European Journal of Drug Metabolism and Pharmacokinetics最新文献

{"title":"Effect of Gastric pH on the Pharmacokinetics of Atorvastatin and its Metabolites in Healthy Participants.","authors":"Bridget Louise Morse, Xiaosu Ma, Rong Liu, Shobha N Bhattachar, Clare Nicoll, Noel Mathew Varghese, Ronan Philip Kelly, Stephen Dion Stamatis, Edward John Pratt","doi":"10.1007/s13318-025-00937-4","DOIUrl":"https://doi.org/10.1007/s13318-025-00937-4","url":null,"abstract":"<p><strong>Background and objective: </strong>Atorvastatin is dosed in its active acid form although it exists in equilibrium with its inactive lactone form in vivo. Although in vitro atorvastatin acid displays pH-dependent conversion to the lactone metabolite, pharmacokinetic (PK) data on the effect of elevated gastric pH on atorvastatin and major atorvastatin-related species are not currently available. In this dedicated study, we investigated the effect of food and acid-reducing agents on the PK of atorvastatin and its three major metabolites in humans.</p><p><strong>Methods: </strong>This was an open label, randomized, crossover study conducted in 17 healthy volunteers. Part 1 examined the PK of a 10-mg dose of atorvastatin co-administered with or without a 600-mg dose of sodium bicarbonate in fasted and fed states. Part 2 was a single assessment to examine the PK of a 10-mg dose of atorvastatin in the fasted state following a 5-day treatment course of 40-mg daily esomeprazole. Gastric pH was monitored during treatments using Heidelberg capsules. A linear mixed effects model was used to derive ratios for PK parameters of atorvastatin and metabolites between treatments.</p><p><strong>Results: </strong>Similar to previous food effect studies, food significantly decreased the maximum concentration (C_max) and increased the time to C_max (t_max) of atorvastatin, with minimal effect on total exposure of atorvastatin or metabolites. Neither sodium bicarbonate, in the fed or fasted state, nor treatment with esomeprazole had a clinically meaningful effect on the exposure of atorvastatin or its metabolites.</p><p><strong>Conclusions: </strong>According to these results, atorvastatin PK does not appear to be sensitive to changes in gastric pH.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Critical Care Pharmacology of Antiretroviral Therapy in Adults.","authors":"Luigi La Via, Andrea Marino, Giuseppe Cuttone, Giuseppe Nunnari, Cristian Deana, Manfredi Tesauro, Antonio Voza, Raymond Planinsic, Yaroslava Longhitano, Christian Zanza","doi":"10.1007/s13318-025-00934-7","DOIUrl":"https://doi.org/10.1007/s13318-025-00934-7","url":null,"abstract":"<p><p>The clinical pharmacology of antiretroviral therapy (ART) in critical care presents unique challenges due to the complex interplay between HIV infection, critical illness, and drug management. This comprehensive review examines the pharmacokinetic and pharmacodynamic considerations of antiretroviral drugs in critically ill patients, where altered absorption, distribution, metabolism, and excretion significantly impact drug effectiveness and safety. Critical illness can substantially modify drug pharmacokinetics through various mechanisms, including impaired gastrointestinal motility, fluid shifts, hypoalbuminemia, hepatic dysfunction, and altered renal function. These changes, combined with potential drug-drug interactions in the polypharmacy environment of intensive care units, necessitate careful consideration of dosing strategies and monitoring approaches. The review addresses specific challenges in various critical care scenarios, including management of ART in patients with organ dysfunction, during renal replacement therapy, and in special populations such as those with sepsis or acute respiratory distress syndrome. It also explores the role of therapeutic drug monitoring in optimizing antiretroviral therapy and managing drug toxicities in critical care settings. Emerging areas of research, including long-acting formulations, nanotechnology-based drug delivery systems, and personalized medicine approaches, are discussed as potential future directions for improving ART management in critical care. The review emphasizes the importance of a multidisciplinary approach involving critical care physicians, infectious disease specialists, and clinical pharmacists to optimize outcomes in this complex patient population. This review provides clinicians with practical guidance for managing ART in critically ill patients while highlighting areas requiring further research to enhance our understanding and improve patient care in this challenging setting.