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Clinical Pharmacokinetics

Michel Tod, S Goutelle, N Bleyzac, L Bourguignon
BACKGROUND AND OBJECTIVE: The In Vivo Mechanistic Static Model (IMSM) is a powerful method used to predict the magnitude of drug-drug interactions (DDIs) mediated by cytochromes. The objective of this study was to extend the IMSM paradigm to DDIs mediated by efflux transporters and cytochromes. METHODS: First, a generic model for this kind of interaction was devised. A flexible approach was then developed to estimate the characteristic parameters [the contribution ratios (CRs) and inhibition or induction potencies (IXs)] from clinical data by non-linear regression...
September 8, 2018: Clinical Pharmacokinetics
Yanhua Gao, Stefanie Hennig, Michael Barras
OBJECTIVES: The objective of this article is to investigate the influence of blood sampling times on tobramycin exposure estimation and clinical decisions and to determine the best sampling times for two estimation methods used for therapeutic drug monitoring. METHODS: Adult patients with cystic fibrosis, treated with once-daily intravenous tobramycin, were intensively sampled over one 24-h dosing interval to determine true exposure (AUC0-24 ). The AUC0-24 s were then estimated using both log-linear regression and Bayesian forecasting methods for 21 different sampling time combinations...
August 24, 2018: Clinical Pharmacokinetics
Felix Stader, Marco Siccardi, Manuel Battegay, Hannah Kinvig, Melissa A Penny, Catia Marzolini
BACKGROUND: Aging is characterized by anatomical, physiological, and biological changes that can impact drug kinetics. The elderly are often excluded from clinical trials and knowledge about drug kinetics and drug-drug interaction magnitudes is sparse. Physiologically based pharmacokinetic modeling can overcome this clinical limitation but detailed descriptions of the population characteristics are essential to adequately inform models. OBJECTIVE: The objective of this study was to develop and verify a population database for aging Caucasians considering anatomical, physiological, and biological system parameters required to inform a physiologically based pharmacokinetic model that included population variability...
August 21, 2018: Clinical Pharmacokinetics
Juliette Berger, Marie Vigan, Bruno Pereira, Thu Thuy Nguyen, Roseline Froissart, Nadia Belmatoug, Florence Dalbiès, Agathe Masseau, Christian Rose, Christine Serratrice, Yves-Marie Pers, Ivan Bertchansky, Fabrice Camou, Monia Bengherbia, Céline Bourgne, Catherine Caillaud, Magali Pettazzoni, Amina Berrahal, Jérôme Stirnemann, France Mentré, Marc G Berger
BACKGROUND AND OBJECTIVES: Intravenous imiglucerase enzyme replacement therapy for Gaucher disease type 1 administered every 2 weeks is at variance with the imiglucerase plasma half-life of a few minutes. We hypothesized that studying the pharmacokinetics of imiglucerase in blood Gaucher disease type 1 monocytes would be more relevant for understanding enzyme replacement therapy responses. METHODS: Glucocerebrosidase intra-monocyte activity was studied by flow cytometry...
August 21, 2018: Clinical Pharmacokinetics
Ahmed A Suleiman, Amit Khatri, Mukul Minocha, Ahmed A Othman
BACKGROUND AND OBJECTIVES: Risankizumab is a humanized anti-interleukin-23 monoclonal antibody in development for the treatment of several inflammatory diseases. This work characterized the pharmacokinetics of risankizumab and evaluated covariates that may affect its exposures using phase I and II trial data in subjects with psoriasis and Crohn's disease. METHODS: Plasma concentration measurements from a phase I study and a phase II study in subjects with psoriasis (n = 157; single doses of 0...
August 20, 2018: Clinical Pharmacokinetics
Neeraj Gupta, Michael J Hanley, Cindy Xia, Richard Labotka, R Donald Harvey, Karthik Venkatakrishnan
Ixazomib, the first oral proteasome inhibitor, is approved in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. Ixazomib is a selective, potent, and reversible inhibitor of the 20S proteasome, and preferentially binds to and inhibits the β5 chymotrypsin-like proteolytic site. Ixazomib absorption is rapid, with a median time to reach maximum plasma concentration of approximately 1 h post-dose. Ixazomib pharmacokinetics (PK) are adequately described by a three-compartment model (terminal half-life of 9...
