8,043 results match your criteria two-compartment disposition


Role of Toxicokinetic and Toxicodynamic Parameters in Explaining the Sensitivity of Zebrafish Larvae to Four Metals.

Environ Sci Technol 2021 Jun 15. Epub 2021 Jun 15.

Key Laboratory of Pollution Process and Environmental Criteria of Ministry of Education and Tianjin Key Laboratory of Environmental Remediation and Pollution Control, College of Environmental Science and Engineering, Nankai University, Tianjin 300071, P. R. China.

Given the persistence and toxic potencies of metal contaminants in ecosystems, animals, and human beings, they are considered to be hazardous global pollutants. While the lethality of metal toxicities (e.g. Read More

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Exploring different mechanisms of biochars in removing hexavalent chromium: Sorption, reduction and electron shuttle.

Bioresour Technol 2021 Jun 10;337:125382. Epub 2021 Jun 10.

State Environmental Protection Engineering Center for Urban Soil Contamination Control and Remediation, Shanghai Academy of Environmental Sciences, Shanghai 200233, China.

The role of different biochars in Cr(VI) removal process is not clear. Two raw materials with distinct components were prepared into biochars at various pyrolysis temperatures. The biochar derived from cotton stark (with less lignin than walnut shell) always had more surface functional groups. Read More

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Toward pharmacogenetic SLCO1B1-guided dosing of methotrexate in arthritis using a murine Slco1b2 knockout model.

Clin Transl Sci 2021 Jun 13. Epub 2021 Jun 13.

Division of Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati.

Low-dose methotrexate (MTX) is a first-line therapy for the treatment of arthritis. However, there is considerable inter-individual variability in MTX exposure following standard dosing. Polymorphisms in SLCO1B1 significantly effect MTX clearance, altering therapeutic response. Read More

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Comparison of Various Approaches to Translate Non-Linear Pharmacokinetics of Monoclonal Antibodies from Cynomolgus Monkey to Human.

Eur J Drug Metab Pharmacokinet 2021 Jun 13. Epub 2021 Jun 13.

Translation Bioscience, Human Health Therapeutics, National Research Council of Canada, Ottawa, ON, Canada.

Background And Objectives: The prediction of pharmacokinetics of monoclonal antibodies (mAbs) exhibiting non-linear pharmacokinetics in preclinical species to human is challenging, and very limited scientific work has been published in this field of research. Therefore, we have conducted an elaborate comparative assessment to determine the most reliable preclinical to clinical scaling strategy for mAbs with non-linear pharmacokinetics.

Methods: We have compared three different scaling approaches to predict human pharmacokinetics from cynomolgus monkey. Read More

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Selecting software pipelines for change in flortaucipir SUVR: Balancing repeatability and group separation.

Neuroimage 2021 Jun 9;238:118259. Epub 2021 Jun 9.

Department of Radiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester 55905, MN, USA.

Since tau PET tracers were introduced, investigators have quantified them using a wide variety of automated methods. As longitudinal cohort studies acquire second and third time points of serial within-person tau PET data, determining the best pipeline to measure change has become crucial. We compared a total of 415 different quantification methods (each a combination of multiple options) according to their effects on a) differences in annual SUVR change between clinical groups, and b) longitudinal measurement repeatability as measured by the error term from a linear mixed-effects model. Read More

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Population Pharmacokinetics of Oral Levofloxacin in Healthy Volunteers and Dosing Optimization for Multidrug-resistant Tuberculosis Therapy.

Biopharm Drug Dispos 2021 Jun 11. Epub 2021 Jun 11.

Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkla, 90110, Thailand.

Background: Levofloxacin is considered to be a key component of multidrug-resistant tuberculosis (MDR-TB) regimen. However, there is considerable concern regarding the subtherapeutic concentrations of currently used doses and the development of drug resistance.Therefore, this study aimed to describe the population pharmacokinetics of oral levofloxacin in healthy volunteers and to evaluate the probability of target attainment (PTA) in an attempt to optimize the dosing regimens for MDR-TB therapy. Read More

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A Target-Mediated Drug Disposition (TMDD) Model to Explain Non-Linear Pharmacokinetics of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor SPI-62 in Healthy Adults.

J Clin Pharmacol 2021 Jun 10. Epub 2021 Jun 10.

Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa.

