Clinical Pharmacokinetics最新文献

{"title":"Innovating Thiopurine Therapeutic Drug Monitoring: A Systematic Review and Meta-Analysis on DNA-Thioguanine Nucleotides (DNA-TG) as an Inclusive Biomarker in Thiopurine Therapy.","authors":"Ahmed B Bayoumy, A R Ansari, C J J Mulder, K Schmiegelow, Timothy Florin, N K H De Boer","doi":"10.1007/s40262-024-01393-0","DOIUrl":"10.1007/s40262-024-01393-0","url":null,"abstract":"<p><strong>Background and objective: </strong>Thioguanine (TG), azathioprine (AZA), and mercaptopurine (MP) are thiopurine prodrugs commonly used to treat diseases, such as leukemia and inflammatory bowel disease (IBD). 6-thioguanine nucleotides (6-TGNs) have been commonly used for monitoring treatment. High levels of 6-TGNs in red blood cells (RBCs) have been associated with leukopenia, the cutoff levels that predict this side effect remain uncertain. Thiopurines are metabolized and incorporated into leukocyte DNA. Measuring levels of DNA-incorporated thioguanine (DNA-TG) may be a more suitable method for predicting clinical response and toxicities such as leukopenia. Unfortunately, most methodologies to assay 6-TGNs are unable to identify the impact of NUDT15 variants, effecting mostly ethnic populations (e.g., Chinese, Indian, Malay, Japanese, and Hispanics). DNA-TG tackles this problem by directly measuring thioguanine in the DNA, which can be influenced by both TPMT and NUDT15 variants. While RBC 6-TGN concentrations have traditionally been used to optimize thiopurine therapy due to their ease and affordability of measurement, recent developments in liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques have made measuring DNA-TG concentrations in lymphocytes accurate, reproducible, and affordable. The objective of this systematic review was to assess the current evidence of DNA-TG levels as marker for thiopurine therapy, especially with regards to NUDT15 variants.</p><p><strong>Methods: </strong>A systematic review and meta-analysis were performed on the current evidence for DNA-TG as a marker for monitoring thiopurine therapy, including methods for measurement and the illustrative relationship between DNA-TG and various gene variants (such as TPMT, NUDT15, ITPA, NT5C2, and MRP4). PubMed and Embase were systematically searched up to April 2024 for published studies, using the keyword \"DNA-TG\" with MeSH terms and synonyms. The electronic search strategy was augmented by a manual examination of references cited in articles, recent reviews, editorials, and meta-analyses. A meta-analysis was performed using R studio 4.1.3. to investigate the difference between the coefficients (Fisher's z-transformed correlation coefficient) of DNA-TG and 6-TGNs levels. A meta-analysis was performed using RevMan version 5.4 to investigate the difference in DNA-TG levels between patients with or without leukopenia using randomized effect size model. The risk of bias was assessed using the Newcastle-Ottowa quality assessment scale.</p><p><strong>Results: </strong>In this systematic review, 21 studies were included that measured DNA-TG levels in white blood cells for either patients with ALL (n = 16) or IBD (n = 5). In our meta-analysis, the overall mean difference between patients with leukopenia (ALL + IBD) versus no leukopenia was 134.15 fmol TG/µg DNA [95% confidence interval (CI) (83.78-184.35), P < 0.00001; heterogeneity chi squared of 5.62, I<","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1089-1109"},"PeriodicalIF":4.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11343975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731054","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 Machine Learning Algorithm to Predict the Starting Dose of Daptomycin.","authors":"Florence Rivals, Sylvain Goutelle, Cyrielle Codde, Romain Garreau, Laure Ponthier, Pierre Marquet, Tristan Ferry, Marc Labriffe, Alexandre Destere, Jean-Baptiste Woillard","doi":"10.1007/s40262-024-01405-z","DOIUrl":"10.1007/s40262-024-01405-z","url":null,"abstract":"<p><strong>Background and objective: </strong>The dosage of daptomycin is usually based on body weight. However, it has been shown that this approach yields too high an exposure in obese patients. Pharmacokinetic and pharmacodynamic indexes (PK/PD) have been proposed for daptomycin's antibacterial effect (AUC/CMI >666) and toxicity (C0 > 24.3 mg/L). We previously developed machine learning (ML) algorithms to predict starting doses based on Monte Carlo simulations. We propose a new way to perform probability of target attainment based on an ML algorithm to predict the daptomycin starting dose.