Clinical Pharmacokinetics最新文献

{"title":"Population Pharmacokinetics of Epcoritamab Following Subcutaneous Administration in Relapsed or Refractory B Cell Non-Hodgkin Lymphoma.","authors":"Tommy Li, Leonid Gibiansky, Apurvasena Parikh, Marcel van der Linden, Kinjal Sanghavi, Matthew Putnins, Mariana Sacchi, Huaibao Feng, Tahamtan Ahmadi, Manish Gupta, Steven Xu","doi":"10.1007/s40262-024-01464-2","DOIUrl":"10.1007/s40262-024-01464-2","url":null,"abstract":"<p><strong>Background and objectives: </strong>Epcoritamab is a CD3xCD20 bispecific antibody approved for the treatment of adults with different types of relapsed or refractory (R/R) B cell non-Hodgkin lymphoma (B-NHL) after ≥ 2 lines of systemic therapy. Here we report the first results from a population pharmacokinetic model-based analysis using data from 2 phase 1/2 clinical trials (EPCORE<sup>®</sup> NHL-1, NCT03625037 and EPCORE NHL-3, NCT04542824) evaluating epcoritamab in patients with R/R B-NHL.</p><p><strong>Methods: </strong>Plasma concentration-time data included 6819 quantifiable pharmacokinetic samples from 327 patients with R/R B-NHL. A wide range of subcutaneous epcoritamab doses, 0.004-60 mg, was explored, with most patients (n = 298) following the approved dosing regimen: step-up dose (SUD) 1 of 0.16 mg on cycle 1 day 1 and SUD 2 of 0.8 mg on cycle 1 day 8, followed by a full dose of 48 mg administered weekly during cycles 1-3, biweekly in cycles 4-9, and every 4 weeks thereafter. Each cycle lasted 28 days. The data were analyzed using nonlinear mixed-effects modeling.</p><p><strong>Results: </strong>Quasisteady-state approximation of a two-compartment target-mediated drug disposition model with first-order absorption adequately characterized pharmacokinetics of epcoritamab following subcutaneous administration. After the first full dose and at the end of the weekly dosing regimen (end of cycle 3), the estimated median time to maximum concentration (t<sub>max</sub>) was 4 and 2.3 days, respectively. Age and body weight were significant covariates on the pharmacokinetics of epcoritamab. The geometric mean (coefficient of variation [CV], %) of the apparent total volume of distribution was 25.6 L (82%) for patients with R/R large B cell lymphoma in EPCORE NHL-1. Epcoritamab elimination exhibited nonlinear characteristics, with exposure increasing more than proportionally over 1.5-48 mg doses. The geometric mean (CV%) values of apparent total clearance and terminal half-life were 0.53 L/day (40%) and 22 days (58%), respectively, at the end of cycle 3 for the 48 mg full dose. Clinical data analyses did not identify any association between assessed characteristics, including body weight or age, and clinical efficacy or safety. After accounting for body weight, no clinically significant differences in epcoritamab pharmacokinetics were observed for sex, race, renal or hepatic function, or other disease characteristics. Age was not found to significantly affect epcoritamab pharmacokinetic exposure. Antidrug antibodies developed in 4 (2.6%) of 156 evaluable patients treated with the approved 0.16/0.8/48 mg regimen. Antidrug antibody status did not affect epcoritamab pharmacokinetics.</p><p><strong>Conclusions: </strong>Epcoritamab pharmacokinetics in R/R B-NHL were well characterized by the population pharmacokinetic model. No dosage adjustments are recommended in subpopulations based on body weight, age, sex, race, mild-to-moderate renal ","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"127-141"},"PeriodicalIF":4.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871600","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":"A Pooled Pharmacokinetic Analysis for Piperacillin/Tazobactam Across Different Patient Populations: From Premature Infants to the Elderly.","authors":"Daming Kong, Jason A Roberts, Jeffrey Lipman, Fabio Silvio Taccone, Michael Cohen-Wolkowiez, Fekade B Sime, Danny Tsai, Pieter A J G De Cock, Sutep Jaruratanasirikul, Sofie A M Dhaese, Andrew A Udy, Timothy W Felton, Robin Michelet, Céline Thibault, Jeroen V Koomen, Douglas J Eleveld, Michel M R F Struys, Jan J De Waele, Pieter J Colin","doi":"10.1007/s40262-024-01460-6","DOIUrl":"10.1007/s40262-024-01460-6","url":null,"abstract":"<p><strong>Background and objectives: </strong>The pharmacokinetics (PK) of piperacillin/tazobactam (PIP/TAZ) is highly variable across different patient populations and there are controversies regarding non-linear elimination as well as the fraction unbound of PIP (f_{UNB_PIP}). This has led to a plethora of subgroup-specific models, increasing the risk of misusing published models when optimising dosing regimens. In this study, we aimed to develop a single model to simultaneously describe the PK of PIP/TAZ in diverse patient populations and evaluate the current dosing recommendations by predicting the PK/pharmacodynamics (PD) target attainment throughout life.