SPI-62 is a selective and potent small-molecule inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1). SPI-62 has demonstrated substantial and complex nonlinear pharmacokinetics (PK) in humans that is characterized by unusually low plasma exposures at low doses; dose-dependent volume of distribution; nonlinear PK following the first dose and dose-proportional PK at steady state; as well as unusually high accumulation ratios at low doses. The most likely explanation for the observed nonlinearity of SPI-62 is the saturable binding of SPI-62 to its pharmacological target HSD-1, a phenomenon known as target-mediated drug disposition (TMDD). Read More

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Population Pharmacokinetic And Exposure-Response Analyses Of Intravenous And Subcutaneous Rituximab In Patients With Chronic Lymphocytic Leukemia.

CPT Pharmacometrics Syst Pharmacol 2021 Jun 10. Epub 2021 Jun 10.

Roche Innovation Center Basel, Basel, Switzerland.

A subcutaneous formulation of the anti-CD20 antibody rituximab has been developed. Fixed-dose subcutaneous rituximab delivers non-inferior serum trough concentrations (C ), ensuring similar target saturation and comparable efficacy/safety to intravenous rituximab, but with simplified and shortened preparation and administration. We aimed to characterize the pharmacokinetic and exposure-response properties of subcutaneous rituximab. Read More

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Population pharmacokinetic and exploratory exposure-response analysis of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer in the FeDeriCa study.

Cancer Chemother Pharmacol 2021 Jun 9. Epub 2021 Jun 9.

Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.

Purpose: To characterize pertuzumab pharmacokinetics (PK) in FeDeriCa (NCT03493854: fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] versus intravenous pertuzumab plus trastuzumab); derive individual pertuzumab exposures in the PH FDC SC arm for subsequent pertuzumab exposure-response (ER) analyses; compare observed trastuzumab PK with predicted exposures from a previous SC trastuzumab model; assess whether pertuzumab affects trastuzumab PK; evaluate pertuzumab exposure-efficacy and -safety relationships and support the approved SC dosing regimen.

Methods: Population pharmacokinetic modeling and simulations were used to describe the data. Standard goodness-of-fit diagnostics and prediction-corrected visual predictive checks were used for model performance assessment. Read More

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Novel in vivo and ex vivo hybrid in vivo imaging system (IVIS) imaging offers a convenient and precise way to measure the glomerular filtration rate in conscious mice.

J Pharmacol Toxicol Methods 2021 Jun 5;110:107084. Epub 2021 Jun 5.

Comparative Medicine, Pfizer Worldwide R&D and Medical, Groton, CT 06340, United States. Electronic address:

Introduction: In pharmacology and toxicology studies, the glomerular filtration rate (GFR) is the gold standard for the assessment of renal function, and the renal clearance of inulin in blood measured by photometers is known as a filtration marker for the determination of GFR. Preclinically, a non-invasive GFR measurement method was recently developed in which near-infrared fluorescently labelled inulin (GFR-Vivo 680) was scanned with fluorescence molecular tomography (FMT). However, measurement of GFR using FMT has major disadvantages and technical challenges, such as requiring experienced skills in animal handling and rapid and precise time management. Read More

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Population Pharmacokinetic Analysis of Darunavir and Tenofovir Alafenamide in HIV-1-Infected Patients on the Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Single-Tablet Regimen (AMBER and EMERALD Studies).

AAPS J 2021 Jun 7;23(4):82. Epub 2021 Jun 7.

Janssen Research and Development, Turnhoutseweg 30, B-2340, Beerse, Belgium.

The single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg has undergone phase III studies AMBER (NCT02431247) and EMERALD (NCT02269917) in HIV-infected patients. An existing population pharmacokinetic (PopPK) model for cobicistat-boosted darunavir (DRV) was updated to describe DRV PK in AMBER and EMERALD. For TAF, a PopPK model was developed using richly sampled phase I/II data and updated with sparsely sampled AMBER data. Read More

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Assessment of stunned and viable myocardium using manganese-enhanced MRI.

Open Heart 2021 Jun;8(1)

Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK.

Objective: In a proof-of-concept study, to quantify myocardial viability in patients with acute myocardial infarction using manganese-enhanced MRI (MEMRI), a measure of intracellular calcium handling.

Methods: Healthy volunteers (n=20) and patients with ST-elevation myocardial infarction (n=20) underwent late gadolinium enhancement (LGE) using gadobutrol and MEMRI using manganese dipyridoxyl diphosphate. Patients were scanned ≤7 days after reperfusion and rescanned after 3 months. Read More

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Population Pharmacokinetics of Meropenem and Vaborbactam Based on Data from Non-Infected Subjects and Infected Patients.