</p><p><strong>Methods: </strong>The Dvorchik model of daptomycin was implemented in the mrgsolve R package and 4950 pharmacokinetic profiles were simulated with doses ranging from 4 to 12 mg/kg. We trained and benchmarked four machine learning algorithms and selected the best to iteratively search for the optimal dose of daptomycin maximizing the event (AUC/CMI > 666 and C0 < 24.3 mg/L). The ML algorithm was evaluated in simulations and an external database of real patients in comparison with population pharmacokinetics.</p><p><strong>Results: </strong>The performance of the Xgboost algorithms developed to predict the event (ROC AUC) in the training and test set were 0.762 and 0.761, respectively. The most important prediction variables were dose, creatinine clearance, body weight and sex. In the external database of real patients, the starting dose administered based on the ML algorithm significantly improved the target attainment by 7.9% (p-value = 0.02929) in comparison with the dose administered based on body weight.</p><p><strong>Conclusion: </strong>The developed algorithm improved the target attainment for daptomycin in comparison with weight-based dosing. We built a Shiny app to calculate the optimal starting dose.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1137-1146"},"PeriodicalIF":4.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859216","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":"Physiologically Based Pharmacokinetic Model of OATP1B Substrates with a Nonlinear Mixed Effect Approach: Estimating Empirical In Vitro-to-In Vivo Scaling Factors.","authors":"Rui Li, Emi Kimoto, Yi-An Bi, David Tess, Manthena V S Varma","doi":"10.1007/s40262-024-01408-w","DOIUrl":"10.1007/s40262-024-01408-w","url":null,"abstract":"<p><strong>Background and objective: </strong>Physiologically based pharmacokinetic (PBPK) models are valuable for translating in vitro absorption, distribution, metabolism, and excretion (ADME) data to predict clinical pharmacokinetics, and can enable discovery and early clinical stages of pharmaceutical research. However, in predicting pharmacokinetics of organic anion transporting polypeptide (OATP) 1B substrates based on in vitro transport and metabolism data, PBPK models typically require additional empirical in vitro-to-in vivo scaling factors (ESFs) in order to accurately recapitulate observed clinical profiles. As model simulation is very sensitive to ESFs, a critical evaluation of ESF estimation is prudent. Previously studies have applied classic 'two-stage' and 'naïve pooled data' approaches in identifying a set of compound independent ESFs. However, the 'two-stage' approach has the parameter identification issue in separately fitting data for individual compounds, while the 'naïve pooled data' approach ignores interstudy variability, leading to potentially biased ESF estimates.</p><p><strong>Methods: </strong>In this study, we have applied a nonlinear mixed-effect approach in estimating ESF of the PBPK model and incorporated additional data from 86 runs of in vitro uptake assay and 49 clinical studies of 12 training compounds in model development to further enhance the translation of in vitro data to predict the pharmacokinetics of OATP1B substrate drugs. To test predication accuracy of the model, a 'leave-one-out' analysis has been performed.</p><p><strong>Results: </strong>The established model can reasonably describe the clinical observations, with both mean values and interstudy variabilities quantified for ESF and volume of distribution parameters. The mean estimates are largely consistent with values in the previous reports. The interstudy variabilities of these parameters are estimated to be at least 50% (as coefficient of variation). Most compounds can be reasonably predicted in the 'leave-one-out' analysis.</p><p><strong>Conclusion: </strong>This study improves the confidence in predicting the pharmacokinetics of OATP1B substrates in individual studies of small sample sizes, and quantifies the variability associated with the prediction.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1177-1189"},"PeriodicalIF":4.