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Jason Shafrin, Jeffrey Sullivan, Jacquelyn W Chou, Michael N Neely, Justin F Doan, J Ross Maclean
Objective: To examine how observed medication nonadherence to 2 second-line, oral anticancer medications (axitinib and everolimus) affects progression-free survival (PFS) among patients with renal cell carcinoma. Methods: We used an adherence-exposure-outcome model to simulate the impact of adherence on PFS. Using a pharmacokinetic/pharmacodynamic (PK/PD) population model, we simulated drug exposure measured by area under the plasma concentration-time curve (AUC) and minimum blood or trough concentration (Cmin) under 2 scenarios: 1) optimal adherence and 2) real-world adherence...
2017: Cancer Management and Research
Zoubir Djerada, Catherine Feliu, Yoann Cazaubon, Faouzi Smati, Philippe Gomis, Dominique Guerrot, Beny Charbit, Olivier Fernandes, Jean-Marc Malinovsky
BACKGROUND: Ropivacaine is frequently used in spinal anesthesia but the relationship between plasma concentrations and sensory block level remains unknown. OBJECTIVE: The aim of this study was to assess the relationship between plasma ropivacaine concentrations and effects during spinal anesthesia. METHODS: Sixty patients aged between 18 and 82 years were included in this study after providing written informed consent. Patients were randomly assigned to receive intrathecal administration of ropivacaine 15, 20 or 25 mg...
December 13, 2017: Clinical Pharmacokinetics
Daniel Câmara De Souza, Morgan Craig, Tyler Cassidy, Jun Li, Fahima Nekka, Jacques Bélair, Antony R Humphries
A comparison of the transit compartment ordinary differential equation modelling approach to distributed and discrete delay differential equation models is studied by focusing on Quartino's extension to the Friberg transit compartment model of myelosuppression, widely relied upon in the pharmaceutical sciences to predict the neutrophil response after chemotherapy, and on a QSP delay differential equation model of granulopoiesis. An extension to the Quartino model is provided by considering a general number of transit compartments and introducing an extra parameter that allows for the decoupling of the maturation time from the production rate of cells...
December 13, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Yu-Wei Lin, Qi Tony Zhou, Mei-Ling Han, Ke Chen, Nikolas J Onufrak, Jiping Wang, John D Turnidge, Benjamin P Howden, Alan Forrest, Hak-Kim Chan, Jian Li
Pharmacokinetics/pharmacodynamics (PK/PD) of aerosolized colistin was investigated against Acinetobacter baumannii and Klebsiella pneumoniae over 24 h in a neutropenic mouse lung infection model. Dose fractionation studies were performed over 2.64 to 23.8 mg/kg/day, and the data were fitted to a sigmoid inhibitory model. AUC/MIC in the epithelial lining fluid was the most predictive PK/PD index for aerosolized colistin against both pathogens. Our study provides important pharmacological information for optimizing aerosolized colistin...
December 11, 2017: Antimicrobial Agents and Chemotherapy
Margreke J E Brill, Anders N Kristoffersson, Chenyan Zhao, Elisabet I Nielsen, Lena E Friberg
BACKGROUND: Deriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic/pharmacodynamic (PK/PD) index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens...
December 8, 2017: Clinical Microbiology and Infection
Vanessa Gonzalez-Covarrubias, Javier Urena-Carrion, Beatriz Villegas-Torres, J Eduardo Cossío-Aranda, Sergio Trevethan-Cravioto, Raul Izaguirre-Avila, O Javier Fiscal-López, Xavier Soberon
Coumarins are widely prescribed worldwide, and in Mexico acenocumarol is the preferred form. It is well known that despite its efficacy, coumarins show a high variability for dose requirements. We investigated the pharmacogenetic variation of 110 genes in patients receiving acenocumarol using a targeted NGS approach. We report relevant population differentiation for variants on CYP2C8, CYP2C19, CYP4F11, CYP4F2, PROS, and GGCX, VKORC1, CYP2C18, NQO1. A higher proportion of novel-to-known variants for 10 genes was identified on 41 core pharmacogenomics genes related to the PK (29), PD (3), of coumarins, and coagulation proteins (9) including, CYP1A1, CYP3A4, CYP3A5, and F8, and a low proportion of novel-to-known variants on CYP2E1, VKORC1, and SULT1A1/2...
2017: Frontiers in Pharmacology
Zhixin Lei, Qianying Liu, Bing Yang, Haseeb Khaliq, Jiyue Cao, Qigai He
Marbofloxacin is a fluoroquinolone antibiotic and highly effective treatment for respiratory diseases. Here we aimed to evaluate the ex vivo activity of marbofloxacin against Streptococcus suis in pig serum, as well as the optimal dosages scheme for avoiding the fluoroquinolone resistance development. A single dose of 8 mg/kg body weight (bw) was administrated orally to healthy pigs and serum samples were collected during the next 72 h. Serum marbofloxacin content was determined by high-performance liquid chromatography...
