Clinical Pharmacokinetics最新文献

{"title":"Pharmacometabolomics Detects Various Unreported Metoprolol Metabolites in Urine of (Potential) Living Kidney Donors and Kidney Transplant Recipients.","authors":"Wietske A Heddema, Marieke A J Hof, Piotr Sosnowski, Stephan J L Bakker, Gérard Hopfgartner, Frank Klont","doi":"10.1007/s40262-025-01502-7","DOIUrl":"10.1007/s40262-025-01502-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Metoprolol is primarily metabolized via the polymorphic cytochrome P450-2D6 (CYP2D6) enzyme, which underlies interindividual variation in conversion rates and may benefit from pharmacogenetics-driven therapy personalization. However, the field relies heavily on knowledge of a drug's metabolism, often originating from early-phase clinical trials with single-dose administration in small samples of healthy volunteers. Pharmacogenetics could thus benefit from real-world drug metabolism studies.</p><p><strong>Methods: </strong>We conducted a real-world drug metabolism study for metoprolol in 18 (potential) living kidney donors and 374 kidney transplant recipients from the Transplant Lines Food and Nutrition Biobank and Cohort Study (NCT02811835) using existing liquid chromatography-high resolution mass spectrometry pharmacometabolomic data.</p><p><strong>Results: </strong>In both groups, we confirmed the presence of seven expected metabolites, including the high-abundance substances metoprolol acid and hydroxymetoprolol. We were unable to detect deisopropylmetoprolol and a metabolite known as \"H 119/68\". However, we did find putative further oxidized forms, namely the expected variant of deisopropylmetoprolol in which the primary amine is removed and the leftover methyl group is oxidized into a carboxylic acid (\"H 104/83\") and an unknown/unreported metoprolol metabolite that we refer to as \"metoprolol benzoic acid\". Moreover, we found nine other previously unknown/unreported metabolites, putatively reflecting N-glucuronidated metoprolol, four glucuronidated versions of hydroxymetoprolol, and a formylated, a glucuronidated, and two hydroxylated versions of metoprolol acid. Interestingly, the same metabolites were detected in potential living kidney donors and kidney transplant recipients, and metabolite profiles did not differ between both groups in principal component analysis.</p><p><strong>Conclusion: </strong>We found more metoprolol metabolites than previously reported, calling for replication studies and evaluation of pharmacogenetic testing approaches to realize safer, more effective metoprolol therapy.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"779-789"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970934","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 Modelling of Remdesivir and Its Metabolite GS-441524 in Hospitalised Patients with COVID-19.","authors":"Darren M Roberts, Xin Liu, Suzanne L Parker, Andrew Burke, Jenny Peek, Jane E Carland, Bridin Murnion, Vincent Seah, Steven C Wallis, Chandra D Sumi, Saurabh Pandey, Hergen Buscher, Anthony Byrne, Indy Sandaradura, David Bowen, Simon Holz, Adam G Stewart, Krispin M Hajkowicz, Jason A Roberts","doi":"10.1007/s40262-025-01496-2","DOIUrl":"10.1007/s40262-025-01496-2","url":null,"abstract":"<p><strong>Background and objectives: </strong>There are limited data testing whether the licensed dose of remdesivir and its active metabolite GS-441524 achieve target concentrations in hospitalised patients with confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of coronavirus disease-2019 (COVID-19). The objectives of this study were to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalised patients treated for COVID-19 and develop a model to inform dose optimisation in clinical use.</p><p><strong>Methods: </strong>This was a prospective, open-labelled, multi-centre, observational study in four Australian hospitals in adults with confirmed SARS-CoV-2 infection. Patients were administered the licensed remdesivir dose. Remdesivir and GS-441524 concentrations were quantified in multiple plasma samples at different times in the dosing interval by ultra-high-performance liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Patients were divided into two groups: pharmacokinetic model building and external validation. A population pharmacokinetic analysis was built using non-linear mixed-effects modelling. Monte Carlo simulations were performed to describe the impact of age, kidney function and dosing regimen on drug concentrations.