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Determination of Intrinsic Clearance and Fraction Unbound in Human Liver Microsomes and In Vitro-In Vivo Extrapolation of Human Hepatic Clearance for Marketed Central Nervous System Drugs.","authors":"Veera Raghava Chowdary Palacharla, Ramakrishna Nirogi, Nitesh Kumar, Krishnadas Nandakumar","doi":"10.1007/s13318-025-00935-6","DOIUrl":"https://doi.org/10.1007/s13318-025-00935-6","url":null,"abstract":"","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dosage Recommendations for Off-label Use of Mycophenolate Mofetil in Pediatric Patients with Thalassemia Undergoing Hematopoietic Stem Cell Transplantation: An Approach Based on Population Pharmacokinetic Studies.","authors":"Lu-Lu Niu, Yong-Jun Liu, Yun Wu, Tian-Min Huang, Ting-Qing Wu, Yang Xiao, Xin Chen, Yi-Lin Luo, Tao-Tao Liu","doi":"10.1007/s13318-025-00936-5","DOIUrl":"https://doi.org/10.1007/s13318-025-00936-5","url":null,"abstract":"<p><strong>Background and objectives: </strong>As an immunosuppressant, mycophenolate mofetil (MMF) is used to prevent graft versus host disease (GVHD) in patients after hematopoietic stem cell transplantation (HCT). This study aimed to establish a population pharmacokinetic model and simulate the dosage protocol in HCT patients with thalassemia (TM) to fill the gap of lacking MMF dosing regimen.</p><p><strong>Methods: </strong>The mycophenolic acid (MPA) plasma concentrations were obtained from HCT patients with TM after using MMF. The population pharmacokinetic (PPK) parameters were obtained by NONMEM (Version VII, Level 2.0; ICON Development Solutions, Ellicott City, MD, USA) program. Monte Carlo simulations were used to determine the optimal dosing.</p><p><strong>Results: </strong>A total of 239 blood samples from 31 pediatric patients were available, the PPK of MPA was described as a two-compartment model. The typical values for MPA clearance (CL), central distribution volume (V₂), peripheral distribution volume (V₃), intercompartmental clearance (Q), and absorption rate constant (Ka) were 14.9 L/h, 83.5L, 141L, 3.13 L/h, and 1.37/h respectively. The inter-individual variability (IIV) of CL and V₂ were 35% and 41%, respectively. Simulation results suggested that, as the patient's body surface area (BSA) value increased, MMF dosage initiated from 500 mg twice daily was effective.</p><p><strong>Conclusions: </strong>A 'tiered' dosage regimen including patient urea and with doses stratified across BSA quartiles, rather than a 'one dose fits all' regimen, would help individualize MMF therapy in this population.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging Model-Based Simulations to Optimize Extended Dosing of Leuprolide 6-Month Intramuscular Depot Formulation.","authors":"Li-Feng Hsu","doi":"10.1007/s13318-024-00932-1","DOIUrl":"https://doi.org/10.1007/s13318-024-00932-1","url":null,"abstract":"<p><strong>Background and objective: </strong>A gonadotropin-releasing hormone (GnRH) agonist such as leuprolide is widely used to achieve sustained suppression of testosterone levels, which play a critical role in the treatment of prostate cancer. Recent advances in drug delivery systems have led to the development of long-acting depot formulations, such as the 6-month intramuscular (IM) leuprolide formulation, which aim to simplify dosing and improve convenience for both patients and healthcare providers. Exploring extended dosing intervals for such formulations represents a promising approach to further optimize treatment regimens, potentially balancing efficacy with patient-centered care. The objective was to evaluate the efficacy of various extended dosing regimens of the leuprolide 6-month IM depot formulation for prostate cancer treatment. The primary objective was to assess whether extended dosing intervals could maintain testosterone concentrations below the castrate threshold of < 0.5 ng/ml and < 0.2 ng/ml in over 90% of subjects, as outlined in regulatory criteria.</p><p><strong>Methods: </strong>The study utilized a previously published pharmacokinetic/pharmacodynamic model to simulate the testosterone suppression profiles for different extended dosing regimens, including every 6 months (Q6M), 7 months (Q7M), 8 months (Q8M), 9 months (Q9M), 10 months (Q10M), 11 months (Q11M), and 12 months (Q12M). The simulations were carried out with 1000 virtual subjects. Sensitivity analyses were also conducted to account for variability in baseline testosterone levels and fraction of drug absorbed.</p><p><strong>Results: </strong>The simulation results indicated that extending the dosing interval from Q6M to Q8M could ensure that over 90% of subjects maintain testosterone concentrations below 0.2 ng/ml. Similarly, extending the dosing interval to Q9M would keep testosterone concentrations below 0.5 ng/ml in over 90% of subjects. The sensitivity analyses confirmed that these extended dosing regimens consistently achieved and maintained target testosterone levels across various scenarios.