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    10935 results match your criteria British journal of clinical pharmacology[Journal]

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    Oral Anticoagulants in German nursing home residents - Drug use patterns and predictors for treatment choice.
    Br J Clin Pharmacol 2017 Nov 17. Epub 2017 Nov 17.
    Department of Health Services Research, Carl von Ossietzky University Oldenburg, Oldenburg, Germany.
    Aims: Information on utilization of oral anticoagulants (OACs) in nursing homes is scarce. This study aimed to (i) describe OAC use in German nursing home residents, (ii) examine factors influencing whether treatment is initiated with vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) and (iii) assess which conditions predict switching to NOAC instead of continuing VKA.

    Methods: Using claims data (2010-2014), we studied a cohort of new nursing home residents aged ≥ 65 years receiving OAC. Read More

    Drug-related deaths in hospital inpatients: A retrospective cohort study.
    Br J Clin Pharmacol 2017 Nov 17. Epub 2017 Nov 17.
    Department of Clinical Pharmacology, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain.
    Objectives: To determine the incidence of drug-related deaths (DRD) in a university hospital in 2015, to describe their characteristics, and to discover risk factors of DRD.

    Methods: An analytic and retrospective cohort study. Patients with a death diagnose predefined from a list of medical conditions potentially caused by drugs were the selected cases for further review. Read More

    Growth factors for diabetic foot ulcers: Mixed treatment comparison analysis of randomized clinical trials.
    Br J Clin Pharmacol 2017 Nov 17. Epub 2017 Nov 17.
    Department of Oral Health, College of Medicine, Nursing and Health Sciences, Fiji National University, Suva, Fiji.
    Aims: Topical growth factors accelerate wound healing in patients with diabetic foot ulcers (DFU). Due to the absence of head to head comparisons, we carried out Bayesian network meta-analysis to compare the efficacy and safety of growth factors.

    Methods: Using an appropriate search strategy, randomized controlled trials on topical growth factors compared with standard of care in patients with DFU, were included. Read More

    Incident diuretic drug use and adverse respiratory events among older adults with COPD.
    Br J Clin Pharmacol 2017 Nov 15. Epub 2017 Nov 15.
    Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
    Aims: Diuretic drugs may theoretically improve respiratory health outcomes in COPD through several possible mechanisms, but they might also lead to respiratory harm. We evaluated the association of incident oral diuretic drug use with respiratory-related morbidity and mortality among older adults with COPD.

    Methods: This was a population-based, retrospective cohort study using health administrative data from Ontario, Canada, for the period 2008-2013. Read More

    Dicloxacillin induces CYP2C19, CYP2C9 and CYP3A4 in vivo and in vitro.
    Br J Clin Pharmacol 2017 Nov 4. Epub 2017 Nov 4.
    Department of Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
    Aim: The aim of this study was to study potential cytochrome P450 induction by dicloxacillin.

    Methods: We performed an open-label randomized two-phase 5-drug clinical pharmacokinetic cocktail crossover study in 12 healthy men with and without pretreatment with 1g dicloxacillin three times daily for 10 days. Plasma and urine was collected over 24 hours and the concentration of all five drugs and their primary metabolites was determined using a LC-MS/MS method. Read More

    Measuring the impact of medicines regulatory interventions - systematic review and methodological considerations.
    Br J Clin Pharmacol 2017 Nov 5. Epub 2017 Nov 5.
    Head of Surveillance and Epidemiology Service, Pharmacovigilance and Epidemiology Department, Inspections Human Medicines Pharmacovigilance and Committees Division, European Medicines Agency (EMA), London, E14 5EU, United Kingdom.
    Aim: Evaluating the public health impact of regulatory interventions is important but there is currently no common methodological approach to guide this evaluation. This systematic review provides a descriptive overview of the analytical methods for impact research.

