British Journal of Clinical Pharmacology Impact Factor & Information

Publisher: British Pharmacological Society, Wiley

Journal description

The Journal of The British Pharmacological Society. Published on behalf of the British Pharmacological Society, the British Journal of Clinical Pharmacology contains papers and reports on all aspects of drug action in humans: invited review articles, original papers, short communications and correspondence. The Journal enjoys a wide readership, bridging the gap between the medical profession, clinical research and the pharmaceutical industry. Proceedings of the meetings of the Clinical Section of the British Pharmacological Society are published in abstract form and supplements containing information on new methods, new drugs and new approaches to treatment are supplied free of charge.

Current impact factor: 3.69

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2013 / 2014 Impact Factor 3.688
2012 Impact Factor 3.578
2011 Impact Factor 2.958
2010 Impact Factor 3.063
2009 Impact Factor 3.246
2008 Impact Factor 3.128
2007 Impact Factor 2.681
2006 Impact Factor 2.718
2005 Impact Factor 2.777
2004 Impact Factor 2.546
2003 Impact Factor 2.531
2002 Impact Factor 2.274
2001 Impact Factor 2.213
2000 Impact Factor 2.151
1999 Impact Factor 2.545
1998 Impact Factor 1.846
1997 Impact Factor 1.809
1996 Impact Factor 2.214
1995 Impact Factor 2.048
1994 Impact Factor 1.922
1993 Impact Factor 1.891
1992 Impact Factor 1.733

Impact factor over time

Impact factor

Additional details

5-year impact 3.56
Cited half-life 8.70
Immediacy index 1.15
Eigenfactor 0.02
Article influence 0.99
Website British Journal of Clinical Pharmacology website
Other titles British journal of clinical pharmacology (Online), BJCP
ISSN 1365-2125
OCLC 45425630
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details


  • Pre-print
    • Author can archive a pre-print version
  • Post-print
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  • Restrictions
    • 12 months embargo
  • Conditions
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    • On author's personal website, institutional repositories, arXiv, AgEcon, PhilPapers, PubMed Central, RePEc or Social Science Research Network
    • Author's pre-print may not be updated with Publisher's Version/PDF
    • Author's pre-print must acknowledge acceptance for publication
    • On a non-profit server
    • Publisher's version/PDF cannot be used
    • Publisher source must be acknowledged with citation
    • Must link to publisher version with set statement (see policy)
    • If OnlineOpen is available, BBSRC, EPSRC, MRC, NERC and STFC authors, may self-archive after 12 months
    • If OnlineOpen is available, AHRC and ESRC authors, may self-archive after 24 months
    • Publisher last contacted on 07/08/2014
    • This policy is an exception to the default policies of 'Wiley'
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Clopidogrel and angiotensin-converting enzyme (ACE) inhibitors are commonly co-prescribed drugs. Clopidogrel inhibits carboxylesterase 1 (CES1), the enzyme responsible for converting prodrug ACE inhibitors (such as ramipril and perindopril) to their active metabolites. The clinical implications of this potential drug interaction are unknown. We conducted a nested case-control study of Ontarians aged 66 and older treated with clopidogrel between September 1, 2003 and March 31, 2013 following acute myocardial infarction. Cases were subjects who died or were hospitalized for reinfarction or heart failure in the subsequent year, and each was matched with up to 4 controls. The primary outcome was a composite of reinfarction, heart failure or death. The primary analysis examined whether use of the prodrug ACE inhibitors ramipril or perindopril was more common among cases than use of lisinopril, an active ACE inhibitor. Among 45,918 patients treated with clopidogrel following myocardial infarction, we identified 4,203 cases and 14,964 controls. After adjustment, we found no association between the composite outcome and use of perindopril (adjusted odds ratio (aOR) 0.94; 95% confidence interval (CI) 0.76 to 1.16) or ramipril (aOR 0.97; 95% CI 0.80 to 1.18), relative to lisinopril. Secondary analyses of each element of the composite outcome yielded similar findings. Following myocardial infarction, use of clopidogrel with ACE inhibitors activated by CES1 is not associated with an increased risk of adverse cardiovascular outcomes relative to lisinopril. These findings suggest that the recently described drug interaction between clopidogrel and prodrug ACE inhibitors is of little clinical relevance. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 05/2015; DOI:10.1111/bcp.12682
