with inter-individual variability on clearance, central volume, and peripheral volume. Parameter estimates were precise, with typical values of 0.005 L/h for clearance, 0.021 L/h for inter-compartmental clearance, 2.59 L for central volume, and 3.43 L for peripheral volume. Covariates identified in the model included body weight and albumin on clearance and volumes, and sex on volumes, with limited clinically relevant impact. The model was evaluated using parameter precision, goodness-of-fit diagnostics, and prediction-corrected visual predictive checks. The model was used to simulate concentration-time profiles for clinically relevant dosing regimens. Simulations demonstrated the expected steady-state pharmacokinetic behavior, with dose-dependent increases in peak and trough concentrations. Compared with 6 mg/kg every 3 weeks, administration of two 10 mg/kg loading doses followed by 6 mg/kg every 3 weeks accelerated the attainment of steady state. The validated population pharmacokinetic model provides a quantitative foundation for subsequent exposure-response analyses and regimen selection.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"66 9","pages":"e70275"},"PeriodicalIF":2.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148882341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting Oral HIV Pre-Exposure Prophylaxis Efficacy in Cisgender Women Across Pregnancy and Postpartum.","authors":"Yifan Yu, Kristina M Brooks, Gustavo F Doncel, Brookie M Best, Mark A Marzinke, Mark Mirochnick, Peter L Anderson, Landon Myer, Connie Celum, Renee Heffron, Jenell Coleman, Dvora L Joseph Davey, Lanxin Zhang, Max von Kleist, Craig W Hendrix, Jeremiah D Momper, Robert Bies, Rachel K Scott","doi":"10.1002/jcph.70278","DOIUrl":"10.1002/jcph.70278","url":null,"abstract":"<p><p>Cisgender women face an increased risk of HIV acquisition during pregnancy and postpartum. Oral pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir disoproxil fumarate (F/TDF) is recommended in pregnancy despite limited published pharmacokinetic (PK) and efficacy data during pregnancy. Altered PK during pregnancy may reduce prophylactic efficacy and necessitate higher adherence. Tenofovir alafenamide (TAF) is a newer tenofovir prodrug with higher tenofovir diphosphate (TFV-DP) exposure in peripheral blood mononuclear cells (PBMCs), but the prophylactic efficacy of F/TAF across different reproductive stages in women is understudied. We adapted a multiscale modeling framework to predict the prophylactic efficacy of F/TDF and F/TAF across varying adherence levels and during the second trimester, third trimester, and 6-12 weeks postpartum. Clinical trial simulations were conducted utilizing PBMC TFV-DP and emtricitabine triphosphate concentrations as surrogate markers for F/TAF and F/TDF efficacy. For both F/TDF and F/TAF, prophylactic efficacy was lowest during the second trimester, increased in the third trimester (but remained below nonpregnant levels), and was highest postpartum. At high adherence levels of five or more pills per week, predicted effectiveness remained high across pregnancy and postpartum and effectiveness exceeded 97% for both regimens, with maximum decreases in the second trimester of only 0.9 percent point for F/TDF and 0.3 percent point for F/TAF. These findings suggest that adherence is the primary determinant of PrEP effectiveness during pregnancy and postpartum, while pregnancy-related PK changes have a limited impact on efficacy.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"66 9","pages":"e70278"},"PeriodicalIF":2.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148882321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Volumetric Microsampling for Patient-Centric Therapeutic Drug Monitoring in Clinical Pharmacology: A Scoping Review.","authors":"Hari Prabhath Tummala, Abbie D Leino, Nathaniel J Rhodes, Kevin J Downes, Marc H Scheetz, Manjunath P Pai","doi":"10.1002/jcph.70290","DOIUrl":"10.1002/jcph.70290","url":null,"abstract":"<p><p>Accurate drug concentration measurement is essential for precision pharmacotherapy, but conventional therapeutic drug monitoring (TDM) requires venous sampling, increasing patient burden, and potentially limiting participation in TDM and model-informed precision dosing (MIPD). Volumetric microsampling enables self-collection of small, fixed volume capillary samples for centralized analysis and may reduce hematocrit-related volumetric bias associated with conventional dried blood spots. This scoping review, conducted according to the PRISMA Extension for Scoping Reviews, synthesized 67 patient-cohort studies published from 2014 through 2026. Studies spanned at least 18 countries and multiple clinical specialties. Liquid chromatography-tandem mass spectrometry was used in 61 