    Methods: We searched MEDLINE and EMBASE for articles with an empirical analysis evaluating the impact of European Union or non-European Union regulatory actions to safeguard public health published until March 2017. Read More

    "Microdialysis as a tool to determine the local tissue concentration of dicloxacillin in man".
    Br J Clin Pharmacol 2017 Nov 5. Epub 2017 Nov 5.
    Department of Orthopedic Surgery, Vejle Hospital.
    Aim: The most common pathogen in Denmark, to cause postoperative infections, is Staphylococcus (S.) aureus (1). Despite using prophylactic antibiotics, infections are still seen. Read More

    Results and evaluation of a first-in-human study of RG7342, a mGlu5 positive allosteric modulator, utilizing Bayesian adaptive methods.
    Br J Clin Pharmacol 2017 Nov 2. Epub 2017 Nov 2.
    Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Grenzacherstrasse, 124, Basel, Switzerland.
    Aim: The objectives of this first-in-human study were to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics, and to determine the maximum tolerated dose (MTD) of single ascending oral doses of RG7342, a positive allosteric modulator (PAM) of the metabotropic glutamate receptor 5 (mGlu5) for the treatment of schizophrenia, in healthy male subjects.

    Methods: This was a single-centre, randomized, double-blind, adaptive study of 37 subjects receiving single ascending oral doses of RG7342 (ranging from 0.06-1. Read More

    Population Pharmacokinetics of Exendin-(9-39) and Clinical Dose Selection in Patients with Congenital Hyperinsulinism.
    Br J Clin Pharmacol 2017 Oct 27. Epub 2017 Oct 27.
    The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
    Aims: Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycaemia in infants and children. Exendin-(9-39), an inverse glucagon-like peptide 1 (GLP-1) agonist, is a novel therapeutic agent for HI that has demonstrated glucose-raising effect. We reported the first population pharmacokinetic (PopPK) model of the exendin-(9-39) in patients with HI and proposed the optimal dosing regimen for future clinical trials in neonates with HI. Read More

    Risk factors contributing to a low darunavir plasma concentration.
    Br J Clin Pharmacol 2017 Oct 27. Epub 2017 Oct 27.
    Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
    Darunavir is an efficacious drug, however pharmacokinetic variability has been reported. The objective of this study was to find predisposing factors for low darunavir plasma concentrations in patients starting the once- or twice-daily dosage. Darunavir plasma concentrations from January 2010 till December 2014 of HIV-infected individuals treated in the outpatient clinic of the University Medical Center Groningen were retrospectively reviewed. Read More

    Comparative risks of diabetes-related complications of basal insulins: a longitudinal population-based cohort of type 1 diabetes 1999-2013 in Taiwan.
    Br J Clin Pharmacol 2017 Oct 26. Epub 2017 Oct 26.
    Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
    Aim: We compared the effects of basal insulins: long-acting insulin analogues versus intermediate/long-acting human insulin, on diabetes-related complications in type 1 diabetes.

    Methods: 1,188 type 1 diabetes newly on long-acting insulin analogues or intermediate/long-acting human insulin were identified in 2004-2008 and followed until death or 2013. Clinical outcomes included acute (i. Read More

    Urinalysis of MMX-mesalazine as a tool to monitor 5-ASA adherence in daily IBD practice.
    Br J Clin Pharmacol 2017 Oct 26. Epub 2017 Oct 26.
    Department of Gastroenterology and Hepatology, Radboud university Medical center, Nijmegen, The Netherlands.
    Adherence is pivotal but challenging in ulcerative colitis (UC) treatment. Many methods to assess adherence are subjective or have limitations. (Nac-)5-aminosalicylic acid (5-ASA) urinalysis by High-Performance Liquid Chromatography (HPLC) seems feasible and reproducible in healthy volunteers. Read More

    Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children, and adults with inflammation and organ failure.
    Br J Clin Pharmacol 2017 Oct 26. Epub 2017 Oct 26.
    Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
    Aims: Inflammation and organ failure have been reported to impact cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model in both critically ill children and other populations in order to allow the model to be used to guide dosing in clinical practice.