August 17, 2018: Clinical Pharmacokinetics
Sherwin K B Sy, Luning Zhuang, Serubbabel Sy, Hartmut Derendorf
Avibactam is a non-β-lactam, β-lactamase inhibitor of the diazabicyclooctane class that covalently acylates its β-lactamase targets, encompassing extended spectrum of activities that cover serine β-lactamases but not metallo-β-lactamases. Ceftazidime and avibactam have complementary pharmacokinetic (PK) profiles. Both drugs have a half-life of approximately 2 h, making them suitable to be combined in a fixed-dose combination ratio of 4:1 (ceftazidime:avibactam). Renal clearance is the primary elimination pathway of both ceftazidime and avibactam, and dose adjustment is required in patients with moderate and severe renal impairment...
August 11, 2018: Clinical Pharmacokinetics
Sanjoy Ketan Paul, Jason A Roberts, Jeffrey Lipman, Renae Deans, Mayukh Samanta
BACKGROUND AND AIM: Current approaches to antibiotic dose determination in critically ill patients requiring renal replacement therapy are primarily based on the assessment of highly heterogeneous data from small number of patients. The standard modelling approaches limit the scope of constructing robust confidence boundaries of the distribution of pharmacokinetics (PK) parameters, especially when the evaluation of possible association of demographic and clinical factors at different levels of the distribution of drug clearance is of interest...
August 10, 2018: Clinical Pharmacokinetics
Alicja Puszkiel, Gaëlle Noé, Audrey Bellesoeur, Nora Kramkimel, Marie-Noëlle Paludetto, Audrey Thomas-Schoemann, Michel Vidal, François Goldwasser, Etienne Chatelut, Benoit Blanchet
Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that is approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harbouring the BRAFV600E mutation. The recommended dose of dabrafenib is 150 mg twice daily (bid) under fasted conditions. After single oral administration of the recommended dose, the absolute oral bioavailability (F) of dabrafenib is 95%...
August 9, 2018: Clinical Pharmacokinetics
Carlos Fernandez-Teruel, Ignacio Gonzalez, Iñaki F Trocóniz, Rubin Lubomirov, Arturo Soto, Salvador Fudio
BACKGROUND AND OBJECTIVES: Lurbinectedin is an inhibitor of RNA polymerase II currently under clinical development for intravenous administration as a single agent and in combination with other anti-tumor agents for the treatment of several tumor types. The objective of this work was to develop a population-pharmacokinetic model in this patient setting and to elucidate the main predictors to guide the late stages of development. METHODS: Data from 443 patients with solid and hematologic malignancies treated in six phase I and three phase II trials with lurbinectedin as a single agent or combined with other agents were included in the analysis...
August 9, 2018: Clinical Pharmacokinetics
Anne Gardin, Mike Ufer, Eric Legangneux, Gianluca Rossato, Yi Jin, Zhenzhong Su, Parasar Pal, Wenkui Li, Kasra Shakeri-Nejad
OBJECTIVES: The aim of this study was to assess the pharmacokinetics (PK) and safety/tolerability of siponimod in healthy subjects when coadministered with (1) the moderate cytochrome P450 (CYP) 2C9 and CYP3A inhibitor fluconazole (Study A), and (2) with three different CYP2C9 genotype variants (Study B). METHODS: Study A was an open-label, single-dose study comprising periods 1 (14 days; day 1: siponimod 4 mg) and 2 (20 days; day 1: fluconazole 200 mg twice daily; days 2-19: fluconazole 200 mg once daily; day 3: siponimod 4 mg) in healthy subjects (n = 14) with the wild-type CYP2C9 genotype (CYP2C9*1/*1)...
August 7, 2018: Clinical Pharmacokinetics
Robert Hermann, Mats O Karlsson, Ana M Novakovic, Nadia Terranova, Markus Fluck, Alain Munafo
The cladribine prodrug is phosphorylated intracellularly to its active product, 2-chlorodeoxyadenosine triphosphate (Cd-ATP), by deoxycytidine kinase.
