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Children and pharmacokinetics

Miriam Krischke, Georg Hempel, Swantje Völler, Nicolas André, Maurizio D'Incalci, Gianni Bisogno, Wolfgang Köpcke, Matthias Borowski, Ralf Herold, Alan V Boddy, Joachim Boos
PURPOSE: Doxorubicin is a key component in many pediatric oncology treatment regimens; still pharmacology data on which current dosing regimens are based are very limited. METHODS: We conducted a multinational pharmacokinetic study investigating age dependency of doxorubicin metabolism and elimination in children with cancer. One hundred and one patients treated with doxorubicin according to a cancer-specific national or European therapeutic trial were recruited...
October 21, 2016: Cancer Chemotherapy and Pharmacology
Elena S Don, Alexandra G Emelyanova, Natalia N Yakovleva, Nataliia V Petrova, Marina V Nikiforova, Evgeniy A Gorbunov, Sergey A Tarasov, Sergey G Morozov, Oleg I Epstein
The assessment of dose-response is an essential part of drug development in terms of the determination of a drug's effective dose, finding the safety endpoint, estimation of the pharmacokinetic profile and even validation of drug activity, especially for therapeutic agents with a principally novel mechanism of action. Drugs based on released-active forms of antibodies are a good example of such a target. In this study, the efficacy of the antiviral drug Anaferon for children (released-active form of antibodies to interferon-gamma) was tested in a dose-dependent manner (at doses of 0...
October 21, 2016: Journal of Medical Virology
Eva Germovsek, Charlotte Barker, Mike Sharland, Joseph F Standing
AIM(S): When different models for weight and age are used in paediatric pharmacokinetic studies it is difficult to compare parameters between studies or perform model-based meta-analysis. This study aimed to compare published models with the proposed standard (allometric weight(0.75) and sigmoidal maturation function). METHODS: A systematic literature search was undertaken to identify published clearance (CL) reports for gentamicin and midazolam and all published models for scaling clearance in children...
October 21, 2016: British Journal of Clinical Pharmacology
Man-Chiu Poon, Adrienne Lee
Prophylaxis is considered optimal care for hemophilia patients to prevent bleeding and to preserve joint function thereby improving quality of life (QoL). The evidence for prophylaxis is irrefutable and is the standard of care in developed nations. Prophylaxis can be further individualized to improve outcomes and cost effectiveness. Individualization is best accomplished taking into account the bleeding phenotype, physical activity/lifestyle, joint status, and pharmacokinetic handling of specific clotting factor concentrates, all of which vary among individuals...
2016: Thrombosis Journal
Aditya H Gaur, Hilda Kizito, Wasana Prasitsueubsai, Natella Rakhmanina, Mohammed Rassool, Rana Chakraborty, Jagmohan Batra, Pope Kosalaraksa, Wicharn Luesomboon, Danielle Porter, Yongwu Shao, Michael Myers, Lillian Ting, Devi SenGupta, Erin Quirk, Martin S Rhee
BACKGROUND: The prodrug tenofovir alafenamide is associated with improved renal and bone safety compared with tenofovir disoproxil fumarate. We aimed to assess safety, pharmacokinetics, and efficacy of this single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-infected, treatment-naive adolescents. METHODS: We did a 48 week, single-arm, open-label trial in treatment-naive adolescents with HIV from ten hospital clinics in South Africa, Thailand, Uganda, and the USA...
October 17, 2016: Lancet HIV
Ahmad Ismail
Providing effective pain management is necessary for all patients in the intensive care unit (ICU). Because of developmental considerations, caring for children may provide additional challenges. The purpose of this literature review is to describe key challenges in providing effective pain management in pediatric intensive care units (PICUs), with the aim of bringing about a better understanding by health care providers caring for children. Challenges of providing effective pain management in the PICU can be categorized into four levels...
October 15, 2016: Pain Management Nursing: Official Journal of the American Society of Pain Management Nurses
Maxime Luu, Marc Bardou, Philippe Bonniaud, Françoise Goirand
Omalizumab is a subcutaneously administrated monoclonal anti-IgE antibody indicated in adults, adolescents and children 6 years of age and older with moderate to severe allergic asthma uncontrolled by conventional pharmacological treatments and sensitization to at least one perennial allergen. Area covered: This drug evaluation summarizes published data on pharmacokinetic and pharmacodynamic properties of omalizumab, on clinical efficacy and safety, including real-world evidence, and provides a medico-economic evaluation of the drug...