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999515","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 and Target Attainment of Allopurinol and Oxypurinol Before, During, and After Cardiac Surgery with Cardiopulmonary Bypass in Neonates with Critical Congenital Heart Disease.","authors":"Wan-Yu Chu, Maaike Nijman, Raymond Stegeman, Johannes M P J Breur, Nicolaas J G Jansen, Joppe Nijman, Kim van Loon, Erik Koomen, Karel Allegaert, Manon J N L Benders, Thomas P C Dorlo, Alwin D R Huitema","doi":"10.1007/s40262-024-01401-3","DOIUrl":"10.1007/s40262-024-01401-3","url":null,"abstract":"<p><strong>Background: </strong>The CRUCIAL trial (NCT04217421) is investigating the effect of postnatal and perioperative administration of allopurinol on postoperative brain injury in neonates with critical congenital heart disease (CCHD) undergoing cardiac surgery with cardiopulmonary bypass (CPB) shortly after birth.</p><p><strong>Objective: </strong>This study aimed to characterize the pharmacokinetics (PK) of allopurinol and oxypurinol during the preoperative, intraoperative, and postoperative phases in this population, and to evaluate target attainment of the current dosing strategy.</p><p><strong>Methods: </strong>Nonlinear mixed-effects modeling was used to develop population PK models in 14 neonates from the CRUCIAL trial who received up to five intravenous allopurinol administrations throughout the postnatal and perioperative periods. Target attainment was defined as achieving an allopurinol concentration >2 mg/L in at least two-thirds of the patients during the first 24 h after birth and between the start and 36 h after cardiac surgery with CPB.</p><p><strong>Results: </strong>A two-compartment model for allopurinol was connected to a one-compartment model for oxypurinol with an auto-inhibition effect on the conversion, which best described the PK. In a typical neonate weighing 3.5 kg who underwent cardiac surgery at a postnatal age (PNA) of 5.6 days, the clearance (CL) of allopurinol and oxypurinol at birth was 0.95 L/h (95% confidence interval 0.75-1.2) and 0.21 L/h (0.17-0.27), respectively, which subsequently increased with PNA to 2.97 L/h and 0.41 L/h, respectively, before CPB. During CPB, allopurinol and oxypurinol CL decreased to 1.38 L/h (0.9-1.87) and 0.12 L/h (0.05-0.22), respectively. Post-CPB, allopurinol CL increased to 2.21 L/h (1.74-2.83), while oxypurinol CL dropped to 0.05 L/h (0.01-0.1). Target attainment was 100%, 53.8%, and 100% at 24 h postnatally, 24 h after the start of CPB, and 36 h after the end of cardiac surgery, respectively. The combined concentrations of allopurinol and oxypurinol maintained ≥ 90% inhibition of xanthine oxidase (IC90_XO) throughout the postnatal and perioperative period.</p><p><strong>Conclusions: </strong>The minimal target concentration of allopurinol was not achieved at every predefined time interval in the CRUCIAL trial; however, the dosing strategy used was deemed adequate, since it yielded concentrations well exceeding the IC90_XO. The decreased CL of both compounds during CPB suggests influence of the hypothermia, hemofiltration, and the potential sequestration of allopurinol in the circuit. The reduced CL of oxypurinol after CPB is likely attributable to impaired kidney function.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1205-1220"},"PeriodicalIF":4.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11343829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987582","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":"Intrasubject Variability in Intravenous and Oral Probes for Hepatic and First-Pass CYP3A Activity.","authors":"Evan D Kharasch, Christine Hoffer, Pamela Bedynek","doi":"10.1007/s40262-024-01406-y","DOIUrl":"10.1007/s40262-024-01406-y","url":null,"abstract":"<p><strong>Background and objectives: </strong>Clearances and the area under the plasma concentration-time curve extrapolated to infinity (AUC_0-∞) of intravenous (IV) and oral midazolam and alfentanil are probes for hepatic and first-pass cytochrome P450 3A (CYP3A) activity, drug interactions, and phenotyping. Single-time plasma concentrations are also used as a proxy for clearance and AUC_0-∞. Pupil diameter change is a noninvasive surrogate for plasma alfentanil. An ideal probe should have minimal intrasubject (interday) variability. Despite their widespread use, the intrasubject variability of CYP3A probes is not well characterized. This investigation determined the intrasubject (interday) variability of midazolam and alfentanil metrics of hepatic and first-pass CYP3A.