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    ABSTRACT: To investigate the QT effect of a single-dose combination regimen of piperaquine phosphate (PQP) and a novel aromatic trioxolane, OZ439, for malaria treatment. Exposure response (ER) analysis was performed on data from a placebo-controlled, single-dose, study with OZ439 and PQP. Fifty-nine healthy subjects aged 18 to 55 years received OZ439 alone or placebo in a first period, followed by OZ439 plus PQP or matching placebos in Period 2. OZ439 and PQP doses ranged from 100-800 mg and 160-1440 mg, respectively. 12-lead ECG tracings and PK samples were collected serially pre- and post-dosing. A significant relation between plasma levels and placebo-corrected change-from-baseline QTcF (∆∆QTcF) was demonstrated for piperaquine, but not for OZ439, with a mean slope of 0.047 ms per ng/mL (90% CI: 0.038 to 0.057). Using an ER model that accounts for plasma concentrations of both piperaquine and OZ439, a largest mean QTcF effect of 14 ms (90% CI: 10 to 18 ms) and 18 ms (14 to 22 ms) was predicted at expected plasma levels of a single- dose 800 mg OZ439 combined with PQP 960 mg (188 ng/mL) and 1440 mg (281 ng/mL), respectively, administered in the fasted state. Piperaquine prolongs the QTc interval in a concentration-dependent way. A single-dose regimen combining 800 mg OZ439 with 960 mg or 1440 mg PQP is expected to result in lower peak piperaquine plasma levels compared to available 3-day PQP - artemisinin combinations and can therefore be predicted to cause less QTc prolongation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 05/2015; DOI:10.1111/bcp.12680
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    ABSTRACT: Selective serotonin reuptake inhibitors (SSRIs), specifically citalopram and escitalopram, are thought to give QTc prolongation, although studies showed contradictory results. Nevertheless, a maximum citalopram dosage of 20 mg in high-risk patients (e.g. >60 years of age) is recommended. We aimed to investigate the association between use of (individual) SSRIs and QTc in a population-based study in older adults. This study, which was part of the prospective Rotterdam Study (period: 1991-2012), included participants with up to 5 electrocardiograms (ECGs). We used linear mixed models to compare QTcF (QT corrected according to Fridericia) measured during use of individual SSRIs with QTcF measured during non-use of any antidepressant. For citalopram, analyses were additionally restricted to a maximum dosage of 20 mg in participants aged 60 years and older. We included 12,589 participants with a total of 26,620 ECGs of which 436 ECGs were made during SSRI use. The mean QTcF was similar during use of any drugs from the SSRI class and during non-use. After stratifying to individual SSRIs, ECGs recorded during use of citalopram had the longest QTc compared with ECGs recorded during non-use (+12.8 ms; 90% CI: 7.5 - 18.2). This result remained similar in the analysis comprising participants aged 60 years and older with a maximum prescribed daily dosage of 20 mg of citalopram. Although no SSRI class effect was observed, use of citalopram was associated with a longer QTcF, even after considering the recommended restrictions. Other SSRIs may not give a clinically relevant QTcF prolongation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 05/2015; DOI:10.1111/bcp.12681