</p><p><strong>Methods: </strong>Population PK models were separately built for PIP and TAZ based on data from 13 studies in various patient populations. In the development of those single-drug models, postnatal age (PNA), postmenstrual age (PMA), total body weight (TBW), height, and serum creatinine (SCR) were tested as covariates. Subsequently, a combined population PK model was established and the correlations between the PK of PIP and TAZ were tested. Monte Carlo simulations were performed based on the final combined model to evaluate the current dosing recommendations.</p><p><strong>Results: </strong>The final combined model for PIP/TAZ consisted of four compartments (two for each drug), with covariates including TBW, PMA, and SCR. For a 70-kg, 35-year-old patient with SCR of 0.83 mg L^-1, the PIP values for V₁, CL, V₂ and Q₂ were 10.4 L, 10.6 L h^-1, 11.6 L and 15.2 L h^-1, respectively, and the TAZ values were 10.5 L, 9.58 L h^-1, 13.7 L and 16.8 L h^-1, respectively. The CL for both drugs show maturation in early life, reaching 50% at 54.2 weeks PMA. With advancing age, CL of TAZ declines to 50% at 61.6 years PMA, whereas CL of PIP declines more slowly, reaching 50% at 89.1 years PMA. The f_{UNB_PIP} was estimated as 64.5% and non-linear elimination was not supported by our data. The simulation results indicated considerable differences in PK/PD target attainment for different patient populations under current recommended dosing regimens.</p><p><strong>Conclusions: </strong>We developed a combined population PK model for PIP/TAZ across a broad range of patients covering the extremes of patient characteristics. This model can be used as a robust a priori model for Bayesian forecasting to achieve individualised dosing. The simulations indicate that adjustments based on the allometric theory as well as maturation and decline of CL of PIP may help the current dosing recommendations to provide consistent target attainment across patient populations.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"107-126"},"PeriodicalIF":4.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892132","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 and Toxicity Analysis of High-Dose Methotrexate in Patients with Central Nervous System Lymphoma.","authors":"Anyue Yin, Fleur A de Groot, Henk-Jan Guchelaar, Marcel Nijland, Jeanette K Doorduijn, Daan J Touw, Thijs Oude Munnink, Brenda C M de Winter, Lena E Friberg, Joost S P Vermaat, Dirk Jan A R Moes","doi":"10.1007/s40262-024-01452-6","DOIUrl":"10.1007/s40262-024-01452-6","url":null,"abstract":"<p><strong>Background: </strong>High-dose methotrexate (HD-MTX)-based polychemotherapy is widely used for patients with central nervous system (CNS) lymphoma. The pharmacokinetic (PK) variability and unpredictable occurrence of toxicity remain major concerns in HD-MTX treatment.</p><p><strong>Objectives: </strong>This study aimed to characterize the population PK of HD-MTX in patients with CNS lymphoma and to identify baseline predictors and exposure thresholds that predict a high risk of nephro- and hepatotoxicity.</p><p><strong>Methods: </strong>Routinely monitored serum MTX concentrations after intravenous infusion of HD-MTX and MTX dosing information were collected retrospectively. Acute event of toxicity (≥ grade 1) was defined according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 on the basis of serum creatinine and alanine aminotransferase. A population PK model was developed in NONMEM. Toxicity data were analyzed using a logistic regression model, and potential baseline and exposure-related predictors were investigated.</p><p><strong>Results: </strong>In total, 1584 MTX concentrations from 110 patients were available for analysis. A two-compartment population PK model adequately described the data. Estimated glomerular filtration rate (eGFR), treatment regimen, albumin, alkaline phosphatase, and body weight were identified as significant covariates that explain the PK variability of HD-MTX. Baseline eGFR and sex were identified as significant predictors for renal toxicity, and MTX dose (mg/m²) was the strongest predictor for hepatotoxicity. The MTX area under the concentration-time curve (AUC_24-∞) and concentration at 24 h (C_24h) were shown to correlate with renal toxicity only, and 49,800 μg/L × h (109.6 μmol/L × h) and C_24h > 3930 μg/L (8.65 μmol/L) were potential exposure thresholds predicting high risk (proportion > 60%).