    Methods: The model was externally evaluated in 136 individuals, including (pre)term neonates, infants, children, and adults (body weight 0. Read More

    Parenteral bilirubin in healthy volunteers: a reintroduction in translational research.
    Br J Clin Pharmacol 2017 Oct 25. Epub 2017 Oct 25.
    Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
    Aim(s): Preclinical results suggest therapeutic potential of mild hyperbilirubinemia in T2DM and cardiovascular disease. Translational data are limited, because an appropriate bilirubin formulation for parenteral human use is lacking. Considering its use in both clinical practice and medical research in the past, we explored the feasibility to reintroduce parenteral bilirubin for translational experiments. Read More

    Comparative safety of systemic and low-bioavailability steroids in inflammatory bowel disease: Systematic review and network meta-analysis.
    Br J Clin Pharmacol 2017 Oct 22. Epub 2017 Oct 22.
    Department of Biomedical Sciences, Humanitas University, Milan, Italy.
    Aims: Oral systemic corticosteroids have been used to induce remission in patients with active inflammatory bowel disease (IBD) for over 50 years; however, the wide array of adverse events (AEs) associated with these drugs prompted the development of steroid compounds with targeted delivery and low systemic bioavailability. This study assessed corticosteroids' comparative harm using network meta-analysis.

    Methods: We searched PubMed, Scopus, Embase, the Cochrane Library, clinical trial registries, regulatory authorities' websites and major conference proceedings, through March 2017. Read More

    QTc-prolongation during ciprofloxacin and fluconazole combination therapy: prevalence and associated risk factors.
    Br J Clin Pharmacol 2017 Oct 22. Epub 2017 Oct 22.
    Department of Hospital Pharmacy, Erasmus University Medical Centre, Rotterdam, the Netherlands.
    Aim (s): Ciprofloxacin and fluconazole combination therapy is frequently used as prophylaxis for and treatment of infections in patients with haematological malignancies. However, both drugs are known to prolong the QTc-interval, which is a serious risk factor for Torsade de Pointes (TdP). Therefore, the aim of this study was to assess the prevalence of QTc-prolongation during ciprofloxacin and fluconazole use. Read More

    Optimal dosing and delivery of PTH and its analogues for osteoporosis and hypoparathyroidism - translating the pharmacology.
    Br J Clin Pharmacol 2017 Oct 19. Epub 2017 Oct 19.
    Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
    In primary hyperparathyroidism (PHPT), bone loss results from the resorptive effects of excess parathyroid hormone (PTH). Under physiological conditions, PTH has actions that are more targeted to homeostasis and to bone accrual. The predominant action of PTH, either catabolic, anabolic, or homeostatic, can be understood in molecular and pharmacokinetic terms. Read More

    A STEP-DOWN PROTOCOL FOR OMALIZUMAB TREATMENT IN ORAL CORTICOSTEROID-DEPENDENT ALLERGIC ASTHMA PATIENTS.
    Br J Clin Pharmacol 2017 Oct 18. Epub 2017 Oct 18.
    Department of Morphological Sciences, Faculty of Medicine, Universitat Autònoma de Barcelona (UAB).
    Background: there are no specific criteria for a step-down or withdrawal dose of omalizumab. Our purpose was to evaluate the viability of a protocol for OMAlizumab DOse REduction (the OMADORE study) in severe allergic asthma (SAA).

    Methods: the study population included 35 SAA patients treated during a minimum period of one year with oral corticosteroids (OC) equivalent to a mean daily dose of 4 mg of methyl-prednisolone. Read More

    Short- and long-term complications of in utero exposure to lamotrigine.
    Br J Clin Pharmacol 2017 Oct 18. Epub 2017 Oct 18.
    Department of Neonatology, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.
    Aims: The present study evaluates the effect of antenatal lamotrigine exposure, on short- and long-term paediatric outcome.