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    ABSTRACT: To examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in lupus nephritis patients. Six blood samples were drawn pre- and at 1-, 2-, 4-, 6- and 8-hours post-dose and total and unbound MPA and prednisolone pre-dose (C0 ), maximum concentration (Cmax ) and area under the concentration-time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events. Dose-normalised AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values [95% CI] of total MPA AUC0-8 (21.5 [15.0-42.0] vs. 11.2 [4.8-30.0] mg∙h/L, p = 0.048) and Cmax (11.9 [6.7-26.3] vs. 6.1 [1.6-9.2] mg/L, p = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1-77.5] vs. 18.5 [11.7-32.7] mg∙h/L, p = 0.038) and unbound MPA AUC0-12 (751 [214-830] vs. 227 [151-389] mg∙h/L, p = 0.004). Unbound prednisolone AUC0-24 was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242-1774] vs. 846 [528-1049] nmol∙h/L, p = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared to patients with middle and higher tertile exposure (17% vs. 74%, p = 0.023). This study suggests a potential role for therapeutic drug monitoring in individualising immunosuppressant therapy in lupus nephritis patients. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 05/2015; DOI:10.1111/bcp.12678
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    ABSTRACT: Darapladib is a potent and reversible orally active inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2 ). This open-label, parallel-group study was conducted to assess the effects of renal impairment on the pharmacokinetics and safety/tolerability of darapladib following 10-day once-daily 160-mg oral dosing in subjects with normal (n = 8) and severe renal impairment (estimated Glomerular Filtration Rate <30 mL/min/1.73 m(2) , n = 8). Plasma concentrations of total and unbound darapladib as well as total darapladib metabolites were determined in samples obtained over 24-hour on day 10. Plasma concentrations of total and unbound darapladib as well as all 3 metabolites were higher in subjects with severe renal impairment. Area under the plasma concentration versus time curve between time zero and 24-hour (AUC0-24 ) and maximum plasma concentration (Cmax ) of total darapladib in severely renally impaired subjects were 52% and 59% higher than those in the matched healthy subjects, respectively. Similar results were found with the darapladib metabolites. Darapladib was highly plasma protein bound with 0.047% and 0.034% unbound circulating in plasma in severely renally impaired and healthy subjects, respectively. Unbound plasma darapladib exposures were more than 2-fold higher in severely renally impaired subjects than in healthy controls. Adverse events (AE) were reported in 38% of healthy subjects and 75% of severely renally impaired subjects most of which were mild or moderate in intensity. The results of this study showed that darapladib exposure was increased in subjects with severe renal impairment compared to healthy controls; however, darapladib was generally well tolerated in both groups. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 05/2015; DOI:10.1111/bcp.12661
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    ABSTRACT: Despite the continuous endeavour to achieve high standards in medical care through effectiveness measures, a quantitative framework for the assessment of the benefit-risk balance (BRB) is lacking prior to drug approval. The aim of this short review is to summarise the approaches currently available for benefit-risk assessment. In addition, we propose the use of pharmacokinetic-pharmacodynamic (PKPD) modelling as the pharmacological basis for evidence synthesis and evaluation of novel therapeutic agents. A comprehensive literature search has been performed using MESH terms in PubMed, in which articles describing benefit-risk assessment and modelling and simulation (M&S) were identified. In parallel, a critical review of multi-criteria decision analysis (MCDA) is presented as a tool for characterising a drug's safety and efficacy profile. A definition of benefits and risks has been proposed by the European Medicines Agency (EMA), in which qualitative and quantitative elements are included. However, in spite of the value of MCDA as a quantitative method, decisions about BRB continue to rely on subjective expert opinion. By contrast, a model-informed approach offers the opportunity for a more comprehensive evaluation of BRB before extensive evidence is generated in clinical practice. BRB should be an integral part of risk management and as such considered prior to drug approval. M&S can be incorporated into MCDA to support the evidence synthesis as well evidence generation taking into account the underlying correlations between favourable and unfavourable effects. In addition, it represents a valuable tool for the optimisation of protocol design in effectiveness trials. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 05/2015; DOI:10.1111/bcp.12674