</p><p><strong>Conclusions: </strong>A population PK model was developed for HD-MTX in patients with CNS lymphoma. The toxicity analysis showed that lower baseline eGFR and male sex, and higher MTX dose are associated with increased risk of acute nephro- and hepatotoxicity, respectively. The proposed exposure thresholds that predict high risk of renal toxicity and the developed models hold the potential to guide HD-MTX dosage individualization and better prevent acute toxicity.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"79-91"},"PeriodicalIF":4.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766897","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":"Pharmacokinetics of Omadacycline in Adults with Cystic Fibrosis.","authors":"Madeline Sanders, Eunjin Hong, Peter S Chung, Adupa P Rao, Paul Beringer","doi":"10.1007/s40262-024-01440-w","DOIUrl":"10.1007/s40262-024-01440-w","url":null,"abstract":"<p><strong>Background: </strong>Omadacycline offers a potential advancement in the management of infections in people with cystic fibrosis (CF) because of its spectrum of activity, intrapulmonary penetration, and oral bioavailability. A prospective single-dose, single-arm study was conducted to characterize the pharmacokinetic (PK) profile of omadacycline in people with CF, considering the known alterations in PK observed in this population (NCT04460586, 2020-07-01).</p><p><strong>Methods: </strong>Plasma samples were obtained from nine adults with CF who received a single dose of intravenous omadacycline 100 mg over 0.5 h followed by a 1-week washout and an oral dose of omadacycline 300 mg. The data were analyzed using noncompartmental PK.</p><p><strong>Results: </strong>The maximum plasma concentration (C_max) and area under the curve extrapolated to infinity (AUC_0-∞) after intravenous administration of omadacycline were similar between healthy volunteers and people with CF. The absorption kinetics of oral omadacycline, encompassing both the rate (C_max and time to C_max [t_max]) and the extent (AUC_0-∞), also showed consistency between healthy volunteers and people with CF. The absolute bioavailability of the oral tablet formulation of omadacycline in people with CF (31.2%) was also consistent with that observed in healthy volunteers (34.5%). In comparing the two routes of administration, intravenous omadacycline 100 mg provided plasma exposures equivalent to those with oral omadacycline 300 mg in people with CF, as evidenced by geometric mean ratios for both AUC_0-∞ (0.9381; 90% confidence intervals [CI] 0.6783-1.2975) and C_max (0.7746; 90% CI 0.5478-1.0951).</p><p><strong>Conclusions: </strong>Overall, the similarity in plasma PK observed in this study when comparing healthy volunteers and infected patients indicates that no dosing alterations are necessary when using omadacycline in people with CF.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1701-1709"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709135","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":"SGLT2 Inhibitors in Patients with Heart Failure: A Model-Based Meta-Analysis.","authors":"Na Wang, Zhen Wu, Jianwei Ren, Xin Zheng, Xiaohong Han","doi":"10.1007/s40262-024-01443-7","DOIUrl":"10.1007/s40262-024-01443-7","url":null,"abstract":"<p><strong>Aims: </strong>This study aimed to quantify the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a therapeutic approach for heart failure.</p><p><strong>Methods: </strong>A systematic literature review was conducted to collect pharmacokinetics (PK) and pharmacodynamics (PD) data on empagliflozin, dapagliflozin, and canagliflozin. Population pharmacokinetic models were developed separately for each drug, along with PK/PD turnover models for SGLT2 inhibitors, to describe the time course of NT-proBNP and simulate its changes over 52 weeks.</p><p><strong>Results: </strong>A total of 42 publications were included in this study. The results showed that baseline NT-proBNP levels, estimated glomerular filtration rate levels, and body weight significantly influenced the therapeutic effects of SGLT2 inhibitors. Among the studied drugs, canagliflozin demonstrated a greater reduction in NT-proBNP at comparable baseline levels.