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
Year

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

Wiley

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • 12 months embargo
  • Conditions
    • Some journals have separate policies, please check with each journal directly
    • 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: Atorvastatin is known to both inhibit and induce cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no well-controlled longer-term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as measured by 4β-hydroxycholesterol to cholesterol ratio (4βHC/C). In this randomised, double-blind, placebo-controlled 6-month study we evaluated the effects of atorvastatin 20 mg/day (n = 15) and placebo (n = 14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by 4βHC/C index. The respective 25-hydroxycholesterol and 5α,6α-epoxycholesterol ratios were used as negative controls. The treatment with atorvastatin decreased 4βHC and 5α,6α-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4βHC/C decreased by 13% (0.214 ± 0.04 to 0.182 ± 0.04, P = 0.024; 95% confidence interval (CI) of the difference -0.0595, -0.00483) in the atorvastatin group while no significant change occurred in the placebo group. The difference in change of 4βHC/C between study arms was statistically significant (atorvastatin -0.032, placebo 0.0055; P = 0.020; 95% CI of the difference -0.069, -0.0067). The ratios of 25-hydroxycholesterol and 5α,6α-epoxycholesterol to cholesterol did not change. The results establish atorvastatin as an inhibitor of CYP3A4 activity. Furthermore, 4βHC/C is a useful index of CYP3A4 activity, including the conditions with altered cholesterol levels. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 06/2015; DOI:10.1111/bcp.12701
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    ABSTRACT: Applying physiologically-based pharmacokinetics (PBPK) modelling in paediatric cancer drug development is still challenging. We aimed to demonstrate how PBPK modelling can be applied to optimize dose and sampling times for a paediatric pharmacokinetic (PK) bridging study in oncology and to compare with the allometric scaling population PK (AS-PopPK) approach, using docetaxel as an example. A PBPK model for docetaxel was first developed for adult cancer patients using Simcyp® and subsequently used to predict its PK profiles in children by accounting for age-dependent physiological differences. Dose (mg/m(2) ) requirements for children aged 0-18 years were calculated to achieve targeted exposure in adults. Simulated data were then analysed using population PK modelling with MONOLIX® in order to perform design optimization with PFIM. In parallel, the AS-PopPK approach was performed for the comparison. The PBPK model developed for docetaxel adequately predicted its PK profiles in both adult and paediatric cancer patients (predicted clearance and volume of distribution within 1.5 fold of observed data). The revised dose of docetaxel for a child over 1.5 years old was higher than the adult dose. Considering clinical constraints, the optimal design contained two groups of 15 patients, having 3 or 4 sampling times and had good predicted relative standard errors (RSE < 30%) for almost all parameters. The AS-PopPK approach performed reasonably well but could not predict to very young children. This research shows the clinical utility of the PBPK modelling in combination with population PK modelling and optimal design to support paediatric oncology development. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 06/2015; DOI:10.1111/bcp.12702
  • British Journal of Clinical Pharmacology 06/2015; DOI:10.1111/bcp.12700
  • British Journal of Clinical Pharmacology 06/2015; DOI:10.1111/bcp.12697
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    ABSTRACT: Paracetamol (acetaminophen) overdose is one of the most common causes of acute liver injury in the Western world. To improve patient care and reduce pressure on already stretched health care providers new biomarkers are needed that identify or exclude liver injury soon after an overdose of paracetamol is ingested. This review highlights the current state of paracetamol poisoning management and how novel biomarkers could improve patient care and save healthcare providers money. Based on the widely used concept of defining a target product profile, a target biomarker profile is proposed that identifies desirable and acceptable key properties for a biomarker in development to enable the improved treatment of this patient population. The current biomarker candidates, with improved hepatic specificity and based on the fundamental mechanistic basis of paracetamol-induced liver injury, are reviewed and their performance compared with our target profile. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 06/2015; DOI:10.1111/bcp.12699
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    ABSTRACT: To assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of octreotide subcutaneous (sc) depot, a novel octreotide formulation. Phase I, randomized, open-label study. After a single dose of octreotide immediate release (IR) 200 µg, subjects were randomized to one of eight groups to receive three monthly injections of octreotide sc depot-A 10, 20, or 30 mg, -B 30 mg, -C 10, 20, or 30 mg, or octreotide LAR 30 mg. 122 subjects were randomized. For all depot variants, onset of octreotide release was rapid, and sustained for up to 4 weeks. The relative octreotide bioavailability of depot variants versus octreotide IR ranged from 0.68 (90% confidence interval [CI], 0.61-0.76) to 0.91 h · ng/ml (90% CI, 0.81-1.02) and was approximately four- to five-fold greater than octreotide LAR: 3.97 (90% CI, 3.35-4.71) to 5.27 h · ng/ml (90% CI, 4.43-6.27). All depot variants showed relatively rapid initial reductions of insulin-like growth factor 1 (IGF-1) compared with octreotide LAR. A trend of octreotide dose dependence was also indicated from the plasma concentrations and suppression of IGF-1. Maximum inhibition of IGF-1 at steady state was highest for depot-B and -C. All depot treatments were well tolerated; the most frequent adverse events were gastrointestinal related. Octreotide sc depot provides greater octreotide bioavailability with a more rapid onset and stronger suppression of IGF-1 than octreotide LAR in healthy volunteers. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 06/2015; DOI:10.1111/bcp.12698