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    ABSTRACT: AimInterindividual epigenetic variation is likely to be an important mechanism contributing to the interindividual variability in expression and function of ATP-binding cassette, sub-family B, member 1 (ABCB1). The aim of this study was to explore the effect of interindividual epigenetic variability in the ABCB1 promoter on ABCB1 expression and function in healthy Chinese subjects.Methods Using bisulfite sequencing PCR and chromatin immunoprecipitation assays, DNA methylation and histone acetylation status of the ABCB1 promoter in stool DNA and exfoliated colonic epithelial cells of 157 healthy Chinese male volunteers were analyzed. ABCB1 mRNA level in colonic epithelial cells was detected by real-time PCR. The digoxin pharmacokinetics in subjects with different epigenetic profiles was investigated after a single oral administration of digoxin (0.5 mg).ResultsThe average methylation ratios of ABCB1 promoter in stool DNA showed a significant interindividual variation, from 0.84% to 18.05%. High methylation level of the ABCB1 promoter was closely related to the low levels of acetylated histone H3 and ABCB1 mRNA expression. In the high methylation group, AUC(0-4 h) and AUC(0-10 h) of digoxin was increased by 19% (95% CI, 10% to 31%; P = 0.024) and 13% (95% CI, 8% to 26%; P = 0.026), Cmax of digoxin was increased by 30% (95% CI, 12% to 41%; P = 0.021) compared to the low methylation group.Conclusions The epigenetic modifications of the ABCB1 promoter show high interindividual variability in healthy Chinese subjects, and are closely related to the interindividual variation in ABCB1 mRNA expression and digoxin 0-4 h plasma concentrations in vivo.
    British Journal of Clinical Pharmacology 05/2015; DOI:10.1111/bcp.12675
  • British Journal of Clinical Pharmacology 05/2015; 79(5):693-4. DOI:10.1111/bcp.12638
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    ABSTRACT: AimsTo evaluate pharmacokinetics/pharmacodynamics (PK/PD), safety and tolerability of single intravenous (IV) doses of PF-05231023, a long acting FGF21 analog being developed for treatment of type 2 diabetes mellitus (T2DM).MethodsT2DM subjects (HbA1c: 7.0-10.5%; on stable metformin therapy and/or diet and exercise) were randomized to receive a single dose of placebo or PF-05231023 (0.5 to 200 mg). Safety evaluations were performed up to 14 days after dosing. PK and PD endpoints were measured and a PK/PD model was developed for triglyceride-an early marker of drug activity.ResultsNo anti-drug-antibody or serious adverse events (AEs) were observed. The most frequent AEs were gastrointestinal but were generally mild. Plasma PF-05231023 levels peaked immediately post IV dosing with mean terminal half-lives of 6.5-7.7 hours and 66.5- 96.6 hours for intact C- and N-termini, respectively. Intact C-terminus exposures increased proportionally with increasing dose, whereas N-terminus exposures appeared to trend higher than dose-proportionally. Although no apparent effect on plasma glucose was seen, dose-dependent decreases in triglyceride were observed with maximum reduction of 48.5 ± 10.0% (mean ± SD) for the 200 mg dose compared to a reduction of 19.1 ± 26.4% for placebo, demonstrating proof of pharmacology. Moreover, reduction in total cholesterol and low density lipoprotein cholesterol and increase in high density lipoprotein cholesterol were observed in high dose groups.Conclusions Single IV doses of PF-05231023 up to 200 mg were generally safe and well tolerated by subjects with T2DM. The observed early sign of pharmacology supports further clinical testing of PF-05231023 upon repeated administration.