</p><p><strong>Conclusions: </strong>Baseline NT-proBNP concentration, renal function, and body weight were covariates affecting the efficacy of SGLT2 inhibitors in reducing NT-proBNP. Canagliflozin showed the most favorable treatment outcomes at similar baseline levels. This model-based meta-analysis approach may support further drug development for SGLT2 inhibitors.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1667-1678"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686261","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":"Time-Efficacy Relationship of Semaglutide in the Treatment of Type 2 Diabetes Mellitus: A Model-Based Meta-Analysis.","authors":"Ke Zhang, Aiping Zhao, Zhen Wang, Kaihe Ye, Zhaosi Xu, Xiao Gong, Guanghu Zhu","doi":"10.1007/s40262-024-01449-1","DOIUrl":"10.1007/s40262-024-01449-1","url":null,"abstract":"<p><strong>Objective: </strong>Our objective was to quantify the efficacy of subcutaneous once-weekly semaglutide in treating type 2 diabetes mellitus (T2DM) over time.</p><p><strong>Methods: </strong>Based on a literature search of the PubMed, Embase, Cochrane, and Web of Science databases, a modified maximum effect (E_max) model including rebound effects was built using model-based meta-analysis with change from baseline in glycated hemoglobin as the efficacy endpoint. This was combined with the covariate model to form a final model, and then theoretical values of E_max and time to reach 50% of E_max (ET₅₀) were obtained for each dose. Model fit and prediction were assessed using goodness-of-fit plots and visual prediction checking.</p><p><strong>Results: </strong>E_max and ET₅₀ were influenced by the proportion of males and the baseline values, respectively. There was no evidence of a placebo effect with semaglutide. The efficacy of other doses became more significant over time, and a rebound effect was observed after maximum efficacy, at a rate of 0.018. Simulation of the typical efficacy at the different doses yielded a maximum efficacy of -1.58% with 0.5 mg and a maximum efficacy of -1.87% with 1 mg. In addition, the six simulated doses (0, 0.1, 0.2, 0.5, 1, and 2 mg) showed a dose-dependent relationship between dose and efficacy except for 0.4 mg and 0.8 mg. A higher dose would result in greater efficacy and a faster onset of action.</p><p><strong>Conclusion: </strong>The efficacy of semaglutide in glucose control was investigated using the model-based meta-analysis method, which yields new insights into the treatment of T2DM with semaglutide.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1679-1688"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643889","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":"Pharmacokinetics of Enteral Lormetazepam in Mechanically Ventilated ICU Patients with COVID-19: An Adjunct Sedative Study.","authors":"Jos L M L le Noble, Kimberly N Shudofsky, Norbert Foudraine, Nieko Punt, Paddy K J Janssen","doi":"10.1007/s40262-024-01455-3","DOIUrl":"10.1007/s40262-024-01455-3","url":null,"abstract":"<p><strong>Background and objective: </strong>During the coronavirus disease 2019 (COVID-19) pandemic, sedative prescriptions surged, leading to shortages of midazolam. This study investigates lormetazepam as an adjunct sedative alternative to midazolam for mechanically ventilated patients with COVID-19. We aimed to determine the clinical pharmacokinetics (PK) of enterally administered lormetazepam and provide dosing recommendations.</p><p><strong>Methods: </strong>Critically ill patients with acute respiratory distress syndrome (ARDS) or COVID-19 requiring mechanical ventilation were enrolled in April 2020. Lormetazepam 2 mg every 12 h was administered enterally. Blood samples were collected to quantify lormetazepam and its glucuronide. PK analysis was conducted using a one-compartment model with the Edsim++ KinPop plugin.</p><p><strong>Results: </strong>The primary PK parameters (means ± coefficient of variation [CV] %) for absorption constant (K_a), volume of distribution (V_d/F), and clearance (CL/F) were 6.4 h^-1, 207 L/70 kg, and 14.5 L/h/kg^0.75, respectively. V_d/F and CL/F median values were 2.64 L/kg and 2.53 mL/kg/min, respectively, with a half-life of 10.7 h. Lormetazepam's median ratio to its glucuronide was 11.5. Trough-guided dosing suggested alternatives of 0.92 mg three times daily, 1.62 mg twice daily, or 5.36 mg once daily.