August 1, 2018: Clinical Pharmacokinetics
Jennifer Hibma, Beverly Knight
BACKGROUND AND OBJECTIVE: Gemtuzumab ozogamicin is an antibody-drug conjugate composed of the anti-CD33 monoclonal antibody hP67.6 covalently linked to N-acetyl-gamma-calicheamicin dimethylhydrazide, a potent cytotoxic antibiotic. The aim of this study was to characterize the population pharmacokinetics of gemtuzumab ozogamicin, represented by total hP67.6 antibody and unconjugated calicheamicin, in adult patients with acute myeloid leukemia to support drug dosing strategies and explore intrinsic and extrinsic factors that may influence exposure...
July 30, 2018: Clinical Pharmacokinetics
Joseph F Standing, Brian J Anderson, Stefanie Hennig, Nick H Holford, Trevor N Johnston, Catherijne A J Knibbe, Dagan O Lonsdale, Amin Rostami-Hodjegan
No abstract text is available yet for this article.
July 20, 2018: Clinical Pharmacokinetics
Sven C van Dijkman, Nico C B de Jager, Willem M Rauwé, Meindert Danhof, Oscar Della Pasqua
No abstract text is available yet for this article.
July 20, 2018: Clinical Pharmacokinetics
Joanna C Masters, Elly Barry, Beverly Knight
BACKGROUND AND OBJECTIVE: To date, the population pharmacokinetics (popPK) of gemtuzumab ozogamicin (GO), a CD33-directed antibody-drug conjugate consisting of hP67.6 antibody linked to N-acetyl gamma calicheamicin used in the treatment of acute myeloid leukemia (AML), has not been characterized in pediatric patients. This report describes the popPK of GO following intravenous administration in 29 pediatric patients aged ≤ 17 years with relapsed or refractory AML who were enrolled in the 0903A1-102-US phase I/II study...
July 19, 2018: Clinical Pharmacokinetics
Marko M Sahinovic, Michel M R F Struys, Anthony R Absalom
Propofol is an intravenous hypnotic drug that is used for induction and maintenance of sedation and general anaesthesia. It exerts its effects through potentiation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) at the GABAA receptor, and has gained widespread use due to its favourable drug effect profile. The main adverse effects are disturbances in cardiopulmonary physiology. Due to its narrow therapeutic margin, propofol should only be administered by practitioners trained and experienced in providing general anaesthesia...
July 18, 2018: Clinical Pharmacokinetics
Nadia Terranova, Christine Hicking, Fernando Dangond, Alain Munafo
INTRODUCTION: Cladribine Tablets (MAVENCLAD® ) selectively reduce absolute lymphocyte counts (ALCs) in patients with multiple sclerosis. The recommended cumulative dose of Cladribine Tablets is 3.5 mg/kg over 4-5 days in months 1 and 2 of treatment years 1 and 2, followed by prolonged efficacy with no additional treatment. After the cladribine-induced reduction, ALCs recover to normal within each treatment year in most patients. Those patients with slow ALC recovery can develop Grade 3-4 lymphopenia, especially those patients with Grade ≥  2 lymphopenia at the start of year 2...
July 11, 2018: Clinical Pharmacokinetics
Robert Hermann, Mats O Karlsson, Ana M Novakovic, Nadia Terranova, Markus Fluck, Alain Munafo
Cladribine Tablets (MAVENCLAD® ) are used to treat relapsing multiple sclerosis (MS). The recommended dose is 3.5 mg/kg, consisting of 2 annual courses, each comprising 2 treatment weeks 1 month apart. We reviewed the clinical pharmacology of Cladribine Tablets in patients with MS, including pharmacokinetic and pharmacometric data. Cladribine Tablets are rapidly absorbed, with a median time to reach maximum concentration (Tmax ) of 0.5 h (range 0.5-1.5 h) in fasted patients. When administered with food, absorption is delayed (median Tmax 1...
July 10, 2018: Clinical Pharmacokinetics
Khaled Abduljalil, Masoud Jamei, Trevor N Johnson
BACKGROUND: The growth of fetal organs is a dynamic process involving considerable changes in the anatomical and physiological parameters that can alter fetal exposure to xenobiotics in utero. Physiologically based pharmacokinetic models can be used to predict the fetal exposure as time-varying parameters can easily be incorporated. OBJECTIVE: The objective of this study was to collate, analyse and integrate the available time-varying parameters needed for the physiologically based pharmacokinetic modelling of xenobiotic kinetics in a fetal population...
July 10, 2018: Clinical Pharmacokinetics
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