</p><p><strong>Methods: </strong>Twelve volunteers were studied in a four-period protocol, with each period identical and separated by approximately 2 weeks. In each period, participants received 1 mg IV midazolam then 15 μg/kg IV alfentanil 1 h later. The next day, they received 3 mg oral midazolam then 60 μg/kg oral alfentanil. Plasma drug concentrations were determined by liquid chromatography-mass spectrometry (LCMS). Dark-adapted pupil diameters were measured coincident with blood sampling. Plasma concentrations and pupil effects (miosis) were analyzed using noncompartmental methods. The results were the coefficient of variation (%CV, mean ± SD) across four sessions in 12 participants.</p><p><strong>Results: </strong>For IV midazolam: AUC_0-∞, clearance, and 5 h concentration, the %CVs were 12 ± 3, 12 ± 3, and 18 ± 8. For IV alfentanil AUC_0-∞, clearance, 2 h concentration, and area under the effect curve from time zero to infinity (AUEC_0-∞), the %CVs were 16 ± 5, 15 ± 4, 22 ± 7, and 50 ± 28. For oral midazolam AUC_0-∞, clearance, and 5 h concentration, %CVs were 19 ± 5, 18 ± 4, and 28 ± 11. For oral alfentanil: AUC_0-∞, clearance, 4 h concentration, and AUEC_0-∞, %CVs were 20 ± 4, 21 ± 4, 42 ± 26, and 37 ± 14.</p><p><strong>Conclusions: </strong>Midazolam and alfentanil had comparable intrasubject variabilities of clearance and AUC_0-∞. Single-time point metrics had greater intrasubject variability than AUC_0-∞ and clearance. Miosis was a surrogate for alfentanil concentrations and provided real-time results, but intrasubject variability was greater than that of clearances and AUC_0-∞.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1121-1135"},"PeriodicalIF":4.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787436","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":"Antibiotics Removal during Continuous Renal Replacement Therapy in Septic Shock Patients: Mixed Modality Versus \"Expanded Haemodialysis\".","authors":"Fiorenza Ferrari, Paola Milla, Marco Sartori, Christian Zanza, Manfredi Tesauro, Yaroslava Longhitano, Annalisa De Silvestri, Chiara Abbruzzese, Silvia De Rosa, Sergio Lassola, Sara Samoni, Alessandra Brendolan, Monica Zanella, Vittorio Scaravilli, Giacomo Grasselli, Silvia Arpicco, Claudio Ronco","doi":"10.1007/s40262-024-01397-w","DOIUrl":"10.1007/s40262-024-01397-w","url":null,"abstract":"<p><strong>Background and objective: </strong>Renal replacement therapy (RRT) plays a critical role in antimicrobial removal, particularly for low-molecular-weight drugs with low plasma protein binding, low distribution volume and hydrophilicity. Medium cut-off (MCO) membranes represent a new generation in dialysis technology, enhancing diffusive modality efficacy and increasing the cut-off from 30 to 45 kDa, crucial for middle molecule removal. This monocentric randomized crossover pilot study aimed to evaluate the impact of continuous haemodialysis with MCO membrane (MCO-CVVHD) on the removal of piperacillin, tazobactam and meropenem compared with continuous veno-venous hemodiafiltration with standard high-flux membrane (HFM-CVVHDF).</p><p><strong>Methods: </strong>Twenty patients were randomized to undergo MCO-CVVHD followed by HFM-CVVHDF or vice versa. Extraction ratio (ER), effluent clearance (Cl_eff) and treatment efficiency were assessed at various intervals. Antibiotic nadir plasma levels were measured for both treatment days.</p><p><strong>Results: </strong>HFM-CVVHDF showed greater ER compared with MCO-CVVHD for meropenem (β = - 8.90 (95% CI - 12.9 to - 4.87), p < 0.001) and tazobactam (β = - 8.29 (95% CI - 13.5 to - 3.08), p = 0.002) and Cl_eff for each antibiotic (meropenem β = - 10,206 (95% CI - 14,787 to - 5787), p = 0.001); tazobactam (β = - 4551 (95% CI - 7781 to - 1322), p = 0.012); piperacillin (β = - 3913 (95% CI - 6388 to - 1437), p = 0.002), even if the carryover effect influenced the Cl_eff for meropenem and tazobactam. No difference was observed in nadir plasma concentrations or efficiency for any antibiotic. Piperacillin (β = - 38.1 (95% CI - 47.9 to - 28.3), p < 0.001) and tazobactam (β = - 4.45 (95% CI - 6.17 to - 2.72), p < 0.001) showed lower nadir plasma concentrations the second day compared with the first day, regardless the filter type.</p><p><strong>Conclusion: </strong>MCO demonstrated comparable in vivo removal of piperacillin, tazobactam and meropenem to HFM.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1167-1176"},"PeriodicalIF":4.