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Children and pharmacokinetics

Christelle Rodrigues, Stéphanie Chhun, Catherine Chiron, Olivier Dulac, Elisabeth Rey, Gérard Pons, Vincent Jullien
PURPOSE: The objective of this work was to develop a population pharmacokinetic model for a prolonged-release granule formulation of valproic acid (VPA) in children with epilepsy and to determine the doses providing a VPA trough concentration (Ctrough ) within the target range (50-100 mg/L). METHODS: Ninety-eight children (1-17.6 years, 325 plasma samples) were included in the study. The model was built with NONMEM 7.3. The probability to obtain Ctrough between 50 and 100 mg/L was determined by the Monte Carlo simulations for doses of 20, 30, 40, and 60 mg/kg/day and body weights between 10 and 70 kg...
March 21, 2018: European Journal of Clinical Pharmacology
Anthony J Garcia-Prats, Penelope C Rose, Heather R Draper, James A Seddon, Jennifer Norman, Helen M McIlleron, Anneke C Hesseling, H Simon Schaaf
BACKGROUND: Currently recommended treatment for multidrug-resistant (MDR) tuberculosis (TB) includes 4-8 months of an injectable medication, which is poorly tolerated. We evaluated the impact of co-administering lidocaine on pain and pharmacokinetics of intramuscular injections of amikacin in children with MDR-TB. METHODS: Children 8-18 years of age, receiving amikacin for MDR-TB treatment in Cape Town, South Africa, were eligible for this randomized crossover trial...
March 14, 2018: Pediatric Infectious Disease Journal
Klaus Rose, Jane M Grant-Kels
Importance-Pediatric melanoma occurs, albeit rarely. Should patients be treated by today's medical standards, or be subjected to medically unnecessary clinical studies? Observations-We identified international, industry-sponsored pediatric melanoma studies triggered by regulatory demands in and further pediatric melanoma studies demanded by European Union pediatric investigation plans. We retrieved related regulatory documents from the internet. We analyzed these studies for rationale and medical beneficence on the basis of physiology, pediatric clinical pharmacology and rationale...
March 20, 2018: Children
Michał Romański, Jacek Wachowiak, Franciszek K Główka
Treosulfan is a prodrug that undergoes a highly pH- and temperature-dependent nonenzymatic conversion to the monoepoxide {(2S,3S)-1,2-epoxy-3,4-butanediol 4-methanesulfonate [S,S-EBDM]} and diepoxide {(2S,3S)-1,2:3,4-diepoxybutane [S,S-DEB]}. Currently, treosulfan is tested in clinical trials as an alternative to busulfan in conditioning prior to hematopoietic stem cell transplantation (HSCT). Of note, the optimal dosing of the prodrug is still unresolved, especially in infants. In this paper, the pharmacokinetics of treosulfan, together with its biologically active epoxides, is comprehensively reviewed for the first time, with the focus on conditioning prior to HSCT...
March 19, 2018: Clinical Pharmacokinetics
Anne M Schijvens, Rob Ter Heine, Saskia N de Wildt, Michiel F Schreuder
Nephrotic syndrome is one of the most common glomerular disorders in childhood. Glucocorticoids have been the cornerstone of the treatment of childhood nephrotic syndrome for several decades, as the majority of children achieves complete remission after prednisone or prednisolone treatment. Currently, treatment guidelines for the first manifestation and relapse of nephrotic syndrome are mostly standardized, while large inter-individual variation is present in the clinical course of disease and side effects of glucocorticoid treatment...
March 16, 2018: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Benjamin H Goot, Jon Kaufman, Zhaoxing Pan, David W A Bourne, Francis Hickey, Mark Twite, Jeffrey Galinkin, Uwe Christians, Jeannie Zuk, Eduardo M da Cruz
OBJECTIVES: To assess if morphine pharmacokinetics are different in children with Down syndrome when compared with children without Down syndrome. DESIGN: Prospective single-center study including subjects with Down syndrome undergoing cardiac surgery (neonate to 18 yr old) matched by age and cardiac lesion with non-Down syndrome controls. Subjects were placed on a postoperative morphine infusion that was adjusted as clinically necessary, and blood was sampled to measure morphine and its metabolites concentrations...
March 15, 2018: Pediatric Critical Care Medicine
Orrin Devinsky, Anup D Patel, Elizabeth A Thiele, Matthew H Wong, Richard Appleton, Cynthia L Harden, Sam Greenwood, Gilmour Morrison, Kenneth Sommerville
OBJECTIVE: To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome. METHODS: Patients aged 4-10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N -desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol)...