studies (91%), and most reported validation using or referencing EMA, FDA, IATDMCT, or CLSI criteria. Recovery was minimally affected across evaluated hematocrit ranges for most analytes, and many analytes remained stable in dried samples, although stability varied by analyte and storage conditions. Where assessed, patient preference was high (80%-100%). However, interpretation against established plasma therapeutic ranges often required whole-blood-to-plasma or capillary-to-venous conversion, with inconsistent derivation and validation methods. Fixed conversion factors performed well for lacosamide and levetiracetam but were less reliable for lamotrigine at high concentrations. Several analyte-matrix combinations, including cefepime, vancomycin, meropenem, paclitaxel, abiraterone, and mitotane, did not consistently meet agreement criteria. Volumetric microsampling can support patient-centered drug monitoring when validated for the specific analyte, matrix, device, and clinical application. Future research should prioritize drug-specific optimization, multicenter validation, standardized conversion reporting, and integration with MIPD platforms.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"66 9","pages":"e70290"},"PeriodicalIF":2.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Food on Balcinrenone/Dapagliflozin Pharmacokinetics and the Pharmacokinetics of Balcinrenone When Dosed with a P-gp Inhibitor.","authors":"Anna L Eriksson, Deeyen Karsanji, Amy H Shi, Joanna Parkinson, Maria Heijer, Edward Austin, Bosse Lindmark, Charlotta Vedin-Nilsson, Judith Hartleib-Geschwindner, Maria Leonsson-Zachrisson, Hans Ericsson","doi":"10.1002/jcph.70282","DOIUrl":"10.1002/jcph.70282","url":null,"abstract":"<p><p>Balcinrenone (AZD9977) is a novel selective non-steroidal mineralocorticoid receptor antagonist with a distinct mode of action being developed as a fixed-dose combination with the sodium-glucose cotransporter-2 inhibitor dapagliflozin for the treatment of heart failure with impaired kidney function, and chronic kidney disease. In this Phase 1 randomized open-label three-way crossover study we investigated the effect of food on balcinrenone/dapagliflozin pharmacokinetics, and the pharmacokinetics of balcinrenone when dosed with a P-glycoprotein (P-gp) inhibitor. Fourteen healthy participants were administered an oral capsule of balcinrenone/dapagliflozin 40 mg/10 mg in three dosing periods: fasted (reference), fed (high-fat, high-calorie meal) and with a P-gp inhibitor (quinidine 300 mg × 2). Balcinrenone exposure was comparable in the fed and fasted states (geometric mean ratios [GMRs] [90% CI]: maximum plasma concentration [C_max] 1.05 [0.88, 1.25]; area under the plasma concentration-time curve from time 0 to infinity [AUC_inf] 1.12 [1.06, 1.19]). In the fed state, dapagliflozin AUC_inf was comparable to the fasted state (GMR [90% CI] 1.05 [1.01, 1.09]), whereas C_max was decreased (GMR [90% CI] 0.59 [0.51, 0.69]), in line with previous dapagliflozin food interaction studies. Co-administration with quinidine increased balcinrenone exposure: GMRs (90% CI) 1.48 (1.24, 1.76) and 1.24 (1.17, 1.31) for C_max and AUC_inf, respectively, but AUC fold increase was <2, the level used for classification of sensitive P-gp substrates. All interventions were well tolerated. In conclusion, this study supports dosing of balcinrenone/dapagliflozin without regard to food. Balcinrenone is not considered a sensitive P-gp substrate. No P-gp based dosing precautions are warranted based on this study.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"66 9","pages":"e70282"},"PeriodicalIF":2.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148882276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Pharmacokinetics: Gaps for Rational Use of Medicinal Cannabis.","authors":"Shuang Lu, Xin Liu, Linda Truong, Zheng Liu, Fei Guo, Jennifer Martin, Xiao Zhu","doi":"10.1002/jcph.70284","DOIUrl":"10.1002/jcph.70284","url":null,"abstract":"","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"66 9","pages":"e70284"},"PeriodicalIF":2.