</p><p><strong>Results: </strong>In total, 33 patients were enrolled (median age 70 years, estimated glomerular filtration rate (eGFR) 80 mL/min/1.73 m²). The pharmacokinetics for both compounds were adequately described by a two-compartment model (one compartment for each compound) with first-order elimination. Key covariates included in the final model were age and eGFR. GS-441524 plasma concentrations exceeded the lowest reported half-maximal effective concentration (EC₅₀) with the recommended dosage, and higher dosages exceeded the lowest reported 90%-effective concentration (EC₉₀).</p><p><strong>Conclusions: </strong>The licensed remdesivir dose may achieve target concentrations of GS-441524, but higher dosages may optimise outcomes. Dose adjustments are guided primarily by kidney function.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"743-756"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984152","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 Dose Optimization of Pazopanib in Real-World Patients with Cancer.","authors":"Zhiyuan Tan, Swantje Völler, Anyue Yin, Amy Rieborn, Hans Gelderblom, Tom van der Hulle, Catherijne A J Knibbe, Dirk Jan A R Moes","doi":"10.1007/s40262-025-01504-5","DOIUrl":"https://doi.org/10.1007/s40262-025-01504-5","url":null,"abstract":"<p><strong>Background and objectives: </strong>Pazopanib is approved for metastatic renal cell carcinoma (mRCC) and soft tissue sarcoma (STS) in a dose of 800 mg once daily (QD) taken under fasted conditions. In clinical practice, approximately 60% of patients require dose reductions due to toxicity, with severe liver toxicity necessitating treatment interruptions in over 10% of cases. While a trough concentration (C_min,ss) target of ≥ 20.5 mg/L has been established for mRCC efficacy, no specific threshold exists for liver toxicity. The objectives of this study were to develop a population pharmacokinetic (POPPK), an exposure-liver toxicity, and an exposure-tumor size dynamics model to optimize pazopanib initial dose in real-world patients.</p><p><strong>Methods: </strong>In total, 135 patients were included and treated with a median starting dose of 800 mg (interquartile range, IQR: 600-800 mg) QD pazopanib fasted with a median follow-up of 120 (IQR 63-372) days. A population pharmacokinetic model was developed using 460 concentration measurements from 135 patients. Exposure-liver toxicity was evaluated using time-to-event modeling, and exposure-tumor size dynamics was evaluated using tumor growth modelling.</p><p><strong>Results: </strong>The liver toxicity model, with 27 cases of grade ≥ 2 liver toxicity out of 135 patients (20%), identified a C_min,ss threshold of > 34 mg/L associated with a 3.35-fold increased toxicity risk (P < 0.01). Model simulations showed that an initial dose of 600 mg QD significantly reduced liver toxicity risk (P < 0.001) while maintaining C_min,ss ≥ 20.5 mg/L for 76% of the simulated individuals. Tumor size dynamics were analyzed using baseline and posttreatment tumor size measurements from 111 patients. The introduction of primary resistance by using a mixture model improved the model fit significantly. Tumor growth and decay rates differed between mRCC and STS but showed no pazopanib exposure dependency across the studied range, suggesting maximal tumor inhibition at current exposure levels.</p><p><strong>Conclusions: </strong>These findings suggest that an initial pazopanib dose of 600 mg fasted, followed by model-informed precision dosing to maintain C_min,ss between 20 and 34 mg/L, may improve efficacy-toxicity balance and mitigate treatment interruptions.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"715-728"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980336","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":"Variability in Meropenem Distribution and Clearance in Children with Sepsis: Population-Based Pharmacokinetics with Assessment of Renal Biomarkers.","authors":"Jennifer Le, Julie Huynh, Brandon Vo, Annie Mai, Robert H Mak, Jeremiah D Momper, Edmund V Capparelli, Helen Harvey, Sean Avedissian, Erin Bradley, Amy Sitapati, Karandeep Singh, John S Bradley","doi":"10.1007/s40262-025-01495-3","DOIUrl":"https://doi.org/10.1007/s40262-025-01495-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Meropenem dosing to achieve therapeutic exposure in critically ill children with sepsis is challenging due to a spectrum of renal function, from augmented renal clearance (ARC) to acute kidney injury (AKI). The objective of this study was to define meropenem plasma concentrations and pharmacodynamic exposure metrics in children with septic shock during the first 3 days of PICU hospitalization.