    Methods: The study included the children of 83 epileptic women treated with lamotrigine during pregnancy, at a tertiary medical centre between 2004-2014. All newborns were monitored for vital signs, congenital malformations and Finnegan score. Read More

    Ledipasvir and Tenofovir drug interaction in HIV-HCV co-infected patients: Impact on Tenofovir Ctrough and Renal Safety.
    Br J Clin Pharmacol 2017 Oct 13. Epub 2017 Oct 13.
    APHM Sainte-Marguerite, Service d'Immuno-hématologie clinique, Marseille, France.
    We evaluate the impact of ledipasvir on both tenofovir plasma trough concentration (Ctrough ) and estimated glomerular renal function (eGFR) in HIV-HCV co-infected patients receiving a tenofovir(TDF)-based antiretroviral regimen and treated with ledipasvir/sofosbuvir. Twenty-six patients [81% male, median age: 51years; HCV genotype 1(75%)/4(15%)] were included. Tenofovir Ctrough (interquartile:IQR) increased from 78ng/mL (53-110) at baseline to 141ng/mL (72-176) at M1 (p=0. Read More

    Drug management in acute kidney disease - Report of the ADQI XVI meeting.
    Br J Clin Pharmacol 2017 Oct 11. Epub 2017 Oct 11.
    Cincinnati Children's Hospital Medical Center, Division of Nephrology and Hypertension, Cincinnati, USA.
    Aims: To summarize and extend the main conclusions and recommendations relevant to drug management during acute kidney disease (AKD) as agreed at the 16(th) Acute Disease Quality Initiative (ADQI) consensus conference.

    Methods: Using a modified Delphi method to achieve consensus, experts attending the 16(th) ADQI consensus conference reviewed and appraised the existing literature on drug management during AKD and identified recommendations for clinical practice and future research. The group focussed on drugs with one of the following characteristics: i) predominant renal excretion; ii) nephrotoxicity; iii) potential to alter glomerular function, and iv) presence of metabolites that are modified in AKD and may affect other organs. Read More

    Pharmacological vs. classical approaches in the design of first in man clinical drug trials.
    Br J Clin Pharmacol 2017 Oct 4. Epub 2017 Oct 4.
    Chair of the Central Committee on Research Involving Human Subjects, The Hague, The Netherlands.
    Aims: The aims of the present study were to investigate the role of pharmacology in the design of first-in-man (FIM) trials in the Netherlands, and to evaluate the change in design approaches between 2007 and 2015.

    Methods: All FIM drug trials approved by all Dutch Institutional Review Boards (IRBs) in 2007 and in 2015 were selected. The original trial protocols, investigator's brochures and investigational medicinal product dossiers were the data sources. Read More

    Adulteration of proprietary Chinese medicines and health products with undeclared drugs: experience of a tertiary toxicology laboratory in Hong Kong.
    Br J Clin Pharmacol 2017 Oct 1. Epub 2017 Oct 1.
    Hospital Authority Toxicology Reference Laboratory, Princess Margaret Hospital, Hong Kong.
    Aims: Proprietary Chinese medicines (pCMs) and health products, generally believed to be natural and safe, are gaining popularity worldwide. However, the safety of pCMs and health products has been severely compromised by the practice of adulteration. The current study aimed to examine the problem of adulteration of pCMs and health products in Hong Kong. Read More

    Is acetaminophen associated with a risk of Stevens-Johnson syndrome and toxic epidermal necrolysis? Analysis of the French Pharmacovigilance Database.
    Br J Clin Pharmacol 2017 Sep 30. Epub 2017 Sep 30.
    Centre Régional de Pharmacovigilance, CHU - Centre de Biologie, EA 4681 PEPRADE, Université d'Auvergne, 58 Rue Montalembert -BP 69, 63003 Cedex 1, Clermont-Ferrand, France.
    Aim: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe mostly drug-induced cutaneous reactions. Acetaminophen is an over-the-counter drug used worldwide to treat pain and reduce fever. In 2013, the US Food and Drug Administration informed the public that acetaminophen was associated with a rare risk of SJS/TEN. Read More

    Development of one paediatric and one neonatal formulary list in hospital settings.
    Br J Clin Pharmacol 2017 Sep 30. Epub 2017 Sep 30.
    Department of Clinical Pharmacology, Bispebjerg Hospital, 2400, Copenhagen, Denmark.
    Aims: The aim of this study is to describe the stepwise process towards creating two formulary lists: one for paediatric and one for neonatal patients covering common diseases in hospital settings.