March 14, 2018: Neurology
Rajeshwar Dayal, Yatish Singh, Dipti Agarwal, Manoj Kumar, Soumya Swaminathan, Geetha Ramachandran, Santosh Kumar, Shamrendra Narayan, Ankur Goyal, A K Hemant Kumar
OBJECTIVES: To evaluate pharmacokinetics of first-line antitubercular drugs, isoniazid (INH) and pyrazinamide (PZA), with revised WHO dosages and to assess its adequacy in relation to age and nutritional status. DESIGN: Observational study. SETTING: This study was conducted at Sarojini Naidu Medical College, Agra, and National Institute for Research in Tuberculosis, Chennai. PATIENTS: 40 subjects diagnosed with tuberculosis were registered in the study and started on daily first-line antitubercular regimen based on the revised WHO guidelines...
March 7, 2018: Archives of Disease in Childhood
Alberto Broniscer, Sujuan Jia, Belinda Mandrell, Dima Hamideh, Jie Huang, Arzu Onar-Thomas, Amar Gajjar, Susana C Raimondi, Ruth G Tatevossian, Clinton F Stewart
BACKGROUND: Progressive/recurrent high-grade and diffuse intrinsic pontine gliomas (DIPGs) are fatal. Treatments targeting molecular pathways critical for these cancers are needed. METHODS: We conducted a phase 1 study (rolling-six design) to establish the safety and maximum tolerated dose (MTD) of dasatinib, an oral platelet-derived growth factor receptor A (PDGFRA) inhibitor, and crizotinib, an oral c-Met inhibitor, in such patients. Pharmacokinetics of both agents were performed...
March 7, 2018: Pediatric Blood & Cancer
Andreas Krause, Jochen Zisowsky, Jasper Dingemanse
BACKGROUND: Macitentan is the first endothelin receptor antagonist with demonstrated efficacy on morbidity and mortality in pulmonary arterial hypertension (PAH) in the pivotal study SERAPHIN. METHODS: The pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577, were characterized in a population model. Efficacy and hemodynamics (pharmacodynamics, PD) were related to PK based on PK/PD modeling. RESULTS: Sex, age, and body weight influenced the PK to a statistically significant extent...
February 28, 2018: Pulmonary Pharmacology & Therapeutics
Michał Romański, Franciszek Główka
Currently, there is an urgent need to establish the optimal dosing of TREO in conditioning prior to hematopoietic stem cell transplantation, especially in children. For that purpose, pharmacokinetic analyses are ongoing within clinical phase II and III trials. In this paper, HPLC methods for determination of prodrug treosulfan and/or its biologically active epoxides in human plasma or serum are reviewed for the first time, including the spectrum of analytes being quantified, detection type, and derivatization methodology...
February 24, 2018: Journal of Pharmaceutical and Biomedical Analysis
Muhammad S Zafar, Alejandra M Stewart, David N Toupin, Aaron M Cook, Robert J Baumann
OBJECTIVE: This study describes the use of continuous intravenous valproate as an abortive therapy for pediatric status migrainosus. BACKGROUND: Intravenous valproate as a bolus dose has been shown to be an effective abortive therapy for status migrainosus in children; however, Valproate's pharmacokinetic profile suggests that it would be safer and more therapeutic as a continuous infusion. This dosing strategy results in less serum concentration fluctuations, more consistent therapeutic effects, and less adverse effects...
March 2018: Neurologist
Georgios Schoretsanitis, Michael Paulzen, Stefan Unterecker, Markus Schwarz, Andreas Conca, Gerald Zernig, Gerhard Gründer, Ekkerhard Haen, Pierre Baumann, Niels Bergemann, Hans Willi Clement, Katharina Domschke, Gabriel Eckermann, Karin Egberts, Manfred Gerlach, Christine Greiner, Ursula Havemann-Reinecke, Gudrun Hefner, Renate Helmer, Ger Janssen, Eveline Jaquenoud-Sirot, Gerd Laux, Thomas Messer, Rainald Mössner, Matthias J Müller, Bruno Pfuhlmann, Peter Riederer, Alois Saria, Bernd Schoppek, Margarete Silva Gracia, Benedikt Stegmann, Werner Steimer, Julia C Stingl, Manfred Uhr, Sven Ulrich, Roland Waschgler, Gabriela Zurek, Christoph Hiemke
OBJECTIVES: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalized treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities and forensic patients...
March 1, 2018: World Journal of Biological Psychiatry
N'Diris Barry, Joshua C Uffman, Dmitry Tumin, Joseph D Tobias
OBJECTIVES: Neuromuscular blocking agents (NMBAs) are administered to facilitate endotracheal intubation and provide skeletal muscle relaxation in surgical procedures. Sugammadex (Bridion) recently received approval by the United States Food and Drug Administration for reversal of rocuronium and vecuronium-induced neuromuscular blockade thereby providing an alternative to acetylcholinesterase inhibitors such as neostigmine. This quality improvement analysis sought to investigate the clinical reasons and common clinical perceptions for choosing sugammadex over neostigmine to reverse NMBAs...