</p><p><strong>Methods: </strong>We prospectively evaluated meropenem clearance (CL_MERO) and volume of distribution (V_1-MERO), innovatively assessing renal biomarkers (serum creatinine [SCr], serum cystatin C [SCys], and neutrophil gelatinase-associated lipocalin [SNgal]), in infants aged ≥ 4 weeks and children on intravenous (IV) meropenem 20 mg/kg every 8 h from 2019 to 2023. Cases with sepsis were matched to controls without sepsis.</p><p><strong>Results: </strong>Analysis included 27 participants (19 cases and 8 controls) with 309 meropenem serum concentrations. Median age was 11.8 (range 0.6-19.6) years, weight 36.3 (7.2-98.0) kg, SCr 0.33 (0.09-2.57) mg/dL, SCys 451.1 (178.3-1824.1) ng/mL, and SNgal 180.7 (23.2-1403.0) ng/mL. A 2-compartment, population pharmacokinetic (PK) model via NONMEM best described data, with weight on V_MERO and allometric scaling on CL_MERO. Using the final model with SCys in V_1-MERO and estimated glomerular filtration rate (eGFR)-MS in CL_MERO, the median V_1-MERO was 0.23 (range 0.07-0.57) L/kg and CL_MERO 0.15 (0.05-0.49) L/h/kg, with eGFR-MS 139 (23-365) mL/min/1.73 m² from AKI to ARC. Meropenem clearance, V_1-MERO and eGFR-MS were significantly decreased in cases versus controls, with higher variability of eGFR-MS in cases.</p><p><strong>Conclusion: </strong>Wide variation in meropenem concentrations in children with sepsis as compared to those without sepsis prompt close monitoring of GFR and drug concentrations in this population.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"769-777"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984154","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 and Pharmacodynamics of Fepixnebart (LY3016859) and Epiregulin in Patients with Chronic Pain.","authors":"Douglas E James, Jason Bailey, Jan-Stefan van der Walt, Julia Winkler, Rik Schoemaker","doi":"10.1007/s40262-025-01506-3","DOIUrl":"10.1007/s40262-025-01506-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Fepixnebart (LY3016859), a humanized immunoglobulin G4 monoclonal antibody with high binding affinity to epiregulin and tumor growth factor-α, is being developed as a novel analgesic to treat broad-spectrum chronic pain. Early phase clinical studies demonstrated fepixnebart has nonlinear pharmacokinetics in healthy subjects and patients with diabetic nephropathy. This population pharmacokinetic analysis used data from three 26-week, phase 2, proof-of-concept studies in osteoarthritis, diabetic peripheral neuropathic pain (DPNP), and chronic low back pain (CLBP) to characterize the pharmacokinetics of fepixnebart and predict its target engagement by epiregulin. Covariate relationships were also assessed.</p><p><strong>Methods: </strong>Population analysis was performed using nonlinear mixed-effects modeling software. Covariate relationships were explored graphically by plotting potential covariates versus parameters of interest. Simulated target engagement was predicted using the phase 2 dose regimen for fepixnebart (750 mg intravenous starting dose, followed by 500 mg every 2 weeks).</p><p><strong>Results: </strong>The median simulated target engagement at 2 weeks after the last dose of fepixnebart was predicted to be 92.0%, with 90% of predictions between 86.0 and 96.2% and 68.5% of subjects predicted to exhibit target engagement exceeding 90%.</p><p><strong>Conclusions: </strong>The phase 2 dose regimen is adequate to test the analgesic effect of fepixnebart in patients with osteoarthritis, DPNP, and CLBP. In the final model, female sex and higher glomerular filtration rate were associated with higher clearance, female sex was associated with larger volume of distribution of the central compartment (V_c) than male sex, and DPNP was associated with lower V_c than CLBP. There were no significant effects on the concentration of fepixnebart at which its effect on epiregulin is half-maximal (EC₅₀).</p><p><strong>Trail registry: </strong>ClinicalTrials.gov: NCT04529096, NCT04476108, and NCT04456686.