    Methods: This study presents the concept for developing a formulary list, namely how to: (1) organize the editorial board, (2) procure drug consumption data and database management, including information on labelling status, dosing options, excipients and problematic adverse events, current guidelines, evidence and price, (3) develop the first edition for the formulary list and formulary manual, and (4) to establish a paediatric sub-committee within the Regional Drug and Therapeutic Committee to maintain and continually develop the two formularies.

    Results: The total number of drugs was 411 ATC level 5, which covers 1097 unique item numbers prior to the paediatric formulary list, of which 263 item numbers were included in the final list. Read More

    Population pharmacodynamic modelling of midazolam induced sedation in terminally ill adult patients.
    Br J Clin Pharmacol 2017 Sep 27. Epub 2017 Sep 27.
    Hospital Pharmacy - Clinical Pharmacology, Academic Medical Centre, Amsterdam, The Netherlands.
    Aims: Midazolam is the drug of choice for palliative sedation and is titrated to achieve the desired level of sedation. A previous pharmacokinetic (PK) study showed that variability between patients could be partly explained by renal function and inflammatory status. The goal of this study was to combine this PK information with pharmacodynamic (PD) data, to evaluate the variability in response to midazolam and to find clinically relevant covariates that may predict PD response. Read More

    Adverse effects of a single dose of gentamicin in adults: a systematic review.
    Br J Clin Pharmacol 2017 Sep 21. Epub 2017 Sep 21.
    Whittall Street Clinic, University Hospitals Birmingham NHS Trust, Birmingham, UK.
    Aims: To systematically review the frequency and type of adverse events associated with a single dose of intravenous or intramuscular gentamicin in adults, for any indication, in studies where a comparator was available.

    Methods: A review protocol was developed and registered (PROSPERO: CRD42013003229). Studies were eligible for review if they: recruited participants aged ≥16 years; used gentamicin intramuscularly or intravenously as a single one-off dose; compared gentamicin to another medication or placebo; and monitored adverse events. Read More

    Quantitative analysis of the effect of end-tidal carbon dioxide on regional cerebral oxygen saturation in patients undergoing carotid endarterectomy under general anaesthesia.
    Br J Clin Pharmacol 2017 Sep 23. Epub 2017 Sep 23.
    Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
    Aims: Regional cerebral oxygen saturation (rSO2 ) is currently the most used measure in clinical practice to monitor cerebral ischaemia in patients undergoing carotid endarterectomy (CEA). Although end-tidal carbon dioxide (PET CO2 ) is known as a factor that influences rSO2 , the relationship between PET CO2 and rSO2 has not been quantitatively evaluated in patients with severe arteriosclerosis. This study aimed to evaluate the effect of PET CO2 on rSO2 in patients undergoing CEA under general anaesthesia. Read More

    Protective, repairing and fibrinolytic effects of rivaroxaban on vascular endothelium.
    Br J Clin Pharmacol 2017 Sep 23. Epub 2017 Sep 23.
    Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Travesía da Choupana s/n, Santiago de Compostela, 15706, A Coruña, Spain.
    Aims: Rivaroxaban, a direct inhibitor of activated factor X (FXa), is the only new oral anticoagulant approved for secondary prevention after acute coronary syndrome. Our objective was to identify the possible molecular mechanisms of rivaroxaban that contribute to endothelial function.

    Methods: Cell viability and growth of human umbilical vein endothelial cells (HUVEC) were registered. Read More

    Safety, tolerability, and pharmacokinetics of radavirsen (AVI-7100), an antisense oligonucleotide targeting influenza a M1/M2 translation.
    Br J Clin Pharmacol 2017 Sep 20. Epub 2017 Sep 20.
    National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
    Aims: The aims of the present study were to assess the safety, tolerability and pharmacokinetics of radavirsen following single ascending doses and multiple doses given as intravenous infusions in healthy adults.