    British Journal of Clinical Pharmacology 05/2015; DOI:10.1111/bcp.12676
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    ABSTRACT: The medical and legal risks associated with prescribing unlicensed vitamin D products have recently been highlighted by Davies et al. This prompted a letter from Rhein who raised the concern that this may dissuade practioners from prescribing vitamin D, and exacerbate the failure to adequately address the widespread problem of vitamin D deficiency and insufficiency. Rhein asks whether European licensed preparations could be used in the absence of suitable or affordable UK licensed preparations, with appropriate checks. We address this point with a practical approach to understanding the licensed status of different preparations of vitamin D and the relevance with respect to prescribing and dispensing them, particularly now with the recent licensing of higher doses of vitamin D. We are not setting out to provide guidance on the specific requirements for vitamin D replacement in vitamin D deficiency and insufficiency or advice on specific dosing regimens or selection of specific vitamin D preparations, for which we encourage the reader to consult their local or national guidelines. However, when following such guidelines, the prescriber should be reasonably satisfied that the likely benefits of prescribing higher doses of vitamin D products exceed the likely risks of harms. For example, with respect to evidence of benefit in terms of mortality, the Cochrane Review on Vitamin D supplementation for prevention of mortality in adults by Bjelakovic et al., (2011) which included 32 trials of vitamin D3, found that only doses of vitamin D3 below 800 units a day were associated with a significantly decreased mortality; there was no significant effect on mortality with doses at, or above 800 units a day. No effect on mortality was found with vitamin D2. This Commentary focuses on the risks of different categories of vitamin D products, with respect to their licensed status, within the context of the medico-legal framework.
    British Journal of Clinical Pharmacology 05/2015; DOI:10.1111/bcp.12673
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    ABSTRACT: AimsTo investigate the impact of human visceral leishmaniasis (VL) and curative chemotherapy on the activity of CYP3A, CYP2C9 and CYP2C19 in patients from an endemic region in Brazil.Methods Adult patients with parasitologically confirmed VL were given a CYP phenotyping cocktail, comprising midazolam, omeprazole and losartan, immediately before (Study phase 1), 2-3 days (phase 2) and 3-6 months (phase 3) after curative VL chemotherapy. CYP activity was assessed by the apparent clearance of midazolam (CYP3A), omeprazole/5-hydroxyomeprazol ratio in plasma (CYP2C19) and losartan/E3174 ratio in urine (CYP2C9).ResultsMean (95% confidence interval) in phases 1, 2 and 3 were, respectively: log apparent midazolam clearance, 1.21 (1.10-1.31), 1.45 (1.32-1.57) and 1.35 (1.26-1.44) ml/min/Kg; omeprazole/5-hydroxyomeprazole ratio, 0.78 (0.61-0.94), 0.45 (0.27-0.63) and 0.37 (0.20-0.55); losartan/E3174 ratio, 0.66 (0.39-0.92), 0.35 (0.20-0.50) and 0.35 (0.16-0.53). ANOVA revealed significant differences in CYP3A (p = 0.018) and CYP2C19 (p = 0.008), but not CYP2C9 (p = 0.11) phenotypic activity, across the three study phases.Conclusion The phenotypic activities of CYP3A4 and CYP2C19 were significantly reduced during acute VL compared to post-chemotherapy. We propose that increased plasma concentrations of proinflammatory cytokines during active disease account for suppression of CYP activity. The failure to detect significant changes in CYP2C9 activity in the overall cohort may reflect differential effects of the inflammatory process on expression of CYP isoforms, although the possibility of insufficient statistical power cannot be dismissed.