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"757-767"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994211","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 Tarlatamab, a Half-Life Extended DLL3-Directed Bispecific T-Cell Engager in Patients with Previously Treated Small Cell Lung Cancer.","authors":"Stephanie Kong, Mukul Minocha, Po-Wei Chen, Pablo Martinez, Erik S Anderson, Amanda Parkes, Brett E Houk, Chih-Wei Lin","doi":"10.1007/s40262-025-01499-z","DOIUrl":"10.1007/s40262-025-01499-z","url":null,"abstract":"<p><strong>Background and objective: </strong>Tarlatamab is a first in class, half-life extended delta-like ligand 3 (DLL3) directed bispecific T-cell engager (BiTE®) immunotherapy that has shown durable efficacy in patients with previously treated small cell lung cancer (SCLC). The purpose of this analysis was to develop a population pharmacokinetic (PK) model for tarlatamab.</p><p><strong>Methods: </strong>This analysis includes data from 420 patients with previously treated small cell lung cancer (8509 samples) pooled across the Phase 1 DeLLphi-300 study (dose range 0.003-100 mg every 2 weeks and 200 mg every 3 weeks) and Phase 2 DeLLphi-301 study (10 mg and 100 mg every 2 weeks). The data were analyzed using a nonlinear-mixed effects modeling approach implemented in NONMEM (v7.5) software and validated using standard statistical approaches. The effects of intrinsic and extrinsic factors on PK parameters and exposures of tarlatamab were evaluated, and the impact of identified covariates were further assessed using simulations.</p><p><strong>Results: </strong>Tarlatamab serum concentration data were best described by a two-compartment model with linear elimination. Tarlatamab clearance (CL) and central volume of distribution (V_C) were 0.649 L/day and 3.44 L, respectively, for a typical 73-kg individual. The model-estimated median terminal phase elimination half-life was 11.2 days. Tarlatamab pharmacokinetics were not impacted by age, sex, ethnicity, estimates of renal and hepatic function, prior lines of therapy, or baseline disease status. The presence of antidrug antibody (ADA) at any time during the study and bodyweight were found to be statistically significant covariates on CL, and Asian race and bodyweight were found to be statistically significant covariates on V_C; however, they did not lead to a clinically meaningful impact on exposures.</p><p><strong>Conclusions: </strong>The pharmacokinetics of tarlatamab was well-described by a two-compartment model with linear elimination. No clinically significant differences were observed on the basis of age, sex, bodyweight, race, ethnicity, estimates of renal and hepatic function, prior lines of therapy, baseline disease status, or emergence of ADA. These results support that no dose adjustment is required on the basis of any of the evaluated covariates.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":"64 5","pages":"729-741"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968022","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 Cefepime in Critically Ill Children and Young Adults: Model Development and External Validation for Monte Carlo Simulations and Model-Informed Precision Dosing.","authors":"Ronaldo Morales Junior, H Rhodes Hambrick, Tomoyuki Mizuno, Kathryn E Pavia, Kelli M Paice, Peter Tang, Erin Schuler, Kelli A Krallman, Luana Johnson, Michaela Collins, Abigayle Gibson, Calise Curry, Jennifer Kaplan, Stuart Goldstein, Sonya Tang Girdwood","doi":"10.1007/s40262-025-01485-5","DOIUrl":"10.1007/s40262-025-01485-5","url":null,"abstract":"<p><strong>Background and objective: </strong>This study aimed to develop a population pharmacokinetic model for cefepime in critically ill pediatric and young adult patients to inform dosing recommendations and to evaluate the model's predictive performance for model-informed precision dosing.</p><p><strong>Methods: </strong>Patients in the pediatric intensive care unit receiving cefepime were prospectively enrolled for clinical data collection and opportunistic plasma sampling for cefepime concentrations. Nonlinear mixed effects modeling was conducted using NONMEM. Allometric body weight scaling was included as a covariate with fixed exponents. Monte Carlo simulations determined optimal initial dosing regimens against susceptible pathogens. The model's predictions were evaluated with an external dataset.