    Methods: A phase I safety and pharmacokinetic study of radavirsen was performed in healthy volunteers. The study was divided into two parts. Read More

    Inclusion of pregnant and breastfeeding women in research - efforts and initiatives.
    Br J Clin Pharmacol 2017 Sep 19. Epub 2017 Sep 19.
    Obstetric and Pediatric Pharmacology and Therapeutics Branch at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
    Pregnant and breastfeeding women have been rendered therapeutic orphans as they have been historically excluded from clinical trials. Labelling for most approved drugs does not provide information about safety and efficacy during pregnancy. This lack of data is mainly due to ethico-legal challenges that have remained entrenched in the post-diethylstilbestrol and thalidomide era, and that have led to pregnancy being viewed in the clinical trial setting primarily through a pharmacovigilance lens. Read More

    Pharmacodynamics and pharmacokinetics of ticagrelor vs. clopidogrel in patients with acute coronary syndromes and chronic kidney disease.
    Br J Clin Pharmacol 2017 Sep 15. Epub 2017 Sep 15.
    General Hospital of Shenyang Military Region, Shenyang, China.
    Background: Pivotal clinical trials found that ticagrelor reduced ischaemic complications to a greater extent than clopidogrel, and also that the benefit gradually increased with the reduction in creatinine clearance. However, the underlying mechanisms remains poorly explored.

    Methods: This was a single-centre, prospective, randomized clinical trial involving 60 hospitalized Adenosine Diphosphate (ADP) P2Y12 receptor inhibitor-naïve patients with chronic kidney disease (CKD) (estimated glomerular filtration rate <60 ml min(-1) 1. Read More

    Renal function monitoring in heart failure - what is the optimal frequency? A narrative review.
    Br J Clin Pharmacol 2017 Sep 13. Epub 2017 Sep 13.
    The Wolfson Centre for Personalised Medicine, The University of Liverpool, Liverpool, UK.
    The second most common cause of hospitalization due to adverse drug reactions in the UK is renal dysfunction due to diuretics, particularly in patients with heart failure, where diuretic therapy is a mainstay of treatment regimens. Therefore, the optimal frequency for monitoring renal function in these patients is an important consideration for preventing renal failure and hospitalization. This review looks at the current evidence for optimal monitoring practices of renal function in patients with heart failure according to national and international guidelines on the management of heart failure (AHA/NICE/ESC/SIGN). Read More

    External evaluation of population pharmacokinetic models for ciclosporin in adult renal transplant recipients.
    Br J Clin Pharmacol 2017 Sep 11. Epub 2017 Sep 11.
    Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China.
    Aims: Several population pharmacokinetic (popPK) models for ciclosporin (CsA) in adult renal transplant recipients have been constructed to optimize the therapeutic regimen of CsA. However, little is known about their predictabilities when extrapolated to different clinical centres. Therefore, this study aimed to externally evaluate the predictive ability of CsA popPK models and determine the potential influencing factors. Read More

    Co-administration of cyclosporine and ticagrelor may lead to a higher exposure to cyclosporine: a case report of a 49-year-old man.
    Br J Clin Pharmacol 2017 Sep 11. Epub 2017 Sep 11.
    Department of Internal Medicine, Máxima Medical Center, Veldhoven, The Netherlands.
    Adverse Event: A drug interaction leading to higher exposure to cyclosporine.

    Drugs Implicated: Cyclosporine and ticagrelor.

    The Patient: A 49-year-old man with a stable renal graft, managed with cyclosporine with stable trough blood concentrations for several years, was treated with ticagrelor for unstable angina pectoris. Read More

    Global population pharmacokinetics of the investigational Aurora A kinase inhibitor alisertib in cancer patients: Rationale for lower dosage in Asia.
    Br J Clin Pharmacol 2017 Sep 11. Epub 2017 Sep 11.
    Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
    Aims: This population pharmacokinetic analysis was conducted to quantitatively describe the regional differences and sources of inter-patient variability on the apparent oral clearance of alisertib.