Antimicrob Agents Chemother 2021 Jun 7:AAC0260620. Epub 2021 Jun 7.

Institute for Clinical Pharmacodynamics, Inc. Schenectady, NY.

Meropenem-vaborbactam is a broad-spectrum carbapenem-beta-lactamase inhibitor combination approved in the USA and Europe to treat patients with complicated urinary tract infections and in Europe, other serious bacterial infections, including hospital- acquired and ventilator-associated pneumonia. Population pharmacokinetic (PK) models were developed to characterize the time-course of meropenem and vaborbactam using pooled data from two Phase 1 and two Phase 3 studies. Multi-compartment disposition model structures with linear elimination processes were fit to the data using NONMEM 7. Read More

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CYP2C19 phenotype and body-weight-guided voriconazole initial dose in infants and children after hematopoietic cell transplantation.

Antimicrob Agents Chemother 2021 Jun 7:AAC0062321. Epub 2021 Jun 7.

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.

: Prophylactic voriconazole use is recommended in children undergoing hematopoietic cell transplantation (HCT). Dosing considerations are essential due to its narrow therapeutic index. Known covariates do not sufficiently explain large interindividual pharmacokinetic (PK) variability of voriconazole. Read More

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Pharmacokinetic/pharmacodynamic evaluation of tobramycin dosing in critically ill patients: the Hartford nomogram does not fit.

J Antimicrob Chemother 2021 Jun 7. Epub 2021 Jun 7.

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China.

Objectives: Extended-interval dosing of tobramycin is widely applied in patients with the Hartford nomogram as a representative, while this dosing approach has not been extensively evaluated in critically ill patients. The goal of this study was to characterize the pharmacokinetics of tobramycin and to evaluate the appropriateness of the Hartford nomogram in critically ill patients.

Methods: A retrospective analysis was performed based on a medical critical care database. Read More

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Dynamic mechanism of multiple bursting patterns in a whole-cell multiscale model with calcium oscillations.

J Biol Dyn 2021 Dec;15(1):308-326

School of Physical and Mathematical Sciences, Nanjing Tech University, Nanjing, People's Republic of China.

The dynamic mechanism of a whole-cell model containing electrical signalling and two-compartment Ca signalling in gonadotrophs is investigated. The transition from spiking to bursting by Hopf bifurcation of the fast subsystem about the slow variable is detected via the suitable parameters. When the timescale of K gating variable is changed, the relaxation oscillation with locally small fluctuation, chaotic bursting and mixed-mode bursting (MMB) are revealed through chaos. Read More

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December 2021

A Population Pharmacokinetic-Pharmacodynamic Model of YH12852, a Highly Selective 5-HT Receptor Agonist, in Healthy Subjects and Patients with Functional Constipation.

CPT Pharmacometrics Syst Pharmacol 2021 Jun 4. Epub 2021 Jun 4.

Department of Applied Biomedical Engineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.

YH12852, a novel, highly selective 5-HT receptor agonist, is currently under development to treat patients with functional constipation. In this study, we aimed to develop a pharmacokinetic-pharmacodynamic (PK-PD) model that adequately described the time courses of the plasma concentrations of YH12852 and its prokinetic effect as assessed by the gastric emptying breath test (GEBT) and to predict the prokinetic effect of YH12852 at higher doses through PD simulation. We used the plasma concentrations of YH12852 from patients with functional constipation and healthy subjects and the GEBT results from healthy subjects obtained from a phase 1/2a trial. Read More

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PK/PD modelling of FXI antisense oligonucleotides to bridge the dose-FXI activity relation from healthy volunteers to end-stage renal disease patients.

CPT Pharmacometrics Syst Pharmacol 2021 Jun 4. Epub 2021 Jun 4.

Ionis Pharmaceuticals, Inc, Carlsbad, CA, USA.

IONIS-FXI (BAY2306001) is an antisense oligonucleotide that inhibits the synthesis of coagulation factor XI and has been investigated in healthy volunteers and end-stage renal disease (ESRD) patients. FXI-LICA (BAY2976217) shares the same RNA sequence as IONIS-FXI but contains a GalNAc-conjugation that facilitates asialoglycoprotein receptor (ASGPR)-mediated uptake into hepatocytes. FXI-LICA has been studied in healthy volunteers and is currently investigated in ESRD patients on hemodialysis. Read More

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Population pharmacokinetics of immediate-release and modified-release paracetamol and its major metabolites in a supratherapeutic dosing study.

