Clinical Pharmacology & Therapeutics最新文献

{"title":"Tocilizumab Dosing for Management of T Cell-Engaging Bispecific Antibody-Related CRS in Patients With R/R B-Cell NHL","authors":"Candice Jamois,&nbsp;David C. Turner,&nbsp;Leonid Gibiansky,&nbsp;Feifei Li,&nbsp;Jean-Francois Menuet,&nbsp;Leonardo Roque Pereira,&nbsp;Linda Lundberg,&nbsp;Elena Guerini,&nbsp;David J. Carlile,&nbsp;James Relf,&nbsp;Michael C. Wei,&nbsp;Antonia Kwan,&nbsp;Nicolas Frey,&nbsp;Susan Grange","doi":"10.1002/cpt.3751","DOIUrl":"10.1002/cpt.3751","url":null,"abstract":"<p>The recent surge in T-cell-engaging and chimeric antigen receptor (CAR) T-cell therapies is changing the landscape of cancer therapy. Cytokine release syndrome (CRS) is a systemic inflammatory response syndrome that is a well-known complication of these therapies, of which interleukin-6 (IL-6) is a key mediator. Tocilizumab, an IL-6 receptor (IL-6R) antagonist, is approved for the management of CAR T-cell therapy-induced CRS in adults and in pediatric patients aged ≥ 2 years old. However, the approved dosing schedule was not based on IL-6R occupancy and may not be the most suitable schedule for T-cell-engaging therapies such as bispecific antibodies (bsAb) due to key differences in the levels of released IL-6, the clinical symptomatology of CRS, and the pharmacology of tocilizumab across settings. In this study, we adapted a previously developed tocilizumab and soluble IL-6R (sIL-6R) population pharmacokinetic model to describe and predict tocilizumab concentrations and sIL-6R occupancy over time in patients with anti-CD20 bsAb-induced CRS following tocilizumab dosing. Using this model, which incorporates target binding and receptor occupancy, we propose a new tocilizumab dosing regimen that is based on quantitative clinical pharmacology, cytokine analyses, and clinical practice patterns in patients with relapsed/refractory B-cell non-Hodgkin's lymphoma (R/R B-NHL) treated with the anti-CD20 bsAb mosunetuzumab or glofitamab. This schedule (up to two 8 mg/kg intravenous tocilizumab doses per CRS event at least 8 hours apart and a maximum of three doses in 6 weeks) can be used to effectively manage acute CRS induced by anti-CD20 bsAb in patients with R/R B-NHL.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 4","pages":"917-927"},"PeriodicalIF":5.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of Regression and Categorical Analysis for Pharmacokinetic Data From Renal Impairment Studies","authors":"Gerald Chun-To So,&nbsp;Ying Grace Li,&nbsp;Stephen D. Hall,&nbsp;Jenny Chien,&nbsp;Christopher D. Payne,&nbsp;Maria M. Posada,&nbsp;Maria Lucia Buziqui Piruzeli,&nbsp;Yan Jin","doi":"10.1002/cpt.3745","DOIUrl":"10.1002/cpt.3745","url":null,"abstract":"<p>The US Food and Drug Administration 2024 guidance prefers regression analysis over categorical analysis for pharmacokinetic data for studies that assess pharmacokinetics in patients with impaired renal functions. The objective of this study was to compare these two statistical methods for pharmacokinetic data analysis of renal impairment studies. Baseline data from seven renal impairment studies were pooled to estimate the impact of three creatinine-based equations (Cockcroft-Gault, CKD-EPI₂₀₀₉, and absolute CKD-EPI₂₀₀₉) on classification of participants into different renal impairment categories. Retrospective analyses were performed on two renal impairment studies with three distinct analytes (predominantly renally cleared; and predominantly metabolized by hepatic cytochrome P450 enzymes, or by systemic peptidase) using regression or categorical statistical analysis methods and creatine-based equations. While the three equations were highly correlated, the use of a different equation may result in up to 50% of participants being reclassified into different renal impairment groups. Categorical analysis with analysis of variance provided different point estimates and precision of exposure difference for a given renal impairment group based on the equation used. The use of regression analysis without inclusion of data from participants on hemodialysis, as recommended by the Food and Drug Administration, showed most consistent estimate of the relationship between renal impairment and exposure of three analytes. These retrospective analyses support the Food and Drug Administration recommendations of using regression analysis without data from participants on hemodialysis as the primary analysis of data for renal impairment study; and established a modeling strategy for such analysis.