</p><p><strong>Conclusion: </strong>The findings support the feasibility of extending the dosing intervals for the leuprolide 6-month IM depot formulation beyond the label-recommended 6 months. Specifically, the Q8M and Q9M regimens emerged as viable candidates for further clinical evaluation, offering potential benefits in reducing injection frequency while maintaining therapeutic efficacy. Further clinical studies are necessary to confirm the long-term efficacy of these extended dosing regimens.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Herb-Drug Interaction of Total Glucosides of Paeony and Tripterygium Glycoside with Celecoxib in Beagle Dogs by UPLC-MS/MS.","authors":"Zhifei Zhang, Huijun Wang, Xinli Ren, Xiaotong Li, Xinyu Peng, Xiangjun Qiu","doi":"10.1007/s13318-025-00933-8","DOIUrl":"https://doi.org/10.1007/s13318-025-00933-8","url":null,"abstract":"<p><strong>Background and objective: </strong>Total glucosides of paeony (TGP) capsules, tripterygium glycoside tablets (TGT), and celecoxib are commonly used drugs in clinical practice for the treatment of Rheumatoid arthritis (RA). An UPLC-MS/MS method for the analysis of celecoxib in beagle dogs was developed, the herb-drug interactions (HDIs) between TGP and TGT with celecoxib were studied based on pharmacokinetics.</p><p><strong>Methods: </strong>The method of acetonitrile precipitation was applied to process plasma samples. Celecoxib and furosemide (internal standard, IS) was separated by gradient elution, and detected using multiple reaction monitoring mode under the positive ion. The ion reactions used for quantitative analysis were m/z 379.82 → 315.82 for celecoxib, and m/z 328.74 → 204.88 for IS. HDIs experiments adopt a three-stage experimental design. In the first period, six beagle dogs was orally administered 6.67 mg/kg celecoxib. In the second period, TGP 20 mg/kg was given orally twice a day for 7 consecutive days, then celecoxib was orally administered. And, in the third period, TGT 1.5 mg/kg was orally given, twice a day for 7 consecutive days, then celecoxib was orally administered. The concentration of celecoxib in the three periods was detected, and HDIs were evaluated based on pharmacokinetics.</p><p><strong>Results: </strong>Celecoxib exhibited good linearity in the range of 10-2000 ng/mL. The accuracy, precision, recoveries, matrix effects, and stability all met the standards. When celecoxib was used in combination with TGPC or TGT, the main pharmacokinetic parameters of celecoxib changed, C_max, AUC_(0-t) and AUC_(0-∞) increased, t_½ was prolonged, and CL and V_d decreased.</p><p><strong>Conclusion: </strong>A novel UPLC-MS/MS approach was successfully performed and applied to measure celecoxib in beagle dog plasma. TGP and TGT could inhibit the metabolism of celecoxib in beagle dogs, thereby affecting the pharmacokinetic parameters of celecoxib and increasing plasma exposure to celecoxib.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypertensive Nephropathy Changes the Expression of Drug-Metabolizing Enzymes and Transporters in Spontaneously Hypertensive Rat Liver and Kidney.","authors":"Yueqing Pan, Zhuan Yang, Minlong Wei, Yulin Gan, Menghua Liu, Wei Zou","doi":"10.1007/s13318-024-00923-2","DOIUrl":"10.1007/s13318-024-00923-2","url":null,"abstract":"<p><strong>Background and objectives: </strong>Hypertensive nephropathy (HN) has become one of the main causes of end-stage renal disease. Drug combination therapy is a common clinical treatment for HN. However, the impact of HN on drug-metabolizing enzymes and transporters, which may lead to drug-drug interactions (DDIs) and even trigger toxic side effects, remains unclear. The aim of this study was to investigate changes in major drug-metabolizing enzymes and transporters in the liver and kidney of HN rats to improve the scientific foundations for the clinical treatment of HN.</p><p><strong>Methods: </strong>Spontaneously hypertensive rats (SHRs) were used as an animal HN model because their hypertension is similar to that of humans. Wistar-Kyoto rats (WKYs) were used as the control group. Body weight, blood pressure, hematoxylin-eosin (HE) staining and biochemical analysis were performed to evaluate whether the HN model was successfully constructed. Quantitative real-time polymerase chain reaction (PCR) and western blotting were used to evaluate the mRNA and protein expression of drug-metabolizing enzymes, transporters and related nuclear transcription factors.