    Methods: A population pharmacokinetic analysis was performed on data from 671 cancer patients in Western countries and in Japan/ East Asia administered alisertib 5-150 mg once or twice daily in multiple dosing schedules. The final model was used to simulate alisertib pharmacokinetics in patients in the West and East Asian regions in the single agent schedule of 7 days of dosing in a 21 day cycle. Read More

    Pharmacokinetics of multiple doses of co-crystal of tramadol-celecoxib: findings from a four-way randomized open-label phase I clinical trial.
    Br J Clin Pharmacol 2017 Sep 9. Epub 2017 Sep 9.
    Laboratorios del Dr. Esteve, S.A.U., Barcelona, Spain.
    Aim: We compared the pharmacokinetic (PK) profiles of co-crystal of tramadol-celecoxib (CTC) vs. each reference product (alone and in open combination) after single (first dose) and multiple dosing.

    Methods: Healthy adults aged 18-50 years received, under fasted conditions, 15 twice-daily doses of the following treatments (separated by ≥14-day washout): 200 mg immediate-release (IR) CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; treatment 1); 100 mg IR tramadol (treatment 2), 100 mg celecoxib (treatment 3); and 100 mg IR tramadol and 100 mg celecoxib (treatment 4). Read More

    Factor Xa inhibition by rivaroxaban in the trough steady state can significantly reduce thrombin generation.
    Br J Clin Pharmacol 2017 Sep 9. Epub 2017 Sep 9.
    Department of Cardiology and Nephrology, Dokkyo Medical University, Tochigi, Japan.
    Aims: The aim of the present study was to demonstrate evidence of reduced thrombin generation at the trough plasma rivaroxaban concentration.

    Methods: A single-centre, prospective, nonrandomized, drug-intervention, self-controlled study was conducted in 51 anticoagulation therapy-naïve patients with nonvalvular atrial fibrillation. Plasma rivaroxaban concentration was measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) and the anti-factor Xa chromogenic assay. Read More

    Impact of non-adherence on the safety and efficacy of uric acid-lowering therapies in the treatment of gout.
    Br J Clin Pharmacol 2017 Sep 9. Epub 2017 Sep 9.
    Centre for Health Economic and Medicines Evaluation, Bangor University, Bangor, UK.
    Aims: Dual-urate-lowering therapy (ULT) with xanthine oxidase inhibitor and uricosuric medications is a treatment option for severe gout. Uricosuric agents can cause hyperuricosuria, a risk factor for nephrolithiasis and acute uric acid nephropathy. The aims of the present study were to simulate the relationship between suboptimal drug adherence and efficacy, and to quantify the risk of hyperuricosuria in gout patients receiving mono- and dual-ULTs. Read More

    Hydroxycarbamide in Children with Sickle Cell Anemia After First-dose Vs. Chronic Therapy: Pharmacokinetics and Predictive Models for Drug Exposure.
    Br J Clin Pharmacol 2017 Sep 8. Epub 2017 Sep 8.
    Department of Pediatrics, Section of Clinical Pharmacology and Medical Toxicology, Arkansas Children's Hospital, Little Rock, AR, USA.
    Aims: The purpose of this work was to (1) compare pharmacokinetic (PK) parameters for hydroxycarbamide in children receiving their first dose (HCnew ) versus those receiving chronic therapy (HCchronic ), (2) assess the external validity of a published PK dosing strategy, and (3) explore the accuracy of dosing strategies based on a limited number of HC measurements.

    Methods: Utilizing data from two prospective, multicenter trials of hydroxycarbamide (Pharmacokinetics of Liquid Hydroxyurea in Pediatric Patients with Sickle Cell Anemia; NCT01506544 and Single-Dose (SD) and Steady-State (SS) Pharmacokinetics of Hydroxyurea in Children and Adolescents with Sickle Cell Disease), plasma drug concentration versus time profiles were evaluated with a model independent approach in the HCnew and HCchronic groups. Various predictive senerios were analyzed to evaluate if systemic exposure with hydroxycarbamide could be accurately predicted. Read More

    Drug-drug interaction potential in men treated with enzalutamide: Mind the gap.
    Br J Clin Pharmacol 2017 Sep 7. Epub 2017 Sep 7.
    Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
    Aims: Metastatic castration-resistant prostate cancer (mCRPC) patients are generally older patients with several co-morbidities and are therefore at increased risk of complications due to drug-drug interactions (DDIs). We assessed the prevalence of potential DDIs in a cohort of mCRPC patients treated with enzalutamide.