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888604","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 Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059.","authors":"Jen-Hao Wu, Edoardo Pennesi, Francisco Bautista, May Garrett, Kei Fukuhara, Erica Brivio, Anneke C J Ammerlaan, Franco Locatelli, Inge M van der Sluis, Claudia Rossig, Christiane Chen-Santel, Bella Bielorai, Arnaud Petit, Jan Starý, Cristina Díaz-de-Heredia, Susana Rives, Aengus O'Marcaigh, Carmelo Rizzari, Gernot Engstler, Karsten Nysom, Alba Rubio-San-Simón, Benedicte Bruno, Yves Bertrand, Benoît Brethon, Fanny Rialland, Geneviève Plat, Uta Dirksen, Lucie Sramkova, C Michel Zwaan, Alwin D R Huitema","doi":"10.1007/s40262-024-01386-z","DOIUrl":"10.1007/s40262-024-01386-z","url":null,"abstract":"<p><strong>Background and objective: </strong>Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL.</p><p><strong>Methods: </strong>From 531 adult patients with B-cell non-Hodgkin's lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data.</p><p><strong>Results: </strong>Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration-time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9-35.0] vs 10.1 [9.19-16.1], × 10³ ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants.</p><p><strong>Conclusions: </strong>The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"981-997"},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141440269","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":"Penetration of Antibiotics into Subcutaneous and Intramuscular Interstitial Fluid: A Meta-Analysis of Microdialysis Studies in Adults.","authors":"Pieter-Jan De Sutter, Eline Hermans, Pieter De Cock, Jan Van Bocxlaer, Elke Gasthuys, An Vermeulen","doi":"10.1007/s40262-024-01394-z","DOIUrl":"10.1007/s40262-024-01394-z","url":null,"abstract":"<p><strong>Background and objective: </strong>The interstitial fluid of tissues is the effect site for antibiotics targeting extracellular pathogens. Microdialysis studies investigating these concentrations in muscle and subcutaneous tissue have reported notable variability in tissue penetration. This study aimed to comprehensively summarise the existing data on interstitial fluid penetration in these tissues and to identify potential factors influencing antibiotic distribution.</p><p><strong>Methods: </strong>A literature review was conducted, focusing on subcutaneous and intramuscular microdialysis studies of antibiotics in both adult healthy volunteers and patients. Random-effect meta-analyses were used to aggregate effect size estimates of tissue penetration. The primary parameter of interest was the unbound penetration ratio, which represents the ratio of the area under the concentration-time curve in interstitial fluid relative to the area under the concentration-time curve in plasma, using unbound concentrations.</p><p><strong>Results: </strong>In total, 52 reports were incorporated into this analysis. The unbound antibiotic exposure in the interstitial fluid of healthy volunteers was, on average, 22% lower than in plasma. The unbound penetration ratio values were higher after multiple dosing but did not significantly differ between muscle and subcutaneous tissue. Unbound penetration ratio values were lower for acids and bases compared with neutral antibiotics. Neither the molecular weight nor the logP of the antibiotics accounted for the variations in the unbound penetration ratio. Obesity was associated with lower interstitial fluid penetration. Conditions such as sepsis, tissue inflammation and tissue ischaemia were not significantly associated with altered interstitial fluid penetration.</p><p><strong>Conclusions: </strong>This study highlights the variability and generally lower exposure of unbound antibiotics in the subcutaneous and intramuscular interstitial fluid compared with exposure in plasma. Future research should focus on understanding the therapeutic relevance of these differences and identify key covariates that may influence them.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"965-980"},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491146","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":"Characterizing Enoxaparin's Population Pharmacokinetics to Guide Dose Individualization in the Pediatric Population.","authors":"Fernando O Carreño, Jacqueline G Gerhart, Victória E Helfer, Jaydeep Sinha, Karan R Kumar, Carl Kirkpatrick, Christoph P Hornik, Daniel Gonzalez","doi":"10.1007/s40262-024-01388-x","DOIUrl":"10.1007/s40262-024-01388-x","url":null,"abstract":"<p><strong>Background and objective: </strong>Pediatric dosing of enoxaparin was derived based on extrapolation of the adult therapeutic range to children. However, a large fraction of children do not achieve therapeutic anticoagulation with initial dosing. We aim to use real-world anti-Xa data obtained from children receiving enoxaparin per standard of care to characterize the population pharmacokinetics (PopPK).Author names: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Also, kindly confirm the details in the metadata are correct.The author names are accurately presented and the metadata are correct.  