</p><p><strong>Results: </strong>In HN rats, the mRNA expression of the drug-metabolizing enzymes cytochrome P450 (Cyp) 2b1, Cyp2c11, Cyp3a1 and Cyp7a1 was significantly upregulated. The protein level of CYP3A1 was consistent with its mRNA expression. Interestingly, the mRNA expression of the hepatic transporters organic cation transporter (Oct) 1, Oct2, organic anion transporter (Oat) 1, Oat2, multidrug resistant protein (Mrp) 2, multidrug resistance (Mdr) 1, organic anion transporting polypeptide (Oatp) 1b2 and na+/taurocholate cotransporting polypeptide (Ntcp) was also markedly upregulated. This may be directly influenced by the upregulation of the expression of the nuclear receptors farnesoid X receptor (Fxr), pregnane X receptor (Pxr), liver X-activated receptor (Lxr) and constitutive androstane receptor (Car). In the kidney of HN rats, the mRNA level of the drug-metabolizing enzyme Cyp2b1 significantly increased, while levels of Cyp1a1, Cyp2c11, Cyp3a1 and Cyp3a2 did not significantly change. The mRNA expression of the transporters multidrug and toxin extrusion (Mate) 1 and Mrp2 was obviously increased but was markedly depressed for peptide transporters (Pept) 1 and Pept2. These changes may be related to the cross effects of Pxr, Fxr and Car in kidney.</p><p><strong>Conclusion: </strong>HN pathological status can alter the expression of drug-metabolizing enzymes and transporters in the liver and kidney to varying degrees, thus affecting the disposition of substrate drugs in vivo. This suggests that to avoid potential risks, caution should be exercised when administering combination therapy for HN treatment.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"39-51"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of Zilurgisertib With and Without Food from Single and Multiple Ascending Dose Phase 1 Studies in Healthy Adults.","authors":"Yan-Ou Yang, Xiaohua Gong, Jay Getsy, Phillip Wang, Xiang Liu, Jennifer Sheng, Xuejun Chen, Kevin Rockich","doi":"10.1007/s13318-024-00926-z","DOIUrl":"10.1007/s13318-024-00926-z","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objectives: &lt;/strong&gt;The oral, potent, and highly selective activin receptor-like kinase 2 (ALK2) inhibitor zilurgisertib (INCB000928) is in development as a treatment for fibrodysplasia ossificans progressiva (FOP), and for anemia due to myelofibrosis, myelodysplastic syndromes, and multiple myeloma. Saliva is an attractive alternative to blood for drug monitoring and pharmacokinetic analysis, as it is non-invasive to retrieve. This is beneficial for patients, such as those with FOP, for whom blood draws can be challenging due to soft tissue damage susceptibility that can cause progressive heterotopic ossification, and for whom tourniquet time and blood draws must be minimized. The objectives of these studies were to evaluate zilurgisertib pharmacokinetics, safety, tolerability, and the effect of food in healthy participants from phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Both the SAD and MAD studies were double-blind, randomized, placebo-controlled dose escalation studies. In the SAD study, healthy participants received a single oral dose of zilurgisertib (10, 25, 50, 100, 175, 250, or 500 mg) or placebo in the fasted state. A further group of healthy participants were enrolled into an additional \"food effect\" cohort and randomized to receive a single oral dose of zilurgisertib (100 mg) after either an overnight fast or a high-fat meal in a 2-way crossover manner. In the MAD study, healthy participants received oral zilurgisertib at 50, 100, 150, 200, or 400 mg once daily or 300 mg twice daily in the fasted state. Blood, saliva, and urine samples were collected for zilurgisertib pharmacokinetic analysis. Safety was assessed throughout both studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Overall, 91 participants (70 active, 21 placebo) were enrolled and randomized to the SAD study and 79 participants (59 active, 20 placebo) were enrolled and randomized to the MAD study. Zilurgisertib was generally well tolerated, and adverse events were generally of mild-to-moderate severity. Zilurgisertib was rapidly absorbed, with median time to maximum plasma drug concentration (C&lt;sub&gt;max&lt;/sub&gt;) of 2.0-4.1 h post-dose. Zilurgisertib exposure was more than dose proportional after single and multiple doses over the dose range tested, suggesting non-linear pharmacokinetics. Plasma half-life values ranged from 22.8 to 31.4 h, supporting once-daily dosing. There was a strong correlation between zilurgisertib concentrations in saliva and plasma. No food effect was observed on zilurgisertib pharmacokinetics, with geometric mean ratio (90% confidence interval) C&lt;sub&gt;max&lt;/sub&gt; and area under the plasma concentration-time curve values of 0.98 (0.91 to1.06) and 1.03 (0.97 to 1.10). Renal excretion under fasted conditions was 16% and 27% of total drug clearance with single and multiple doses, respectively; therefore, it was not the predominant pathway for zilurgisertib elimination.