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 4","pages":"885-893"},"PeriodicalIF":5.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Pharmacometric Method for Quantitative Determination of Improvement in Body Composition and Characterization of the Exposure-Response Relationship during Treatment of Obesity with Tirzepatide.","authors":"Emmanuel Chigutsa, Lucy Her, Xiaosu Ma, Shweta Urva, Karen Schneck","doi":"10.1002/cpt.3750","DOIUrl":"https://doi.org/10.1002/cpt.3750","url":null,"abstract":"<p><p>About half of the world's population is living with overweight or obesity. Tirzepatide is an approved treatment for chronic weight management. We sought to characterize the exposure-response relationship for weight reduction in patients with overweight or obesity and quantify the associated changes in body composition. Monthly body weight measurements were available from 2,539 study participants in a phase 3 clinical trial investigating placebo, 5, 10, or 15 mg of tirzepatide administered once-weekly. The dependent variables used for modeling were fat-free mass (FFM) and fat mass. These FFM and fat mass values were calculated for each patient based on their total body weight, height, and sex. The exposure-response model revealed that administration of tirzepatide resulted in three times greater reduction of fat mass than that of FFM. This differential effect resulted in improved body composition over time. The model results showed good agreement with available data from a subset (10%) of clinical trial participants who had dual energy x-ray absorptiometry (DXA) measurements. For the same drug exposure, females achieved greater weight reduction than males. Study participants with higher baseline weight or body mass index at baseline had a slower rate of weight reduction and were expected to take longer to reach their nadir weight. We present and propose the use of a pharmacometric-based body composition model to describe weight reduction in future clinical trials investigating similar drugs in similar patient populations, in lieu of DXA scans. In such future trials, our approach can be used to describe exposure-response relationships, optimize doses, and investigate covariates, while considering potential differences in fat mass and FFM.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of Apixaban Pharmacokinetics/Pharmacodynamics and Dose Assessment in Pediatric Patients with Congenital or Acquired Heart Disease","authors":"Antoinette Ajavon-Hartmann,&nbsp;Praneeth Jarugula,&nbsp;Hyunmoon Back,&nbsp;Obinna Obianom,&nbsp;Elizabeth Ludwig,&nbsp;Christina Crevar,&nbsp;David Marchisin,&nbsp;Zhaoqing Wang,&nbsp;Weidong Chen,&nbsp;Bing He,&nbsp;R. Mark Payne,&nbsp;Kristin M. Burns,&nbsp;Andrew C. Glatz,&nbsp;Christoph Male,&nbsp;Paul Monagle,&nbsp;Vidya Perera,&nbsp;Bindu Murthy,&nbsp;Samira Merali","doi":"10.1002/cpt.3689","DOIUrl":"10.1002/cpt.3689","url":null,"abstract":"<p>Apixaban is an oral direct inhibitor of factor Xa (FXa) that could be a treatment option for thromboembolism prevention in children with congenital or acquired heart disease (CAHD). Data from SAXOPHONE, a phase II pediatric study, were used to update a previously developed population pharmacokinetics (PPK) model and to assess the covariate effect of patient type on PK parameters while retaining previous covariates. Stochastic simulations were performed to assess whether the proposed dosing regimens in pediatric patients aged 28 days to &lt; 18 years matched adult exposures. The relationship between anti-Factor Xa (AXA) and apixaban concentration, as well as apixaban concentration and chromogenic FX, were evaluated. Apixaban dose adjustment in response to the growth of pediatric patients and changes in age and weight were also assessed. Apixaban PK in pediatric patients with CAHD was well characterized by a 2-compartment model with first-order absorption, dose-dependent F1, and first-order elimination. Apixaban apparent clearance (CL/F) and apparent volume of distribution in the central compartment (Vc/F) increased with increasing body weight. Apixaban CL/F was lower in pediatric patients with CAHD compared to adults and other pediatric patients. The fixed dose by weight-tiered dosing regimen for pediatric patients with CAHD (28 days to &lt; 18 years) achieved target exposures similar to adult VTE treatment and nonvalvular atrial fibrillation populations. A linear PK/PD relationship between apixaban and AXA was observed. Inhibition of FXa was observed across weight tiers. Apixaban dose adjustment in response to weight gain resulted in exposures similar to target adult exposures.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 2","pages":"365-377"},"PeriodicalIF":5.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3689","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Continuous Intravenous Nimodipine Infusion With Ethanol as Carrier in Aneurysmal Subarachnoid Hemorrhage Does Not Result in Measurable Cerebral Ethanol Levels","authors":"Miriam M. Moser,&nbsp;Karl Rössler,&nbsp;Dorian Hirschmann,&nbsp;Leon Gramss,&nbsp;Walter Plöchl,&nbsp;Johannes Herta,&nbsp;Andrea Reinprecht,&nbsp;Markus Zeitlinger,&nbsp;Arthur Hosmann","doi":"10.1002/cpt.3753","DOIUrl":"10.1002/cpt.3753","url":null,"abstract":"<p>An unimpaired neurological evaluation is essential for detecting delayed cerebral ischemia (DCI) in aneurysmal subarachnoid hemorrhage (aSAH) patients. Nimodipine is currently the only drug approved for DCI prevention. Intravenous nimodipine infusion contains 23.7 vol% ethanol as an excipient, resulting in up to 45 g of ethanol being infused daily, which may interfere with neurological assessment. Therefore, we aimed to measure ethanol concentrations in plasma, cerebrospinal fluid (CSF), and brain parenchyma during the infusion of 0.5–2 mg of nimodipine per hour in aSAH patients to quantify the ethanol neuronal exposure. Ethanol concentrations were determined by headspace gas chromatography-flame ionization detection in plasma and CSF and we set out brain parenchyma measurement using cerebral microdialysis, in 10 aSAH patients. In each compartment four samples were taken over a 6-hour interval during steady-state intravenous nimodipine infusion at four different doses (0.5, 1, 1.5 and 2 mg/hour). A total of 307 samples from plasma and CSF was measured. Ethanol levels were mostly below the quantification limit of 0.002 g/100 mL. In 36 samples ethanol concentration was ≥ 0.002 g/100 mL, ranging from 0.002 to 0.009 g/100 mL. These low values were not reproducible in a second measurement, suggesting these values likely reflected analytical variability rather than true ethanol concentrations. Nimodipine analysis in brain parenchyma was omitted due to insufficient microdialysate volume and low concentrations in blood and CSF. Continuous nimodipine infusion of up to 2 mg/hour is unlikely to impair neurological assessment in aSAH patients, as no significant CSF ethanol concentration (&lt; 0.002 g/100 mL) was detected.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 4","pages":"928-934"},"PeriodicalIF":5.