    British Journal of Clinical Pharmacology 05/2015; DOI:10.1111/bcp.12677
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    ABSTRACT: To determine the efficacy and safety of metformin for the treatment of women with gestational diabetes mellitus (GDM). We searched databases, including PubMed, Embase, and the Cochrane Central Register of Controlled Trials, for randomized controlled trials (RCTs) comparing metformin and insulin treatments in women with GDM. We carried out statistical analyses using RevMan 2011 and used the Grading of Recommendations, Assessment, Development, and Evaluations profiler to rate the quality of evidence of the primary outcomes. We analyzed eight studies involving 1592 subjects. Meta-analysis of the RCTs showed that metformin had statistically significant effects on pregnancy-induced hypertension (PIH; risk ratio [RR], 0.54; 95% confidence interval [CI], 0.31-0.91). However, its effects on neonatal hypoglycemia (RR, 0.80; 95% CI, 0.62-1.02), rate of large-for-gestational age infants (RR, 0.77; 95% CI, 0.55-1.08), respiratory distress syndrome (RR, 1.26; 95% CI, 0.67-2.37), phototherapy (RR, 0.94; 95%CI, 0.67-1.31), and perinatal death (RR, 1.01; 95% CI, 0.11-9.53) were not significant. Our analyses suggest that there is no clinically relevant difference in efficacy or safety between metformin and insulin; however, metformin may be a good choice for GDM because of the lower risk of PIH. The advantages of metformin in terms of glycemic control, PIH incidence, and gestational age at birth are unclear, and must be verified in further trials. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 04/2015; DOI:10.1111/bcp.12672
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    ABSTRACT: The aim of this study was to investigate the effects of the carboxylesterase 1 (CES1) c.428G > A (p.G143E, rs71647871) single nucleotide variation (SNV) on the pharmacokinetics of quinapril and enalapril in a prospective genotype panel study in healthy volunteers. In a fixed-order crossover study, 10 healthy volunteers with the c.428G/A genotype and 12 with the CES1 c.428G/G genotype ingested a single 10-mg dose of quinapril and enalapril with a washout period of at least one week. Plasma concentrations of quinapril and quinaprilat were measured for up to 24 h and those of enalapril and enalaprilat for up to 48 h. Their excretion into urine was measured from 0 to 12 h. The area under the plasma concentration time curve from 0 h to infinity (AUC0-∞ ) of active enalaprilat was 20% lower in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (95% CI of geometric mean ratio, 0.64, 1.00; P = 0.049). The amount of enalaprilat excreted into urine was 35% smaller in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (P = 0.044). The CES1 genotype had no significant effect on the enalaprilat to enalapril AUC0-∞ ratio or any other pharmacokinetic or pharmacodynamic parameter of enalapril or enalaprilat. The CES1 genotype had no significant effect on the pharmacokinetic or pharmacodynamic parameters of quinapril. The CES1 c.428G > A SNV decreased enalaprilat concentrations likely by reducing the hydrolysis of enalapril, but had no observable effect on the pharmacokinetics of quinapril. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 04/2015; DOI:10.1111/bcp.12667
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    ABSTRACT: Arthritis is the commonest cause of disabling chronic pain, and both osteoarthritis (OA) and rheumatoid arthritis (RA) remain major burdens on both individuals and society. Peripheral release of calcitonin gene-related peptide (CGRP) contributes to the vasodilation of acute neurogenic inflammation. Contributions of CGRP to the pain and inflammation of chronic arthritis, however, are only recently being elucidated. Animal models of arthritis are revealing the molecular and pathophysiological events that accompany and lead to progression of both arthritis and pain. Peripheral actions of CGRP in the joint might contribute to both inflammation and joint afferent sensitisation. CGRP and its specific receptors are expressed in joint afferents, and upregulated following arthritis induction. Peripheral CGRP release results in activation of synovial vascular cells, through which acute vasodilatation is followed by endothelial cell proliferation and angiogenesis, key features of chronic inflammation. Local administration of CGRP to the knee also increases mechanosensitivity of joint afferents, mimicking peripheral sensitisation seen in arthritic joints. Increased mechanosensitivity in OA knees, and pain behaviour, can be reduced by peripherally acting CGRP receptor antagonists. Effects of CGRP pathway blockade on arthritic joint afferents, but not in normal joints, suggest contributions to sensitisation rather than normal joint nociception. CGRP therefore might make key contributions to the transition from normal to persistent synovitis, and the progression from nociception to sensitisation. Targeting CGRP or its receptors within joint tissues to prevent these undesirable transitions during early arthritis, or suppress them in established disease, might prevent persistent inflammation and relieve arthritis pain. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 04/2015; DOI:10.1111/bcp.12669