October 17, 2016: Expert Opinion on Drug Metabolism & Toxicology
Imke H Bartelink, Arief Lalmohamed, Elisabeth M L van Reij, Christopher C Dvorak, Rada M Savic, Juliette Zwaveling, Robbert G M Bredius, Antoine C G Egberts, Marc Bierings, Morris Kletzel, Peter J Shaw, Christa E Nath, George Hempel, Marc Ansari, Maja Krajinovic, Yves Théorêt, Michel Duval, Ron J Keizer, Henrique Bittencourt, Moustapha Hassan, Tayfun Güngör, Robert F Wynn, Paul Veys, Geoff D E Cuvelier, Sarah Marktel, Robert Chiesa, Morton J Cowan, Mary A Slatter, Melisa K Stricherz, Cathryn Jennissen, Janel R Long-Boyle, Jaap Jan Boelens
BACKGROUND: Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT...
October 13, 2016: Lancet Haematology
Tawanda Gumbo, Mamodikoe K Makhene, James A Seddon
There has been a recent expansion of preclinical models to predict the efficacy of regimens to treat adults with tuberculosis. Despite increasing global interest in childhood tuberculosis, these same tools have not been employed to develop pediatric regimens. Children differ from adults in bacillary burden, spectrum of disease, the metabolism and distribution of antituberculosis drugs, and the toxicity experienced. The studies documented in this series describe a proof-of-concept approach to pediatric regimen development...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Shashikant Srivastava, Devyani Deshpande, Jotam Pasipanodya, Eric Nuermberger, Soumya Swaminathan, Tawanda Gumbo
BACKGROUND:  When treated with the same antibiotic dose, children achieve different 0- to 24-hour area under the concentration-time curves (AUC0-24) because of maturation and between-child physiological variability on drug clearance. Children are also infected by Mycobacterium tuberculosis isolates with different antibiotic minimum inhibitory concentrations (MICs). Thus, each child will achieve different AUC0-24/MIC ratios when treated with the same dose. METHODS:  We used 10 000-subject Monte Carlo experiments to identify the oral doses of linezolid, moxifloxacin, and faropenem that would achieve optimal target exposures associated with optimal efficacy in children with disseminated tuberculosis...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Devyani Deshpande, Shashikant Srivastava, Eric Nuermberger, Jotam G Pasipanodya, Soumya Swaminathan, Tawanda Gumbo
BACKGROUND:  The regimen of linezolid and moxifloxacin was found to be efficacious in the hollow fiber system model of pediatric intracellular tuberculosis. However, its kill rate was slower than the standard 3-drug regimen of isoniazid, rifampin, and pyrazinamide. We wanted to examine the effect of adding a third oral agent, faropenem, to this dual combination. METHODS:  We performed a series of studies in the hollow fiber system model of intracellular Mycobacterium tuberculosis, by mimicking pediatric pharmacokinetics of each antibiotic...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Devyani Deshpande, Shashikant Srivastava, Jotam G Pasipanodya, Stephen J Bush, Eric Nuermberger, Soumya Swaminathan, Tawanda Gumbo
BACKGROUND:  Infants and toddlers often present with disseminated and lymph node tuberculosis, in which Mycobacterium tuberculosis (Mtb) is predominantly intracellular. Linezolid, used to treat tuberculosis in adults, has not been formally studied in infants. Infants clear linezolid 5 times faster than adults and achieve lower 0- to 24-hour area under the concentration-time curves (AUC0-24). METHODS:  To mimic intracellular disease, we infected human-derived THP-1 macrophages with Mtb and inoculated hollow fiber systems...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Shashikant Srivastava, Devyani Deshpande, Jotam G Pasipanodya, Tania Thomas, Soumya Swaminathan, Eric Nuermberger, Tawanda Gumbo
Children with tuberculosis are treated with drug regimens copied from adults despite significant differences in antibiotic pharmacokinetics, pathology, and the microbial burden between childhood and adult tuberculosis. We sought to develop a new and effective oral treatment regimen specific to children of different ages. We investigated and validated the concept that target drug concentrations associated with therapy failure and death in children are different from those of adults. On that basis, we proposed a 4-step program to rapidly develop treatment regimens for children...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Soumya Swaminathan, Jotam G Pasipanodya, Geetha Ramachandran, A K Hemanth Kumar, Shashikant Srivastava, Devyani Deshpande, Eric Nuermberger, Tawanda Gumbo
BACKGROUND:  The role of drug concentrations in clinical outcomes in children with tuberculosis is unclear. Target concentrations for dose optimization are unknown. METHODS:  Plasma drug concentrations measured in Indian children with tuberculosis were modeled using compartmental pharmacokinetic analyses. The children were followed until end of therapy to ascertain therapy failure or death. An ensemble of artificial intelligence algorithms, including random forests, was used to identify predictors of clinical outcome from among 30 clinical, laboratory, and pharmacokinetic variables...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Priya S Verghese
Successful renal transplantation is the optimal treatment for chronic kidney failure, but this was not always so for children. Beginning with the first kidney transplants in the 1950s, children experienced poorer patient and graft survival rates than adult patients. But over the last 6 decades, an improved understanding of the immune system which has steered pediatric multi-center clinical / pharmacokinetic and mechanistic studies that have sculpted our immunosuppression with markedly better patient and graft survivals...