January 2018: Journal of Pediatric Pharmacology and Therapeutics: JPPT: the Official Journal of PPAG
Million A Tegenge, Iftekhar Mahmood, Zhen Jiang, Richard Forshee
Allometric approaches are widely used for interspecies scaling for the prediction of pharmacokinetic (PK) parameters during drug development. The concept of allometry can also be extended to predict PK parameters from adults to children. Three methods for extrapolating pediatric clearance were developed and evaluated using the clearance values of 4 drugs. The first method was established using a simple allometric (SA) model with estimated coefficient and exponent based on data ranging from children older than 2 years to adult...
February 28, 2018: Journal of Clinical Pharmacology
Sharat Chandra, Tsuyoshi Fukuda, Kana Mizuno, Stella M Davies, Ashley Teusink-Cross, Rich Tarin, Rebecca A Marsh, Alexander A Vinks, Parinda A Mehta
Background: Micafungin has a distinct advantage for antifungal prophylaxis in HSCT owing to its better safety profile, specifically in terms of hepatic and renal toxicity. In children, prophylactic micafungin is given as either 1 mg/kg every day or 3 mg/kg every other day. Objectives: We performed a prospective single-centre observational study that investigated the pharmacokinetics (PK) of a single 5 mg/kg dose of micafungin in young children undergoing HSCT, to ascertain the eventual feasibility of twice-weekly prophylactic administration...
February 21, 2018: Journal of Antimicrobial Chemotherapy
Diane E T Bastiaans, Sibyl P M Geelen, Eline G Visser, Michiel van der Flier, Clementien L Vermont, Angela P H Colbers, Monique Roukens, David M Burger, Annemarie M C van Rossum
In this multicenter pharmacokinetic study in HIV-infected children (6-12 years), we validated the approved once-daily darunavir/ritonavir dosing recommendations.The geometric mean darunavir area under the plasma concentration-time curve was 63.1, substantially lower than the mean value observed in adults. However, all trough levels were adequate and short-term virological outcome was good. These data support the use of the darunavir/ritonavir once-daily dosing recommendations.
February 22, 2018: Pediatric Infectious Disease Journal
Gordon C Weir, Mario R Ehlers, Kristina M Harris, Sai Kanaparthi, Alice Long, Deborah Phippard, Lia J Weiner, Brett Jepson, James G McNamara, Maria Koulmanda, Terry B Strom
OBJECTIVE: To determine the safety and pharmacokinetics of alpha-1 antitrypsin (AAT) in adults and children. RESEARCH DESIGN AND METHODS: Short term AAT treatment restores euglycemia in the non-obese mouse model of type 1 diabetes. A phase I multicenter study in 16 subjects with new-onset type 1 diabetes studied the safety and pharmacokinetics of Aralast NPTM (AAT). This open-label, dose-escalation study enrolled eight adults ages 16-35 and eight children ages 8-15 within 100 days of diagnosis, to receive 12 infusions of AAT: a low dose of 45 mg/kg weekly for six weeks, followed by a higher dose of 90 mg/kg for six weeks...
February 23, 2018: Pediatric Diabetes
Kevin Meesters, Reiner Mauel, Evelyn Dhont, Johan Vande Walle, Pauline De Bruyne
BACKGROUND: Fluoroquinolones (FQ) are increasingly prescribed for children, despite being labeled for only a limited number of labeled pediatric indications. In this multicenter retrospective drug utilization study, we analyzed indications for systemic FQ prescriptions in hospitalized children and the appropriateness of the prescribed dose. METHODS: Using data obtained from electronic medical files, the study included all children who received a systemic FQ prescription in two Belgian university children's hospitals between 2010 and 2013...
February 23, 2018: BMC Infectious Diseases
Jonathan B Wagner, Susan Abdel-Rahman, Leon Van Haandel, Andrea Gaedigk, Roger Gaedigk, Geetha Raghuveer, Ralph Kauffman, J Steven Leeder
This study investigated the impact of allelic variation in SLCO1B1, a gene encoding for the liver-specific solute carrier organic anion transporter family member 1B1 protein (SLCO1B1), on simvastatin and simvastatin acid (SVA) systemic exposure in children and adolescents. Participants (8-20 years old) with at least 1 variant SLCO1B1 c.521T>C allele (521TC, n = 15; 521CC, n = 2) and 2 wild-type alleles (521TT, n = 15) completed a single oral dose pharmacokinetic study. At equivalent doses, SVA exposure was 6...
February 22, 2018: Journal of Clinical Pharmacology
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