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacogenetic Implementation Studies—Lessons Learned From the PREPARE Study","authors":"Henk-Jan Guchelaar,&nbsp;Cathelijne H. van der Wouden,&nbsp;Lisanne E. N. Manson,&nbsp;Heshu Abdullah-Koolmees,&nbsp;Kathrin Blagec,&nbsp;Tanja Blagus,&nbsp;Stefan Böhringer,&nbsp;Erika Cecchin,&nbsp;Ka-Chun Cheung,&nbsp;Vera H. M. Deneer,&nbsp;Siv Jonsson,&nbsp;Candace Joefield-Roka,&nbsp;Katja S. Just,&nbsp;Mats O. Karlsson,&nbsp;Lidija Konta,&nbsp;Rudolf Koopmann,&nbsp;Marjolein Kriek,&nbsp;Thorsten Lehr,&nbsp;Christina Mitropoulou,&nbsp;Victoria Rollinson,&nbsp;Rossana Roncato,&nbsp;Matthias Samwald,&nbsp;Elke Schaeffeler,&nbsp;Maria Skokou,&nbsp;Matthias Schwab,&nbsp;Daniela Steinberger,&nbsp;Julia C. Stingl,&nbsp;Roman Tremmel,&nbsp;Richard M. Turner,&nbsp;Mandy H. van Rhenen,&nbsp;Cristina L. Dávila-Fajardo,&nbsp;Vita Dolžan,&nbsp;George P. Patrinos,&nbsp;Munir Pirmohamed,&nbsp;Gere Sunder-Plassmann,&nbsp;Giuseppe Toffoli,&nbsp;Jesse J. Swen,&nbsp;Ubiquitous Pharmacogenomics Consortium","doi":"10.1002/cpt.3749","DOIUrl":"10.1002/cpt.3749","url":null,"abstract":"<p>The Ubiquitous Pharmacogenomics consortium (www.upgx.eu) has recently completed and published the Preemptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions (PREPARE) study on the implementation of panel-based pharmacogenetic testing. PREPARE has provided interesting lessons for the design, execution, and interpretation of future clinical implementation studies. In this paper, we share our experience and lessons learned from the PREPARE study for future pharmacogenetic implementation studies. Issues addressed are the study population, intervention, endpoint, randomization, blinding, crossover, ethics, real-world changes during the study, and data analysis and reporting.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 4","pages":"803-812"},"PeriodicalIF":5.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","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 Busulfan for Children and Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: A Critical Evaluation of Current PK Models and Dose Recommendations","authors":"Rashudy F. Mahomedradja,&nbsp;Tim Bognàr,&nbsp;Kaj E. van Schie,&nbsp;Ilse T. Kuipers,&nbsp;Moniek A. de Witte,&nbsp;Jurgen H.E. Kuball,&nbsp;Erfan Nur,&nbsp;Bram J. Wilhelm,&nbsp;Marise R. Heerma van Voss,&nbsp;Linda Franken,&nbsp;Arief Lalmohamed,&nbsp;Eleonora (Noortje) L. Swart,&nbsp;Dave C. de Leeuw,&nbsp;Imke H. Bartelink","doi":"10.1002/cpt.3748","DOIUrl":"10.1002/cpt.3748","url":null,"abstract":"<p>Busulfan is administered intravenously in conditioning regimens prior to allogeneic hematopoietic stem cell transplantation (HSCT), with model-informed precision dosing (MIPD) targeting a 4-day cumulative AUC of 80–100 mg*hour/L. Three pharmacokinetic (PK) models—Bognar, Langenhorst, and McCune—were evaluated using data with a minimum of 1 and a median of 2 PK sampling days from pediatric and adult patients at two tertiary hospitals in the Netherlands. Simulations with the best-performing model evaluated dose optimization and the role of therapeutic drug monitoring (TDM). The Bognar and Langenhorst models, with overlapping datasets (25% between models, 21% with the current), accurately described busulfan concentration-time curves in all 535 patients (0.18–72 years), especially in those &gt; 60 years (bias and precision in clearance; −5.6%, 6.48% and 16.55%, 16.95%; in observed concentrations −1.86%, −6.52% and 9.12%, 3.58% for both models &gt; 60 years). The McCune model underestimated clearance by 36% in children &lt; 2 years of age. Despite accounting for age-dependent glutathione depletion, the Langenhorst model did not outperform the simpler Bognar model. Model-based initial dosing did not improve target attainment over SmPC-based dosing. However, TDM-based MIPD with a single TDM on days 2–4 significantly improved target attainment (49% vs. 87%), with a number needed to treat for TDM of 2.5. This study demonstrates the clinical efficacy of simple PK models such as the Bognar model, providing that simplicity does not compromise performance. It highlights the inadequacy of nomogram-based dosing alone and reinforces the critical role of TDM in optimizing busulfan exposure for pediatric and adult myeloablative HSCT patients.