</p><p><strong>Results: </strong>Data from 510 samples across 100 patients were best fit with a two-compartment model with first-order elimination. Estimated glomerular filtration rate and cumulative percentage of fluid balance were identified as significant covariates on clearance and central volume of distribution, respectively. Internal validation showed no model misspecification. External validation confirmed that bias and precision for both population and individual predictions were within commonly accepted ranges. Monte Carlo simulations suggested that the usual dose of 50 mg/kg may require a 3-h infusion or a 6-h dosing interval to keep concentrations above the Pseudomonas aeruginosa minimum inhibitory concentration (≤ 8 mg/L) throughout the dosing interval for patients with normal or augmented renal clearance.</p><p><strong>Conclusion: </strong>A cefepime population pharmacokinetic model for critically ill pediatric patients was successfully developed, accounting for patient renal function, fluid status, and body size, using real-world data. The model was internally and externally validated for use in optimal dosing simulations and model-informed precision dosing.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"553-564"},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482352","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 and Safety of Navitoclax in Hepatic Impairment.","authors":"Maulik Patel, Jalaja Potluri, Thomas Marbury, Eric Lawitz, Juan Carlos Rondon, David M Hoffman, Satya R Siddani, Kennan C Marsh, Elaine J Kim, Muhammad Erfan Uddin, Rajeev M Menon, Akshanth R Polepally","doi":"10.1007/s40262-025-01484-6","DOIUrl":"10.1007/s40262-025-01484-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Navitoclax, an orally bioavailable B-cell lymphoma-2 (Bcl-2) family protein inhibitor, inhibits antiapoptotic Bcl-2 family proteins (with high affinity to Bcl-XL, Bcl-2, and Bcl-W). Navitoclax in combination with ruxolitinib has been investigated to treat patients with myelofibrosis (MF).</p><p><strong>Methods: </strong>Since navitoclax undergoes hepatic metabolism, we evaluated the pharmacokinetics (PK) and safety of single-dose navitoclax 50 mg in a phase 1 study in participants with mild (N = 6), moderate (N = 6), or severe (N = 1) hepatic impairment and matched participants with normal hepatic function (N = 7). All participants in this study were enrolled per Child-Pugh classification, with demographics matched per age, weight, and race.</p><p><strong>Results: </strong>Navitoclax maximum plasma concentration (C_max), area under the plasma concentration-time curve for time zero to infinity (AUC_0-∞), and terminal elimination half-life (t_1/2) in participants with mild or moderate hepatic impairment were comparable to participants with normal hepatic function. The change in C_max and AUC_0-∞ values in participants with mild and moderate hepatic impairment were within 25% of normal hepatic function. Overall, 2/20 (10%) participants receiving a 50 mg single dose reported grade 1 treatment-emergent adverse events of nausea (N = 1) and diarrhea (N = 1).</p><p><strong>Conclusions: </strong>In summary, no new safety issues were identified. On the basis of the pharmacokinetic results, no dose adjustment is required for patients with MF with mild or moderate hepatic impairment.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"611-617"},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718259","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 and Safety of Levofloxacin for Treatment of Rifampicin-Resistant Tuberculosis During Pregnancy and the Postpartum Period: Results from IMPAACT P1026s.","authors":"Jennifer A Hughes, Mauricio Pinilla, Kristina M Brooks, Ahizechukwu C Eke, Alice Stek, Brookie M Best, Mark Mirochnick, Renee Browning, Lubbe Wiesner, Kathleen George, Kevin Knowles, Petra De Koker, James S Ngocho, Lee Fairlie, Nahida Chakhtoura, Anneke C Hesseling, Eric Decloedt, David E Shapiro, Marije van Schalkwyk","doi":"10.1007/s40262-025-01498-0","DOIUrl":"10.1007/s40262-025-01498-0","url":null,"abstract":"<p><strong>Background and objective: </strong>Treatment of rifampicin-resistant tuberculosis (RR-TB) often includes fluoroquinolones, but data on long-term exposure during and after pregnancy are limited. We examined the pharmacokinetics and safety of levofloxacin in an observational cohort of pregnant and postpartum women receiving treatment for RR-TB.</p><p><strong>Methods: </strong>Participants were enrolled in their second or third trimester and underwent intensive pharmacokinetic sampling to quantify levofloxacin plasma concentrations at 20-26 weeks' and 30-38 weeks' gestation and at 2-8 weeks postpartum. The levofloxacin plasma concentration target was 7 µg/mL. Pharmacokinetic parameters over 12 and 24 h were described using non-compartmental analysis and within-participant comparison during pregnancy versus postpartum. Adverse events were extracted from medical records. Infants were enrolled in utero and followed on study for 4-6 months after birth.