    Methods: We conducted a retrospective review of pharmacy records to retrieve individual drug histories of mCRPC patients who started enzalutamide therapy in a tertiary care setting. Read More

    Urinary miR-155-5p and CXCL10 as prognostic and predictive biomarkers of rejection, graft outcome and treatment response in kidney transplantation.
    Br J Clin Pharmacol 2017 Sep 7. Epub 2017 Sep 7.
    Pharmacology and Toxicology Laboratory, CDB, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Spain.
    Aims: MicroRNAs (miRNAs) may be useful biomarkers of rejection and allograft outcome in kidney transplantation. Elevated urinary CXCL10 levels have been associated with acute rejection (AR) and may predict allograft failure. We examined the correlation of miRNA, CXCL10 levels and immunosuppressive drug exposure with AR and graft function in kidney transplant recipients. Read More

    Biomarkers in solid organ transplantation.
    Br J Clin Pharmacol 2017 Sep 7. Epub 2017 Sep 7.
    Department of Hospital Pharmacy, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
    Recipients of solid organs such as the kidney and heart are treated with standard immunosuppressive regimens, and personalized medicine has not yet reached the clinic for this patient population. Biomarkers potentially will allow treatment regimens to be adjusted, according to the needs of the individual patient. Biomarkers may reflect the degree of immunosuppression of the immune system, or they may reflect early damage to the transplanted organ. Read More

    Dose-dependent acute liver injury with hypersensitivity features in humans due to a novel microsomal prostaglandin E synthase 1 inhibitor.
    Br J Clin Pharmacol 2017 Sep 2. Epub 2017 Sep 2.
    Eli Lilly and Company, Indianapolis, Indiana, USA.
    Aims: LY3031207, a novel microsomal prostaglandin E synthase 1 inhibitor, was evaluated in a multiple ascending dose study after nonclinical toxicology studies and a single ascending dose study demonstrated an acceptable toxicity, safety and tolerability profile.

    Methods: Healthy subjects were randomized to receive LY3031207 (25, 75 and 275 mg), placebo or celecoxib (400 mg) once daily for 28 days. The safety, tolerability and pharmacokinetic and pharmacodynamic profiles of LY3031207 were evaluated. Read More

    Evaluation of the pharmacokinetic drug interaction potential of tivantinib (ARQ 197) using cocktail probes in patients with advanced solid tumours.
    Br J Clin Pharmacol 2017 Sep 2. Epub 2017 Sep 2.
    Daiichi Sankyo, Inc., Edison, New Jersey, USA.
    Aims: This phase 1, open-label, crossover study sought to evaluate drug-drug interactions between tivantinib and cytochrome P450 (CYP) substrates and tivantinib and P-glycoprotein.

    Methods: The effect of tivantinib doses on the pharmacokinetics of the probe drugs for CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), and CYP3A4 (midazolam), and for P-glycoprotein (digoxin) was investigated in 28 patients with advanced cancer using a cocktail probe approach. Patients received single doses of probe drugs alone and, after 5 days of treatment, with tivantinib 360 mg twice daily. Read More

    Clinical significance of CYP2C19 polymorphisms on the metabolism and pharmacokinetics of 11β-hydroxysteroid dehydrogenase type-1 inhibitor BMS-823778.
    Br J Clin Pharmacol 2017 Aug 29. Epub 2017 Aug 29.
    Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, NJ, USA.
    Aims: BMS-823778 is an inhibitor of 11β-hydroxysteroid dehydrogenase type-1, and thus a potential candidate for Type 2 diabetes treatment. Here, we investigated the metabolism and pharmacokinetics of BMS-823778 to understand its pharmacokinetic variations in early clinical trials.

    Methods: The metabolism of BMS-823778 was characterized in multiple in vitro assays. Read More

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