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148882278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tamoxifen Therapy Is Associated With Altered Intestinal P-Glycoprotein Activity In Vivo.","authors":"Álef Machado Gomes Pego, Fernanda de Lima Moreira, Ana Flavia Mendes Batista, Adriana Rocha, Maria Paula Marques Pereira, Eduardo Barbosa Coelho, Jurandyr Moreira de Andrade, Geraldo Duarte, Vera Lucia Lanchote, João Paulo Bianchi Ximenez","doi":"10.1002/jcph.70256","DOIUrl":"10.1002/jcph.70256","url":null,"abstract":"<p><p>Preclinical studies suggest that tamoxifen (TAM) may interact with the efflux transporter P-glycoprotein (P-gp); however, its effect on intestinal P-gp activity in vivo remains poorly characterized. This study evaluated intestinal P-gp activity in women receiving tamoxifen therapy using fexofenadine (FEXO) as a probe substrate. Sixteen women receiving tamoxifen (20 mg/day for ≥80 days) and 12 healthy women were enrolled. All participants received a single oral dose of fexofenadine (120 mg), and serial plasma samples were collected over 12 h. Pharmacokinetic parameters were determined by noncompartmental analysis, and plasma fexofenadine concentrations were quantified by LC-MS/MS. Systemic exposure to fexofenadine was lower in women receiving tamoxifen than in healthy women. Geometric mean (95% confidence interval [CI]) AUC_0-12h was 646.55 ng.h/mL (523.50-798.52) in the tamoxifen group and 994.77 ng.h/mL (832.21-1189.07) in healthy women, whereas AUC0-∞ was 715.40 ng.h/mL (588.92-869.05) and 1123.66 ng.h/mL (919.98-1372.43), respectively (P < .05). Apparent oral clearance (CL/F) was higher in women receiving tamoxifen (167.74 vs 106.79 L/h; P < .05), whereas elimination half-life was unchanged between groups. The observed pharmacokinetic profile is consistent with reduced oral bioavailability and suggests modulation of intestinal transporter-mediated drug disposition during tamoxifen therapy. These findings may have implications for the disposition of concomitantly administered orally administered P-gp substrates and warrant further investigation in dedicated clinical pharmacology studies.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"66 8","pages":"e70256"},"PeriodicalIF":2.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148714315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FCGR2A/FCGR3A Gene Polymorphisms and Clinical Variables as Predictors of Response to Tocilizumab and Rituximab in Patients With Rheumatoid Arthritis.","authors":"Alberto Jiménez Morales,&nbsp;Mar Maldonado-Montoro,&nbsp;Juan Enrique Martínez de la Plata,&nbsp;Cristina Pérez Ramírez,&nbsp;Abdelali Daddaoua,&nbsp;Carolina Alarcón Payer,&nbsp;Manuela Expósito Ruiz,&nbsp;Carlos García Collado","doi":"10.1002/jcph.1341","DOIUrl":"https://doi.org/10.1002/jcph.1341","url":null,"abstract":"<p><p>We evaluated the influence of clinical, biochemical, and genetic factors on response in 142 patients diagnosed with rheumatoid arthritis, of whom 87 patients were treated with tocilizumab (61.26%) and 55 patients were treated with rituximab (38.7%;) according to the variables European League Against Rheumatism (EULAR) response, remission, low disease activity, and improvement in Disease Activity Score, 28 joints (DAS28) at 6, 12, and 18 months. A retrospective prospective cohort study was conducted. Patients carrying the FCGR3A rs396991-TT genotype treated with tocilizumab showed higher EULAR response (OR, 5.075; 95%CI, 1.20-21.33; P = .027) at 12 months, those who were naive for biological disease-modifying antirheumatic drugs (bDMARDs) at the beginning of treatment showed satisfactory EULAR response, higher remission, and greater improvement in DAS28 at 6 months. Younger age at start of tocilizumab treatment was associated with satisfactory EULAR response at 18 months and greater remission at 6 and 18 months. Subcutaneous tocilizumab administration was associated with higher remission at 6 months and improved low disease activity rate at 12 months. In patients treated with rituximab, carriers of the FCGR2A rs1801274-TT genotype had higher EULAR response at 6 months (OR, 4.861; 95%CI, 1.11-21.12; P = .035), 12 months (OR, 4.667; p = 0.066, 95%CI, 0.90-24.12; P = .066), and 18 months (OR, 2.487; 95%CI, 0.35-17.31; P = .357), higher remission (OR: 10.625; p = 0.044, CI_95% : 1.07, 105.47) at 6 months, and greater improvement in DAS28 at 12 months (B = 0.782; 95%CI, -0.15 to 1.71; P = .098) and 18 months (B = 1.414; 95%CI, 0.19-2.63; P = .025). The FCGR3A rs396991-G allele was associated with improved low disease activity rate (OR, 4.904; 95%CI, 0.84-28.48; P = .077) and greater improvement in DAS28 (B = -1.083; 95%CI, -1.98 to -0.18; P = .021) at 18 months. Patients with a lower number of previous biological therapies had higher remission at 12 months. We suggest that the FCGR3A rs396991-TT genotype, higher baseline value of DAS28, subcutaneous tocilizumab administration, younger age at the beginning of treatment, and being bDMARD naive are associated with better response to tocilizumab. In patients treated with rituximab, we found better response in those patients with the FCGR2A rs1801274-TT genotype, the FCGR3A rs396991-G allele, and lower number of previous biological therapies.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"517-531"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1341","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36749159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}