2017: Frontiers in Pharmacology
Jansy P Sarathy, Laura E Via, Danielle Weiner, Landry Blanc, Helena Boshoff, Eliseo A Eugenin, Clifton E Barry, Véronique A Dartois
Tuberculosis (TB) recently became the leading infectious cause of death in adults, while attempts to shorten therapy have largely failed. Dormancy, persistence and drug tolerance are among the factors driving the long therapy duration. Assays to measure in situ drug susceptibility of Mycobacterium tuberculosis (Mtb) bacteria in pulmonary lesions are needed if we are to discover new fast acting regimens and address the global TB threat. Here we take a first step towards this goal and describe an ex vivo assay developed to measure the cidal activity of anti-TB drugs against Mtb bacilli present in cavity caseum, obtained from rabbits with active TB...
December 4, 2017: Antimicrobial Agents and Chemotherapy
Alexander J Lepak, Miao Zhao, B VanScoy, Paul G Ambrose, David R Andes
Echinocandins are important in the prevention and treatment of invasive candidiasis but limited by current dosing regimens that include daily intravenous administration. The novel echinocandin CD101 has a prolonged half-life of approximately 130 h in humans making it possible to design once-weekly dosing strategies. The current study examined the pharmacodynamic activity of CD101 using the neutropenic invasive candidiasis mouse model against select C. albicans (n=4), C. glabrata (n=3), and C. parapsilosis (n=3) strains...
December 4, 2017: Antimicrobial Agents and Chemotherapy
Jacqueline M L Halton, Anne-Caroline Picard, Ruth Harper, Fenglei Huang, Martina Brueckmann, Savion Gropper, Hugo Maas, Igor Tartakovsky, Ildar Nurmeev, Lesley G Mitchell, Leonardo R Brandão, Elizabeth Chalmers, Manuela Albisetti
Venous thromboembolism (VTE) is more frequent in infants than in older children. Treatment guidelines in children are adapted from adult VTE data, but do not currently include direct oral anticoagulant use. Dabigatran etexilate (DE) use in the paediatric population with VTE therefore requires verification. We investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationship, safety and tolerability of DE oral liquid formulation (OLF) in infants with VTE (aged < 12 months) who had completed standard anticoagulant treatment in an open-label, phase IIa study...
November 2017: Thrombosis and Haemostasis
Martin Šíma, Jan Hartinger, Tereza Cikánková, Ondřej Slanař
PURPOSE: Delayed achievement of target vancomycin serum concentrations may adversely affect clinical outcomes. The objective of this retrospective study was to explore the real frequency of loading dose use and to evaluate the impact of loading dose for the achievement of vancomycin PK/PD target in adult patients treated with intermittent vancomycin. As a secondary aim we determined optimal vancomycin loading dose based on individual pharmacokinetic calculations. METHODS: Vancomycin pharmacokinetic models were computed using two-compartmental analysis...
November 28, 2017: Journal of Infection and Chemotherapy: Official Journal of the Japan Society of Chemotherapy
Xiaoying Chen, Vahid Farrokhi, Pratap Singh, Mireia Fernandez Ocana, Jenil Patel, Lih-Ling Lin, Hendrik Neubert, Joanne Brodfuehrer
Discovery of the upregulation of fibroblast growth factor-inducible-14 (Fn14) receptor following tissue injury has prompted investigation into biotherapeutic targeting of the Fn14 receptor for the treatment of conditions such as chronic kidney diseases. In the development of monoclonal antibody (mAb) therapeutics, there is an increasing trend to use biomeasures combined with mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling to enable decision making in early discovery. With the aim of guiding preclinical efforts on designing an antibody with optimized properties, we developed a mechanistic site-of-action (SoA) PK/PD model for human application...
November 30, 2017: MAbs
Sabrina De Winter, Joost Wauters, Wouter Meersseman, Jan Verhaegen, Eric Van Wijngaerden, Willy Peetermans, Pieter Annaert, Sandra Verelst, Isabel Spriet
BACKGROUND: Recent studies suggest that ICU patients treated with amikacin frequently do not attain the PK/PD target, i.e. a peak above minimal inhibitory concentration (MIC) ratio of at least 8, when a single dose of 15 mg/kg is used. No data are available for patients admitted to the emergency department (ED). The aim of this study was to determine PK/PD target attainment in patients presenting with severe sepsis or septic shock and treated with 15 vs. 25 mg/kg of amikacin. METHODS: This prospective randomized controlled study was undertaken in ED patients admitted with severe sepsis or septic shock...