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    ABSTRACT: This study aimed to evaluate the risk of hip/femur fractures during the initiation period of alpha-blocker therapy using the National Health Insurance claims database, Taiwan, with a self-controlled case series design. All male beneficiaries aged over 50 years as of 2007, who were incident users of alpha-blockers and also had a diagnosis of hip/femur fracture within the 2007 ~ 2009 study period were identified. The first day when the alpha-blocker was prescribed was set as the index date. We partitioned the initial 21-day period following the index date as the post-exposure risk period 1; days 22-60 after the index date as the post-exposure risk period 2; the 21-day period prior to the index date as the pre-exposure risk period 1, and days 22-60 prior to the index date as the pre-exposure risk period 2. The remainder of the study period was defined as the unexposed period. The incidence rate ratio (IRR) of hip/femur fractures within each risk period compared with the unexposed period was estimated using a conditional Poisson regression model. A total of 5875 men were included. Compared with the unexposed period, the IRR of hip/femur fractures was 1.36 (95% confidence interval, 1.06-1.74, p = 0.017) within the post-exposure risk period 1 for patients without concomitant prescriptions of anti-hypertensive agents. Use of alpha-blockers was associated with a small but significant increase in the risk of hip/femur fractures during the early initiation period in patients without concomitant prescriptions of anti-hypertensive agents. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 04/2015; DOI:10.1111/bcp.12671
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    ABSTRACT: The regulatory prohibition of ketoconazole as a CYP3A index inhibitor in drug-drug interaction (DDI) studies has compelled consideration of alternative inhibitors. The biomedical literature was searched to identify DDI studies in which oral midazolam (MDZ) was the victim, and the inhibitory perpetrator was either ketoconazole, itraconazole, clarithromycin, or ritonavir. The ratios (RAUC ) of total area under the curve (AUC) for MDZ with inhibitor divided by MDZ AUC in the control condition were aggregated across individual studies for each inhibitor. Mean (± SE) RAUC values were: ketoconazole (15 studies, 131 subjects), 11.5 (±1.2); itraconazole (5 studies, 48 subjects), 7.3 (±1.0); clarithromycin (5 studies, 73 subjects), 6.5 (±10.9); ritonavir (13 studies, 159 subjects), 14.5 (±2.0). Differences among inhibitors were significant (F = 5.31, p < 0.005). RAUC values were not significantly related to inhibitor dosage, or to duration of inhibitor pre-exposure prior to administration of MDZ. Ritonavir produces CYP3A inhibition equivalent to or greater than ketoconazole, and is the best index CYP3A inhibitor alternative to ketoconazole. Cobicistat closely resembles ritonavir in structure and function, and can also be considered. Itraconazole and clarithromycin are not suitable alternatives since they do not produce inhibition comparable to ketoconazole or ritonavir, and have other significant disadvantages as well. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 04/2015; DOI:10.1111/bcp.12668
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    ABSTRACT: Anticholinergic drug exposure is associated with adverse outcomes in older people. While a number of tools have been developed to measure anticholinergic drug exposure, there is limited information about the agreement and overlap between the various scales. The aim of this study was to investigate the agreement and overlap between different measures of anticholinergic drug exposure in a cohort of community-dwelling older men. A cross sectional study was used to compare anticholinergic drug exposure calculated using the Anticholinergic Risk Scale (ARS), the Anticholinergic Drug Scale (ADS), the Anticholinergic Cognitive Burden (ACB) and the Drug Burden Index anticholinergic