October 12, 2016: Pediatric Research
William M Greenberg, Leslie Citrome
Lurasidone hydrochloride, a benzisothiazol derivative, is a second-generation (atypical) antipsychotic agent that has received regulatory approval for the treatment of schizophrenia in the US, Canada, the EU, Switzerland, and Australia, and also for bipolar depression in the US and Canada. In addition to its principal antagonist activity at dopamine D2 and serotonin 5-HT2A receptors, lurasidone has distinctive 5-HT7 antagonistic activity, and displays partial agonism at 5-HT1A receptors, as well as modest antagonism at noradrenergic α2A and α2C receptors...
October 8, 2016: Clinical Pharmacokinetics
Prashant P Kadam, Nithya Jaideep Gogtay, Sunil Karande, V Shah, Urmila M Thatte
OBJECTIVES: Studies on antimalarial kinetics in children or adults who are undernourished or malnourished are both limited and have yielded conflicting results. The present study was carried out with the objectives of evaluating the pharmacokinetics of single dose chloroquine and its metabolite desethylchloroquine in children who were undernourished and compare them with children who were normally nourished. METHODS: Children of either gender between the ages of 5 and 12 years, smear positive for P...
September 2016: Indian Journal of Pharmacology
Andrew D J Pearson, Sara M Federico, Isabelle Aerts, Darren R Hargrave, Steven G DuBois, Robert Iannone, Ryan D Geschwindt, Ruixue Wang, Frank G Haluska, Tanya M Trippett, Birgit Geoerger
PURPOSE: Ridaforolimus is an investigational, potent, selective mTOR inhibitor. This study was conducted to determine the recommended phase 2 dose (RP2D), maximum tolerated dose, safety, pharmacokinetics, and antitumor activity of oral ridaforolimus in children with advanced solid tumors. EXPERIMENTAL DESIGN: In this phase 1, multicenter, open-label study in children aged 6 to <18 years with advanced solid tumors, ridaforolimus was administered orally for 5 consecutive days/week in 28-day cycles until progression, unacceptable toxicity, or consent withdrawal...
October 4, 2016: Oncotarget
B Siegmund, R Atreya, B Bokemeyer, W Kruis, J Mudter, C Sander, S Schreiber, W Reindl, S Zeissig, T Kucharzik
After the expiry date of the patent protection for Infliximab in 2013, the biosimilar CT‑P13 was approved for indications in Crohn's disease and ulcerative colitis in adults as well as in children. The approval has been based on two randomized clinical studies indicating equivalence for the biosimilar with regard to pharmacokinetics, efficacy, as well as side-effects. The clinical experience since, in addition to multiple non-randomized studies, indicate a comparable efficacy and immunogenicity of the Infliximab biosimilar CT-P13 in inflammatory bowel disease...
October 6, 2016: Zeitschrift Für Gastroenterologie
Andrzej Bienczak, Adrian Cook, Lubbe Wiesner, Veronica Mulenga, Cissy Kityo, Addy Kekitiinwa, A Sarah Walker, Andrew Owen, Diana M Gibb, David Burger, Helen McIlleron, Paolo Denti
OBJECTIVES: To characterize the effects of CYP2B6 polymorphisms, diurnal variation and demographic factors on nevirapine pharmacokinetics in African children. METHODS: Non-linear mixed-effects modelling conducted in NONMEM 7.3 described nevirapine plasma concentration-time data from 414 children aged 0.3-15 years. RESULTS: Nevirapine pharmacokinetics was best described using a one-compartment disposition model with elimination through a well-stirred liver model accounting for a first-pass effect and transit-compartment absorption...
October 5, 2016: Journal of Antimicrobial Chemotherapy
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