</p><p><strong>Results: </strong>A total of 11 pregnant women, with a median age of 31 years, received RR-TB treatment including levofloxacin; 6 (55%) were living with HIV. In the second trimester, third trimester, and postpartum, median maximum plasma drug concentration values were 10.3, 10.6, and 10.6 µg/mL, and area under the concentration time curve over 12 h (AUC_0-12) were 69.0, 77.6, and 80.2 µg·h/mL, respectively. Compared with postpartum, median AUCs were lower and clearance was higher in the second but not the third trimester. Eight (72%) women and seven (64%) infants experienced severe or life-threatening adverse events or outcomes that were unlikely to be related to levofloxacin.</p><p><strong>Conclusions: </strong>Levofloxacin AUC_0-12 was lower in the second trimester than the third trimester of pregnancy and the postpartum period, but exposures overall were within target ranges. Further research is warranted to explore the clinical significance of these findings.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"619-630"},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742485","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 and Target Attainment of Teicoplanin: A Systematic Review.","authors":"Jaap W A Mouton, Arnaud De Clercq, Peter De Paepe, Mirko Petrovic, Tania Desmet, Roger J Brüggemann, Jeroen A Schouten, Nynke G L Jager, Pieter A De Cock","doi":"10.1007/s40262-025-01483-7","DOIUrl":"10.1007/s40262-025-01483-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Teicoplanin is a glycopeptide antibiotic used to treat severe Gram-positive infections. This systematic review provides a comprehensive overview of the current knowledge on the pharmacokinetics of teicoplanin across the entire population, with the aim to identify gaps in the existing literature, prioritise pharmacokinetic research, and support optimal dosing strategies.</p><p><strong>Methods: </strong>A systematic literature search of the MEDLINE, Embase, Web of Science, and Scopus databases was conducted. Articles published until 1 October 2024 were identified as eligible when they included a pharmacokinetic analysis of teicoplanin. Relevant pharmacokinetic data were extracted from all included articles. Allometric scaling was carried out for reported values of clearance (CL) and volume of distribution (Vd) to an individual of 70 kg. Articles were categorised into eight subgroups. A qualitative assessment of the included studies was conducted using the clinical pharmacokinetic statement checklist.</p><p><strong>Results: </strong>In total, 85 articles were included in this review. Pharmacokinetic data for 186 healthy volunteers, 130 neonates, 788 children, 1434 adult patients, 48 older adults (≥ 65 years), 674 critically ill patients, 33 patients with impaired renal function, and 159 patients with extracorporeal elimination techniques were extracted for a total of 3452 subjects. Unbound concentrations were assessed in 7.1% of the articles. The Vd_scaled ranged from 1.5 to 583 L/70 kg. The CL_scaled ranged from 0.0073 to 6.38 L/h/70 kg. Covariates on drug disposition were identified in 55.3% of studies, 65.6% of which identified a relationship between renal function and CL. Target attainment was described in 42.4% of articles. Dosing recommendations were provided in 61.2% of all studies. Studies had an average quality score of 69.9% ± standard deviation 15.7.</p><p><strong>Conclusion: </strong>Individual dosing strategies based on renal function need to be developed, particularly in patients with immature or impaired renal function, using state-of-the art pharmacokinetic/pharmacodynamic modelling approaches. Since teicoplanin is highly plasma protein bound and it is suggested that total concentrations cannot be easily translated to unbound concentrations, future research should also include the measurement of unbound concentrations for pharmacokinetic and target attainment evaluation.</p><p><strong>Trial registration: </strong>Prospectively registered in PROSPERO.</p><p><strong>Trial registration number: </strong>CRD42023483334. Registration date: 03/12/2023.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"467-509"},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596352","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}