</p><p><strong>Conclusion: </strong>This is the first study to report a validated PK model for enterally administered lormetazepam as a sedative adjunct in critically ill adults on mechanical ventilation for ARDS and COVID-19. The model was internally validated using a bootstrap procedure. Adequate lormetazepam concentrations were achieved at prescribed doses, with no significant alterations in clearance or half-life. This population model may aid in dose optimization and sedation management for future intensive care unit (ICU) patients.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1769-1776"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638608","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 Pharmacokinetics of Ensitrelvir in Healthy Participants and Participants with SARS-CoV-2 Infection in the SCORPIO-SR Study.","authors":"Toru Ishibashi, Ryosuke Shimizu, Ryuji Kubota","doi":"10.1007/s40262-024-01446-4","DOIUrl":"10.1007/s40262-024-01446-4","url":null,"abstract":"<p><strong>Introduction: </strong>Ensitrelvir, a novel oral inhibitor of the 3C-like protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has shown efficacy and safety in participants with mild to moderate coronavirus disease 2019 (COVID-19) with once-daily multiple doses of 375 mg on day 1 followed by 125 mg on days 2-5. The aims of this study were to characterize the pharmacokinetics of ensitrelvir and to explore its exposure-response relationships on the dose regimen.</p><p><strong>Methods: </strong>Pharmacokinetic data, including 8034 plasma concentration datasets from 2060 participants, from two phase I and one phase II/III study in healthy participants and participants infected with SARS-CoV-2 were used to develop a population pharmacokinetic model. The correlation between exposure and drug response was evaluated using observed plasma concentrations and estimated pharmacokinetic parameters as pharmacokinetic indexes and viral RNA as drug response.</p><p><strong>Results: </strong>A two-compartment model with a first-order absorption model effectively described plasma ensitrelvir concentrations. The effects of body weight on clearance and volume of distribution and of food conditions and formulation on the absorption rate constant were selected as significant covariates. The efficacy indexes changed in the active group, but the responses were similar across the exposure range in the phase II/III study (SCORPIO-SR) regardless of the effects of the pharmacokinetic covariates.</p><p><strong>Conclusion: </strong>Population pharmacokinetics revealed that body weight is the most important covariate in the pharmacokinetics of ensitrelvir. The antiviral effect, independent of ensitrelvir exposure, was demonstrated on the current dose regimen for treatment of SARS-CoV-2 infection.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1723-1734"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675007","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":"Pharmacokinetics of Tarlatamab, a Delta-Like Ligand-3 (DLL3) Targeted Half-Life Extended Bispecific T-Cell Engager (BiTE^®) Immunotherapy in Adult Patients with Previously Treated Small-Cell Lung Cancer: Results from DeLLphi-300, a Phase I Multiple-Dose-Escalation Study.","authors":"Mukul Minocha, Corbin G Thompson, Alexis Murphy, Yanchen Zhou, Christian Brandl, Amanda Parkes, Xi Chen, Brian Yu, Pablo Martinez, Brett E Houk","doi":"10.1007/s40262-024-01451-7","DOIUrl":"10.1007/s40262-024-01451-7","url":null,"abstract":"<p><strong>Background: </strong>Tarlatamab binds to delta-like ligand 3 on cancer cells and cluster of differentiation-3 on T cells, leading to T-cell-mediated tumor lysis, and has demonstrated a promising safety and efficacy profile in patients with previously treated small-cell lung cancer (SCLC). Here, we present pharmacokinetic results from DeLLphi-300 (NCT03319940), an ongoing international, open-label, first-in-human study in previously treated adult patients with SCLC.</p><p><strong>Methods: </strong>Multiple escalating doses of tarlatamab were administered every 2 weeks (Q2W; 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, and 100 mg) in a 28-day cycle. To reduce the risk of cytokine-release syndrome, starting at the 3 mg dose level, a step dose regimen was employed consisting of a 1 mg infusion on cycle 1 day 1 (C1D1), followed by the target dose on C1D8, C1D15, and Q2W thereafter. All doses were infused over 1 h. Other tarlatamab dosing regimens were also explored, either for patient convenience (every 3 weeks) or to mitigate cytokine-release syndrome (extended intravenous infusion over a period of 3 days). Intensive pharmacokinetic samples were collected during cycles 1 and 2, and additional samples for pharmacokinetic and immunogenicity measurement were collected at regular intervals in later cycles. Pharmacokinetic data were analyzed using noncompartmental analysis, and antidrug antibody (ADA) incidence, including any effect on tarlatamab pharmacokinetic parameters, was summarized.