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 3","pages":"723-734"},"PeriodicalIF":5.5,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3748","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure-Response Relationships for Axatilimab in Patients with Chronic Graft-Versus-Host Disease","authors":"Yan-ou Yang,&nbsp;Alina Volkova,&nbsp;Victor Sokolov,&nbsp;Xing Liu,&nbsp;Cristina Leon,&nbsp;Yuri Kosinsky,&nbsp;Jennifer Sheng,&nbsp;Xuejun Chen","doi":"10.1002/cpt.3731","DOIUrl":"10.1002/cpt.3731","url":null,"abstract":"<p>Axatilimab, a high-affinity humanized monoclonal antibody that targets colony-stimulating factor 1 receptor, is approved for the treatment of chronic graft-versus-host disease (cGVHD). Here, we describe the exposure-response relationships for efficacy and safety in patients with cGVHD who received axatilimab. Exposure-efficacy relationships were assessed in treated patients in the AGAVE-201 study (<i>n</i> = 239); exposure-safety relationships were assessed in treated patients in AGAVE-201 (<i>n</i> = 239) and the phase 1/2 SNDX-6352-0503 study (<i>n</i> = 39). For binary or time-to-event endpoints, logistic or Cox regression analyses, respectively, were performed using axatilimab exposure metrics that were derived from a previously developed population pharmacokinetic/pharmacodynamic model. Overall response and ≥ 7-point improvement in modified Lee Symptom Scale responses were associated with axatilimab exposure, with lower axatilimab exposure increasing the odds of a response. Duration of response was not associated with axatilimab exposure. Ten of 11 safety endpoints were associated with axatilimab exposure, with higher axatilimab exposure increasing the odds of adverse events. Among the 3 regimens evaluated in AGAVE-201, the 0.3 mg/kg once every 2 weeks (Q2W) regimen had the highest predicted probability of response. Additionally, this dose group had the lowest predicted probability of event occurrence across all 10 safety endpoints associated with exposure among the evaluated regimens. Despite body weight influencing axatilimab exposure by &gt; 20%, its effect on efficacy and safety endpoints remained minimal, with a maximum difference of ≤ 0.4% and ≤ 4.4% between the 1st and 4th quartiles of body weight, respectively. Taken together, these findings support the benefit–risk profile of axatilimab 0.3 mg/kg Q2W in patients with cGVHD.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 4","pages":"853-864"},"PeriodicalIF":5.5,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetic/Toxicodynamic Model for Polymyxin B in Critically Ill Patients to Identify the Risk of Nephrotoxicity","authors":"Patrick O. Hanafin,&nbsp;Ramya Mahadevan,&nbsp;Gauri G. Rao,&nbsp;Alexandre P. Zavascki,&nbsp;Ana Maria Sandri,&nbsp;Andrea Kwa,&nbsp;Marc H. Scheetz,&nbsp;Christine J. Kubin,&nbsp;Jayesh Shah,&nbsp;Benjamin P.Z. Cherng,&nbsp;Michael T. Yin,&nbsp;Jiping Wang,&nbsp;Lu Wang,&nbsp;David P. Calfee,&nbsp;Maureen Bolon,&nbsp;Anthony W. Purcell,&nbsp;Roger L. Nation,&nbsp;Jason M. Pogue,&nbsp;Jian Li,&nbsp;Keith S. Kaye","doi":"10.1002/cpt.3729","DOIUrl":"10.1002/cpt.3729","url":null,"abstract":"<p>Polymyxins are used against highly resistant Gram-negative pathogens, and nephrotoxicity (acute kidney injury, AKI) is the major dose-limiting adverse effect. We aimed to develop a well-informed population pharmacokinetic/toxicodynamic (PK/TD) model using the largest polymyxin B-treated critically ill patient population studied to inform polymyxin B dosing strategies. Critically ill patients receiving intravenous polymyxin B for at least 48 hours were enrolled in an observational study. Serum creatinine (SCr) concentrations were collected from electronic medical records. PK/TD analysis and Monte Carlo simulations were performed to determine the probability of AKI, <i>P</i>(AKI), for clinically relevant treatments. Patients (<i>N</i> = 117) aged 18–94 received intravenous polymyxin B (1.33–6.00 mg/kg/day) for 1–50 days. The changes in SCr were described using an indirect response model. The effects of polymyxin B-induced functional kidney injury were characterized using 9 transit compartments (mean time to onset ~7 days), leading to a reduction in SCr elimination. Sex was identified as a