&lt;/p&gt;","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"65-80"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11802711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of Piperacillin-Tazobactam Population Pharmacokinetic Models in Neonates: An External Validation.","authors":"Bhim Bahadur Chaudhari, Jaya Shree Dilli Batcha, Arun Prasath Raju, Saikumar Matcha, Leslie E Lewis, Sudheer Moorkoth, Surulivelrajan Mallayasamy","doi":"10.1007/s13318-024-00929-w","DOIUrl":"10.1007/s13318-024-00929-w","url":null,"abstract":"<p><strong>Background and objective: </strong>Neonatal pharmacotherapy has gained attention from clinicians and regulatory agencies for optimizing the dosage of the drug which improves therapeutic outcomes in this special population. Piperacillin-tazobactam antibiotic is commonly used as a therapeutic option for treatment of severe infection in neonatal intensive care units. There are few population pharmacokinetic (PopPK) studies of piperacillin and tazobactam published for this specific population and which were not validated in other study settings. The aim of this study was to externally evaluate the published population pharmacokinetic models for piperacillin-tazobactam.</p><p><strong>Methods: </strong>A systematic review was conducted through Scopus, PubMed, and Embase databases to identify PopPK models. Clinical data collected in neonates treated with piperacillin-tazobactam were used for evaluation of these models. Various prediction-based metrics were used for assessing the bias and precision of PopPK models using individual predictions.</p><p><strong>Results: </strong>Three PopPK models were identified for external evaluation. A total of 53 plasma samples were collected from 46 neonates admitted in the neonatal intensive care unit. The PopPK models reported by Cohen-Wolkowiez et al. for piperacillin and Li et al. for tazobactam were able to predict well for our clinical data.</p><p><strong>Conclusion: </strong>The PopPK models by Cohen-Wolkowiez et al. and Li et al. predicted our data well for piperacillin and tazobactam with the lower relative median absolute predictive error (rMAPE) of 8.61% and 16.48% and relative root mean square error (rRMSE) of 0.01 and 0.03, respectively. External evaluation of the published PopPK models of piperacillin and tazobactam resulted in enhancing their credibility to be implemented in clinical practice.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"81-89"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the Clinical Outcomes of Cyclosporine Short Infusion Versus Continuous Infusion Postallogenic Stem Cell Transplantation.","authors":"Shaymaa M M El-Awady, Amal M El Afifi, Rania Afifi, Nagwa A Sabri, Marwa Adel Ahmed","doi":"10.1007/s13318-024-00927-y","DOIUrl":"10.1007/s13318-024-00927-y","url":null,"abstract":"<p><strong>Background and objective: </strong>Cyclosporin A (CsA) exhibits a narrow therapeutic index and large inter-individual variation in pharmacokinetics. Two intermittent and 24-h continuous infusions (CI) are both commonly used regimens in hematopoietic stem cell transplantation (HSCT), with no universal consensus. The objective of this study was to assess whether CsA as a 2-h, twice-daily intravenous infusion (2 h/12 h) is non-inferior to 22 h CI every 24 h (22 h-CI/24 h) in terms of acute graft-versus-host disease (aGVHD) incidence and adverse events in allogeneic HSCT adult patients.</p><p><strong>Methods: </strong>An open-label randomized trial recruited 31 allogeneic HSCT patients to receive the 2 h/12 h or 22 h-CI/24 h regimen. The primary outcomes were the incidence of aGVHD and CsA-related adverse events. The secondary outcomes included the correlation between the time concentration and area under the concentration-time curve (AUC) of 2 h/12 h versus 22 h-CI/24 h regimens.</p><p><strong>Results: </strong>Six (19.4%) patients developed aGVHD. There was no statistically significant difference between the two groups concerning the incidence of aGVHD (13.3% in 2 h/12 h vs. 25% in 22 h-CI/24 h; p = 0.359). The distribution of different aGVHD types (p = 0.20) and mortality (p = 0.9) were not significantly different between the two groups. The two groups did not differ at any time with respect to AUCs, nephrotoxicity, hepatotoxicity, or electrolyte disturbance.</p><p><strong>Conclusion: </strong>The study suggested that the 2 h/12 h regimen is non-inferior to the conventional regimen (22 h CI/24 h) in terms of aGVHD incidence and adverse events. Further research is necessary to validate these findings and to guide practice, considering the small sample size of this study.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identifier NCT04575779 with initial release on 19 September 2020-Retrospectively registered, https://clinicaltrials.gov/study/NCT04575779 .</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"53-64"},"PeriodicalIF":1.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142727287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}