</p><p><strong>Results: </strong>Pharmacokinetic data were available from 203 patients. The median age was 62 years (range 32-80), and 55.7% (n = 113) of patients were male, 78.3% (n = 159) were white, and 8.3% (n = 17) were of Japanese descent. Following intravenous infusion, serum tarlatamab concentrations declined with time in a biphasic manner. Serum exposures increased in an approximately dose-proportional manner across the evaluated target dose range with a mean (standard deviation) estimated terminal phase elimination half-life of 5.8 (1.6) days, and steady state achieved by approximately C2D15. Of the 183 evaluable patients, 12 (6.6%) developed treatment-emergent ADAs; the distribution of dose-normalized serum concentrations were similar between patients who were ADA positive and ADA negative. In addition, the distribution of exposures was comparable in Japanese and non-Japanese patients.</p><p><strong>Conclusion: </strong>In patients with previously treated SCLC, tarlatamab demonstrated dose-proportional pharmacokinetic and extended half-life characteristics that support a Q2W dosing interval. Neither Japanese race nor ADA had a clinically relevant impact on exposures.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1757-1768"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715062","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":"Population Pharmacokinetics of Intravenous Paracetamol and Its Metabolites in Extreme Preterm Neonates in the Context of Patent Ductus Arteriosus Treatment.","authors":"Faheemah Padavia, Jean-Marc Treluyer, Gilles Cambonie, Cyril Flamant, Aline Rideau, Manon Tauzin, Juliana Patkai, Géraldine Gascoin, Mirka Lumia, Outi Aikio, Frantz Foissac, Saïk Urien, Sihem Benaboud, Gabrielle Lui, Léo Froelicher Bournaud, Yi Zheng, Ruth Kemper, Marine Tortigue, Alban-Elouen Baruteau, Jaana Kallio, Mikko Hallman, Alpha Diallo, Léa Levoyer, Jean-Christophe Roze, Naïm Bouazza","doi":"10.1007/s40262-024-01439-3","DOIUrl":"10.1007/s40262-024-01439-3","url":null,"abstract":"<p><strong>Aims: </strong>Our aim was to describe the pharmacokinetics of paracetamol and its metabolites in extreme preterm neonates in the context of patent ductus arteriosus treatment. Factors associated with inter-individual variability and metabolic pathways were studied. The association between drug exposure and clinical outcomes were investigated.</p><p><strong>Methods: </strong>Preterm neonates of 23-26 weeks' gestational age received paracetamol within 12 h after birth. Plasma concentrations of paracetamol and its metabolites were measured throughout 5 days of treatment. Clinical success was defined as ductus closure on two consecutive days or at day 7. Aspartate aminotransferase and alanine aminotransferase levels were used as surrogates for liver damage.</p><p><strong>Results: </strong>Data from 30 preterm neonates were available for pharmacokinetic analysis. Paracetamol pharmacokinetics were described using a two-compartment model with significant positive effects of weight on clearance and of birth length on peripheral compartment volume. Paracetamol was mainly metabolised into sulphate (89%) then glucuronide (6%), and the oxidative metabolic pathway was reduced (4%). The glucuronidation pathway increased with gestational age, whereas the sulfation pathway decreased. No difference was observed in drug exposure between successful and unsuccessful patients. No increase in aspartate aminotransferase and alanine aminotransferase levels were observed during treatment, and no association was found with either paracetamol or oxidative metabolite exposures.</p><p><strong>Conclusion: </strong>The relative proportions of the metabolic pathways were characterised with gestational age. In the range of observed drug exposures, no association was found with clinical response or liver biomarkers. These findings may suggest that paracetamol concentrations were within the range that already guarantee a maximum effect on ductus closure.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1689-1700"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692703","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}