METHODS: A PopPK analysis was performed using NONMEM, and a stepwise covariate modeling approach was applied for the covariate selection. The final PopPK model, developed with data from 1293 patients ranging in age from 1 day to 18 years, was used to simulate enoxaparin subcutaneous dosing for prophylaxis and treatment based on total body weight (0-18 years, TBW) or fat-free mass (2-18 years, FFM). Simulated exposures in children with obesity (body mass index percentile ≥95th percentile) were compared with those without obesity.</p><p><strong>Results: </strong>A linear, one-compartment PopPK model that included allometric scaling using TBW (<2 years) or FFM (≥2 years) characterized the enoxaparin pharmacokinetic data. In addition, serum creatinine was identified as a significant covariate influencing clearance. Simulations indicated that in patients aged <2 years, the recommended 1.5 mg/kg TBW-based dosing achieves therapeutic simulated concentrations. In pediatric patients aged ≥2 years, the recommended 1.0 mg/kg dose resulted in exposures more comparable in children with and without obesity when FFM weight-based dosing was applied.</p><p><strong>Conclusion: </strong>Using real-world data and PopPK modeling, enoxaparin's pharmacokinetics were characterized in pediatric patients. Using FFM and twice-daily dosing might reduce the risk of overdosing, especially in children with obesity.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"999-1014"},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11288483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491145","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":"The OCT2/MATE1 Interaction Between Trifluridine, Metformin and Cimetidine: A Crossover Pharmacokinetic Study.","authors":"Niels A D Guchelaar, Stefan A J Buck, Leni van Doorn, Koen G A M Hussaarts, Yorick Sandberg, Annemieke van der Padt-Pruijsten, Robbert J van Alphen, Laura Poppe-Manenschijn, Isolde Vleut, Peter de Bruijn, Roelof W F van Leeuwen, Bianca Mostert, Ferry A L M Eskens, Esther Oomen-de Hoop, Stijn L W Koolen, Ron H J Mathijssen","doi":"10.1007/s40262-024-01390-3","DOIUrl":"10.1007/s40262-024-01390-3","url":null,"abstract":"<p><strong>Background and objectives: </strong>Trifluridine/tipiracil, registered for the treatment of patients with metastatic gastric and colorectal cancer, is a substrate and inhibitor for the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein 1 (MATE1), which raises the potential for drug-drug interactions with other OCT2/MATE1 modulators. Therefore, we prospectively examined the effect of an OCT2/MATE1 inhibitor (cimetidine) and substrate (metformin) on the pharmacokinetics of trifluridine.</p><p><strong>Methods: </strong>In this three-phase crossover study, patients with metastatic colorectal or gastric cancer were sequentially treated with trifluridine/tipiracil alone (phase A), trifluridine/tipiracil concomitant with metformin (phase B) and trifluridine/tipiracil concomitant with cimetidine (phase C). The primary endpoint was the relative difference in exposure of trifluridine assessed by the area under the curve from timepoint zero to infinity. A > 30% change in exposure was considered clinically relevant. A p-value of < 0.025 was considered significant because of a Bonferroni correction.</p><p><strong>Results: </strong>Eighteen patients were included in the analysis. Metformin did not significantly alter the exposure to trifluridine (- 12.6%; 97.5% confidence interval - 25.0, 1.8; p = 0.045). Cimetidine did alter the exposure to trifluridine significantly (+ 18.0%; 97.5% confidence interval 4.5, 33.3; p = 0.004), but this increase did not meet our threshold for clinical relevance. Metformin trough concentrations were not influenced by trifluridine/tipiracil.</p><p><strong>Conclusions: </strong>Our result suggests that the OCT2/MATE1 modulators cimetidine and metformin can be co-administered with trifluridine/tipiracil without clinically relevant effects on drug exposure.</p><p><strong>Clinical trial registration: </strong>NL8067 (registered 04-10-2019).</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1037-1044"},"PeriodicalIF":4.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476100","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}