subscale (DBI-ACH) in a cohort of community-dwelling men aged 70 years and older (n = 1,696). Statistical agreement, expressed as Cohen's kappa (κ), between these measurements was calculated. Differences were found between the tools regarding the classification of anticholinergic drug exposure for individual participants. Thirteen percent of the population used a drug listed as anticholinergic on the ARS, 39% used a drug listed on the ADS and the ACB, and 18% of the population used one or more anticholinergic drugs listed on the DBI-ACH. While agreement was good between the ACB and ADS (κ = 0.628, 95% CI 0.593 - 0.664), little agreement was found between remaining tools (κ = 0.091-0.264). With the exception of the ACB and ADS, there was poor agreement regarding anticholinergic drug exposure among the four tools compared in this study. Great care should be taken when interpreting anticholinergic drug exposure using existing scales due to the wide variability between the different scales. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 04/2015; DOI:10.1111/bcp.12670
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    ABSTRACT: A prospectively enrolled patient cohort was used to assess whether the prediction of CYP2D6 phenotype activity from genotype data could be improved by reclassification of diplotypes or alleles. 355 patients receiving tamoxifen 20 mg/day were genotyped for CYP2D6 and tamoxifen metabolite concentrations were measured. The endoxifen/N-desmethly-tamoxifen metabolic ratio, as a surrogate of CYP2D6 activity, was compared across four diplotypes (EM/IM, EM/PM, IM/IM, IM/PM) that are typically collapsed into an intermediate metabolizer (IM) phenotype. The relative metabolic activity of each allele type (UM, EM, IM, and PM) and each EM and IM allele was estimated for comparison with the activity scores typically assigned; 2, 1, 0.5, and 0, respectively. Each of the four IM diplotypes have distinct CYP2D6 activity from each other and from the EM and PM phenotype groups (each p < 0.05). Setting the activity of an EM allele at 1.0, the relative activities of a UM, IM, and PM allele were 0.85, 0.67 and 0.52, respectively. The activity of the EM alleles were statistically different (p < 0.0001), with the CYP2D6*2 allele (scaled activity = 0.63) closer in activity to an IM than an EM allele. The activity of the IM alleles were also statistically different (p = 0.014). The current systems for translating CYP2D6 genotype into phenotype are not optimally calibrated, particularly in regards to IM diplotypes and the *2 allele. Additional research is needed to improve the prediction of CYP2D6 activity from genetic data for individualized dosing of CYP2D6 dependent drugs. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 04/2015; DOI:10.1111/bcp.12665
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    ABSTRACT: The aim of the phase Ib, two-part SAWYER study (BO25341; NCT01292603) was to investigate the pharmacokinetics and safety of subcutaneous (SC) rituximab compared with intravenous (IV) rituximab, both in combination with fludarabine and cyclophosphamide (FC), as first-line treatment for patients with chronic lymphocytic leukaemia (CLL). During Part 1 (dose-finding), CLL patients received rituximab IV followed by a single dose of rituximab SC at one of three fixed doses (1400, 1600 or 1870 mg) in cycle 6. The primary objective was to identify a fixed SC dose that would achieve comparable rituximab serum trough concentrations (Ctrough ) to those achieved with the standard 4-weekly 500 mg/m(2) rituximab IV dose. Fifty-five patients received a fixed dose of rituximab SC; 16 received 1400 mg, 17 received 1600 mg and 22 received 1870 mg. The 1600 mg dose was predicted to achieve non-inferior Ctrough to standard rituximab IV treatment. The rituximab SC safety profile was comparable to rituximab IV, except that local administration-related reactions, mainly mild/moderate injection site reactions, occurred more frequently with rituximab SC, which was not unexpected. SC administration was preferred to IV administration by > 90% of patients and nurses (n = 112). SAWYER Part 1 data predict that rituximab SC 1600 mg will achieve non-inferior Ctrough levels to rituximab IV 500 mg/m(2) , administered 4-weekly. This fixed SC dose is currently undergoing formal non-inferiority assessment in SAWYER Part 2. In future, first-line CLL treatment regimens comprising rituximab SC and oral FC could substantially reduce IV chair time. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 04/2015; DOI:10.1111/bcp.12662
  • British Journal of Clinical Pharmacology 04/2015; DOI:10.1111/bcp.12659