November 24, 2017: International Journal of Antimicrobial Agents
Xiaohui Wei, Leonid Gibiansky, Yehong Wang, Franklin Fuh, Rich Erickson, Sharon O'Byrne, Meina T Tang
Etrolizumab, a humanized monoclonal antibody, specifically binds to the β7 subunit of the heterodimeric integrins α4β7 and αEβ7. Pharmacokinetic (PK) and pharmacodynamic (PD) data were collected from an etrolizumab phase 1 trial in patients with moderate to severe ulcerative colitis (UC). We developed a mechanism-based model to simultaneously describe the kinetics of serum etrolizumab concentration and free β7 receptors on circulating intestinal-homing CD4+ T lymphocytes. Included in the analysis were 38 phase 1 UC patients who received single or 3 monthly doses of etrolizumab intravenously or subcutaneously across a dose range of 0...
November 26, 2017: Journal of Clinical Pharmacology
Andreas Krause, Daniele D'Ambrosio, Jasper Dingemanse
BACKGROUND: Ponesimod is currently the only S1P receptor modulator studied in psoriasis. In a dose-finding study, the active doses showed similar efficacy. OBJECTIVE: Prediction of efficacy at lower doses to aid clinical phase 3 planning with respect to dose selection, duration of treatment, and patient inclusion criteria based on pharma-co-kinetic/pharmacodynamic (PK/PD) modeling and simulation. METHODS: The dose-finding study treated 326 patients (67 on placebo, 126 on 20mg, and 133 on 40mg) over 16 weeks...
November 20, 2017: Journal of Dermatological Science
Donglin Zeng, Jean Pan, Kuolung Hu, Eric Chi, D Y Lin
To improve patients' access to safe and effective biological medicines, abbreviated licensure pathways for biosimilar and interchangeable biological products have been established in the US, Europe, and other countries around the world. The US Food and Drug Administration and European Medicines Agency have published various guidance documents on the development and approval of biosimilars, which recommend a "totality-of-the-evidence" approach with a stepwise process to demonstrate biosimilarity. The approach relies on comprehensive comparability studies ranging from analytical and nonclinical studies to clinical pharmacokinetic/pharmacodynamic (PK/PD) and efficacy studies...
November 27, 2017: Journal of Biopharmaceutical Statistics
O Takenaka, J Ferry, K Saeki, A Laurenza
OBJECTIVES: Explore perampanel pharmacokinetics (PK) in all subjects (aged ≥12 years) vs adolescents (aged ≥12 to ≤17 years) with partial-onset seizures (POS) and identify factors explaining between-subject variability in efficacy using a population PK/pharmacodynamic (PD) analysis. MATERIALS & METHODS: Population PK analysis was performed using nonlinear mixed-effect modeling with data from phase II/III randomized, double-blind, placebo-controlled studies of adjunctive perampanel in POS...
November 23, 2017: Acta Neurologica Scandinavica
Patrick M Honore, Rita Jacobs, Elisabeth De Waele, Herbert D Spapen
Continuous renal replacement therapy (CRRT) is progressively supplanting intermittent hemodialysis (IHD) in critically ill patients. CRRT indeed offers more appropriate hemodynamic, fluid, and metabolic stability but concern is rising about its impact on concomitant drug, and in particular antimicrobial, treatment. Antimicrobial dose recommendations have been elaborated to avoid drug accumulation and toxicity in patients undergoing IHD. However, these dosing regimens resulted in significant underdosing in patients undergoing CRRT thereby increasing the risk of treatment failure and development of resistance...
November 24, 2017: Anaesthesiology Intensive Therapy
Eleni Samaridou, Maria José Alonso
Nose-to-brain (N-to-B) delivery offers to protein and peptide drugs the possibility to reach the brain in a non-invasive way. This article is a comprehensive review of the state-of-the-art of this emerging peptide delivery route, as well as of the challenges associated to it. Emphasis is given on the potential of nanosized drug delivery carriers to enhance the direct N-to-B transport of protein or peptide drugs. In particular, polymer- and lipid- based nanocarriers are comparatively analyzed in terms of the influence of their physicochemical characteristics and composition on their in vivo fate and efficacy...
November 4, 2017: Bioorganic & Medicinal Chemistry
Benjamin N Atkinson, Hannah L Woodward, James Sipthorp, Paul V Fish
A new efficient chiral synthesis of enantiopure arimoclomol (2) is reported from (R)-(-)-glycidyl nosylate (11) with complete retention of chiral integrity. Off-target pharmacology of arimoclomol (2) was evaluated against a representative set of drug targets and showed modest binding to a few kinases. Pharmacokinetic data was generated in vivo in mouse and showed a low brain : plasma ratio. These studies will be helpful towards a better understanding of the PK-PD relationship of 2 in disease models.
November 21, 2017: Organic & Biomolecular Chemistry
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