Clin Toxicol (Phila) 2021 Jun 3:1-8. Epub 2021 Jun 3.

School of Pharmacy, University of Otago, Dunedin, New Zealand.

Objectives: Overdose with paracetamol modified-release (MR) formulation, a bilayer tablet containing 69% slow-release component, has been increasing since its introduction to the market. However, little evidence exists for the management of MR paracetamol overdose. We aimed to develop a population pharmacokinetic (PK) model for immediate-release (IR) and MR paracetamol and its major metabolism, and quantitatively understand the formulation difference in toxicity assessment based on the nomogram line. Read More

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Population Pharmacokinetics of Belantamab Mafodotin, a BCMA-targeting Agent in Patients with Relapsed/Refractory Multiple Myeloma.

CPT Pharmacometrics Syst Pharmacol 2021 Jun 2. Epub 2021 Jun 2.

GlaxoSmithKline, Collegeville, PA, USA.

Belantamab mafodotin (belamaf) is an antibody-drug conjugate (ADC) targeting B-cell maturation antigen (BCMA). Nonlinear mixed-effects models were developed to characterize the population pharmacokinetics (PopPK) of ADC, total monoclonal antibody (mAb), and cysteine-maleimidocaproyl-MMAF (cys-mcMMAF) after 0.03-4. Read More

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Translating potentiometric detection into non-enzymatic amperometric measurement of HO.

Talanta 2021 Sep 1;232:122489. Epub 2021 May 1.

Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research (YIC), Chinese Academy of Sciences (CAS); Shandong Provincial Key Laboratory of Coastal Environmental Processes, YICCAS, Yantai Shandong, 264003, PR China; Laboratory for Marine Biology and Biotechnology, Pilot National Laboratory for Marine Science and Technology, Qingdao, 26620, PR China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, Shandong, 266071, PR China.

The developments of alternative signal readout strategies for the ion-selective electrodes (ISEs) are necessary in order to break through the limitation of the Nernst equation. In this work, a simple, convenient and easily operated strategy based on the non-enzymatic amperometric measurement of HO is proposed to read out the potentiometric responses for the ISEs. The proposed amperometric signal readout based on HO is carried out in a two compartment electrochemical cell configuration containing a detection cell and a sample cell, physically connected by a salt bridge. Read More

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September 2021

The role of endoplasmic reticulum in in vivo cancer FDG kinetics.

PLoS One 2021 1;16(6):e0252422. Epub 2021 Jun 1.

Dipartimento di Matematica, Università di Genova, Genova, Italy.

A recent result obtained by means of an in vitro experiment with cancer cultured cells has configured the endoplasmic reticulum as the preferential site for the accumulation of 2-deoxy-2-[18F]fluoro-D-glucose (FDG). Such a result is coherent with cell biochemistry and is made more significant by the fact that the reticular accumulation rate of FDG is dependent upon extracellular glucose availability. The objective of the present paper is to confirm in vivo the result obtained in vitro concerning the crucial role played by the endoplasmic reticulum in FDG cancer metabolism. Read More

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Fractional calculus tracer kinetic compartment model for quantification of microvascular perfusion.

Physiol Meas 2021 May 28. Epub 2021 May 28.

Universitätsklinikum Essen, Essen, Nordrhein-Westfalen, GERMANY.

We evaluate a tracer kinetic model for quantification of physiological perfusion and microvascular residue time kurtosis in skeletal muscle vasculature with first pass bolus experiments in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). A decreasing stretched Mittag-Leffler function (f1C model) was obtained as the impulse response solution of a rate equation of real-valued (,,fractional'') derivation order. The method was validated in skeletal muscle in the lower limb of seven female pigs examined by DCE-MRI. Read More

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Quantitative Clinical Pharmacology Supports the Bridging from IV Dosing and Approval of SC Rituximab in B-Cell Hematological Malignancies.

Clin Pharmacol Ther 2021 May 26. Epub 2021 May 26.

Clinical Pharmacology, Pharmaceutical Sciences, Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.

A fixed-dose subcutaneous (SC) formulation of the anti-CD20 antibody, rituximab, has been developed to address safety, infusion time, and patient comfort concerns relating to intravenous (IV) dosing, and has been approved based upon a pharmacokinetics (PK)-clinical bridging strategy, which demonstrated non-inferiority of SC vs. IV dosing in malignancies including follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). A clinical development plan was undertaken to identify rituximab SC doses achieving non-inferior exposure to rituximab IV, and to confirm PK-clinical bridging, with the same efficacy and similar safety. Read More

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Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study.