significant covariate for baseline SCr₀. Concomitant amikacin or vancomycin use resulted in increased sensitivity to polymyxin B. On day 21, Low (<i>f</i>AUC_0–24,_SS = ~10 mg·h/L), medium (<i>f</i>AUC_0–24,SS = ~20 mg·h/L ), and high (<i>f</i>AUC_0–24,SS = ~40 mg·h/L) drug exposures resulted in a <i>P</i>(AKI) (&gt; 1-fold SCr increase) of 25.8%, 32.5%, and 40.4%, respectively. This study, the largest to date, suggests that regimens ranging from low to high polymyxin B exposures can minimize <i>P</i>(AKI) over a longer duration (14 days). However, supratherapeutic exposure can be administered relatively safely when limited to a shorter duration (≤ 4 days). The population PK/TD model may be used to improve polymyxin B dosing to help conserve this last-line agent.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 4","pages":"841-852"},"PeriodicalIF":5.5,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12353974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comedications Associated with Immune-Related Adverse Events from Immune-Checkpoint Inhibitors","authors":"Léonard Laurent,&nbsp;Baptiste Abbar,&nbsp;Kevin Bihan,&nbsp;Elise Dumas,&nbsp;Floriane Jochum,&nbsp;Bénédicte Lebrun-Vignes,&nbsp;Jean-Philippe Spano,&nbsp;Joe-Elie Salem,&nbsp;Anne-Sophie Hamy,&nbsp;Fabien Reyal,&nbsp;Paul Gougis","doi":"10.1002/cpt.3721","DOIUrl":"10.1002/cpt.3721","url":null,"abstract":"<p>Immune-checkpoint inhibitors (ICI) have revolutionized cancer treatment but are responsible for various immune-related adverse events (irAE). The impact of non-anticancer medications (comedications) on irAE occurrence remains largely unexplored. The objective of this study was to assess comedications associated with an increased reporting of irAE with ICIs. In this pharmacovigilance study, all individual case safety reports (ICSRs) involving ICIs reported in the World Health Organization international pharmacovigilance database Vigibase up to January 2024 were extracted. All suspect or interacting comedications were analyzed individually and as drug classes using Anatomical Therapeutic Chemical classification level 4. The primary outcome was the reporting odds ratio (ROR) of irAE in patients who received both an ICI and the comedication of interest, compared with ICI-treated patients who did not receive that comedication. Among 169,753 ICSRs involving an ICI, a total of 314,366 comedications were recorded, with 8,122 identified as “suspect or interacting.” Analysis shows an increased reporting of nephritis with proton pump inhibitors (PPI) (ROR = 29.62 [95% CI = 18.61–47.14]) and with non-steroidal anti-inflammatory drugs (ROR = 10.47 [95% CI = 4.15–26.41]), myositis with statins (ROR = 9.41 [95% CI = 3.50–25.30]), ketoconazole with hepatitis (ROR = 20.49 [95% CI = 1.53–274.17]) and autoimmune bullous disease with dipeptyl-peptidase-4 inhibitors (ROR = 46.42 [95% CI = 11.71–184.05]), among others. Various drugs, including PPI (ROR = 8.61 [95% CI = 3.48–21.26]), some anti-infectives (sulfamethoxazole, ROR = 31.31 [95% CI = 13.32–73.61], clavulanic acid, ROR = 18.12 [95% CI = 4.77–68.89]), allopurinol (ROR = 57.11 [95% CI = 11.27–289.39]) or levetiracetam (ROR = 14.91 [95% CI = 2.15–103.64]) were associated with serious cutaneous adverse reactions. Complementary analysis showed higher ROR in the ICI population versus without ICI for the association of nephritis with ibuprofen (ROR_ICI = 27.82 <i>vs.</i> ROR_{VigiBaseWithoutICI} = 3.56, ROR_ratio = 7.81 [95% CI = 1.23–49.50]) and myocarditis with influenza vaccine (ROR_ICI = 22.74 vs. ROR_{VigiBaseWithoutICI} = 0.66, ROR_ratio = 34.45 [95% CI = 1.66–723.24]), suggesting a synergistic toxicity. This study identified multiple comedications associated with an increased reporting of specific irAE. Some of them might be synergistic warranting further investigation.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 3","pages":"593-599"},"PeriodicalIF":5.5,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3721","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}