Clin Pharmacokinet 2021 May 26. Epub 2021 May 26.

Department of Pharmacology and Toxicology, Radboud Institute of Health Sciences, Radboudumc, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands.

Background And Objective: Ceftriaxone is a cornerstone antibiotic for critically ill children with severe infections. Despite its widespread use, information on the pharmacokinetics of ceftriaxone is lacking in this population. We aimed to determine ceftriaxone pharmacokinetics in critically ill children and to propose ceftriaxone dosing guidelines resulting in adequate target attainment using population pharmacokinetic modeling and simulation. Read More

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Population Pharmacokinetic Analysis of Indacaterol/Glycopyrronium/Mometasone Furoate After Administration of Combination Therapies Using the Breezhaler Device in Patients with Asthma.

Eur J Drug Metab Pharmacokinet 2021 May 22. Epub 2021 May 22.

Pharmacokinetic Sciences, Novartis Institutes for Biomedical Research, Cambridge, USA.

Background And Objective: Clinical evidence suggests no clinically relevant pharmacokinetic interactions between indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF). A population pharmacokinetic (popPK) analysis was conducted to identify structural models describing systemic pharmacokinetic profiles of IND, GLY and MF, and estimate the effect of covariates on their pharmacokinetics following inhalation as IND/GLY/MF.

Methods: Pharmacokinetic data from 698 patients with asthma were pooled from two Phase III studies that evaluated IND/MF medium- (150/160 µg) and high-dose (150/320 µg), IND/GLY/MF medium- (150/50/80 μg) and high-dose (150/50/160 μg), and a device bridging Phase II study with MF. Read More

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Comparisons between impedance-based and time-based switching bipolar radiofrequency ablation for the treatment of liver cancer.

Comput Biol Med 2021 May 14;134:104488. Epub 2021 May 14.

School of Engineering and Information Technology, Faculty of Science and Technology, Federation University, VIC, 3350, Australia.

Switching bipolar radiofrequency ablation (bRFA) is a cancer treatment technique that activates multiple pairs of electrodes alternately based on a predefined criterion. Various criteria can be used to trigger the switch, such as time (ablation duration) and tissue impedance. In a recent study on time-based switching bRFA, it was determined that a shorter switch interval could produce better treatment outcome than when a longer switch interval was used, which reduces tissue charring and roll-off induced cooling. Read More

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Population Pharmacokinetic Analysis and Dosing Optimization Based on Unbound Daptomycin Concentration and Cystatin C in Nonobese Elderly Patients with Hypoalbuminemia and Chronic Kidney Disease.

Pharm Res 2021 May 19. Epub 2021 May 19.

Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan.

Purpose: This study evaluated the population pharmacokinetics of daptomycin in nonobese elderly patients with hypoalbuminemia and chronic kidney disease (CKD) using the glomerular filtration rate estimated from cystatin C (eGFRcys) and estimated its optimal dose.

Methods: We performed population pharmacokinetic analysis of the unbound concentrations of daptomycin. The probability of target attainment of 90% for achieving an area under the concentration-time curve of unbound daptomycin at steady state/ minimum inhibitory concentration ratio of ≥66. Read More

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Osteoporosis treatment with risedronate: a population pharmacokinetic model for the description of its absorption and low plasma levels.

Osteoporos Int 2021 May 17. Epub 2021 May 17.

Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15784, Athens, Greece.

To develop a population pharmacokinetic model that describes the absorption and low plasma levels of risedronate in the body. The impact of patients' characteristics on risedronate kinetics is investigated. Simulations revealed the high variability in the concentration levels after different dosage schemes. Read More

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Dose selection for fremanezumab (AJOVY) phase 3 pediatric migraine studies using pharmacokinetic data from a pediatric phase 1 study and a population pharmacokinetic modeling and simulation approach.

Cephalalgia 2021 May 17:3331024211007789. Epub 2021 May 17.

Teva Pharmaceutical Industries, Netanya, Israel.

Background: Potential fremanezumab doses for pediatric patients were evaluated using pharmacokinetic modeling and simulation. An open-label phase 1 pharmacokinetic and safety study was conducted in pediatric patients with migraine. This study's results together with refinement of the adult population pharmacokinetic model were used to determine fremanezumab dose recommendations for phase 3 pediatric studies. Read More

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