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    ABSTRACT: Erectile dysfunction is a common problem among patients with cardiovascular diseases and the influence of cardiovascular drugs is much debated. The aim of this study was to evaluate the short-term potential for different cardiovascular drugs to affect the risk of being prescribed a drug against erectile dysfunction. We employed a symmetry analysis design and included all Danish male individuals born before 1950 who filled their first ever prescription for a cardiovascular drug and a 5-phospodiesterase inhibitor within a six-month interval during 2002-2012. If the cardiovascular drug induces erectile dysfunction, this would manifest as a non-symmetrical distribution of subjects being prescribed the cardiovascular drug first vs persons following the opposite pattern. Furthermore, we calculated the number of patients needed to treat for one additional patient to be treated for erectile dysfunction (NNTH). We identified 20,072 males with a median age of 64 years (IQR: 60-70) who initiated a cardiovascular drug and a 5-phosphodiesterase inhibitor within a six-month interval. Sequence ratios showed minor asymmetry in prescription orders after adjustment for trends in prescribing. This asymmetry was most profound for thiazides (1.28; 95% CI 1.20-1.38), calcium channel blockers (1.29; 95% CI 1.21-1.38) and ACE inhibitors (1.29; 95% CI 1.21-1.37), suggesting a small liability of these drugs to provoke ED. NNTH values were generally large, in the range of 6,400-330, corresponding to small absolute effects. Our study does not suggest that cardiovascular drugs strongly affect the risk of being prescribed a drug against erectile dysfunction on a short-term basis. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 06/2015; DOI:10.1111/bcp.12696
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    ABSTRACT: AimsPhysiological changes in pregnancy are expected to alter the pharmacokinetics of various drugs. The objective of this study was to systematically evaluate the pharmacokinetics of oseltamivir (OS), a drug used in the treatment of influenza during pregnancy.MethodsA multicenter steady state pharmacokinetic study of OS was performed in 35 non-pregnant and 29 pregnant women. Plasma concentration-time profiles were analyzed using both non-compartmental and population pharmacokinetic modeling (POP PK) and simulation approaches. A one compartment population pharmacokinetic model with first order absorption and elimination adequately described the pharmacokinetics of OS.ResultsThe systemic exposure of oseltamivir carboxylate (OC; active metabolite of OS) was reduced approximately 30(19-36)% (p < 0.001) in pregnant women. Pregnancy significantly (p < 0.001) influenced the clearance (CL/F) and volume of distribution (V/F) of OC. Both non-compartmental and population pharmacokinetic approaches documented approximately 45(23-62)% increase in clearance (CL/F) of OC during pregnancy.Conclusion Based on the decrease in exposure of the active metabolite, the currently recommended doses of OS may need to be increased modestly in pregnant women in order to achieve comparable exposure as that of non-pregnant women.
    British Journal of Clinical Pharmacology 06/2015; DOI:10.1111/bcp.12691
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    ABSTRACT: Keen readers will have observed a profusion of guidelines (a total of >81 at last count) aimed at standardizing and/or improving reports of research studies published in medical journals. [1] There bewildering array of acronyms (e.g. CONSORT, STROBE, STARD, PRISMA, MOOSE, TRIPOD) may seem mind-boggling for authors and journal editors alike. Indeed, like blockbuster movies and their inevitable sequels, some of the existing guidelines have even spawned closely related spin-offs such as CONSORT Abstracts and PRISMA-IPD. [2, 3] Amidst this abundance though, we are aware of only one recently published guideline specific to reporting in clinical pharmacology research studies. [4]. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 05/2015; DOI:10.1111/bcp.12683
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    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
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    ABSTRACT: Objective We investigated whether moxifloxacin-induced QTc prolongations in Japanese and Caucasian healthy male volunteers were significantly different.MethodsA 2-periods, randomized, crossover, ICH-E14-compliant thorough QT (TQT) study compared placebo-corrected changes in QTc interval from baseline (ΔΔQTcF) and concentration-effect relationships following administration of placebo and 400 mg moxifloxacin to 40 healthy male volunteers from each ethnic population. The point estimates of ΔΔQTcF for each population, and the difference between the two, were calculated at a geometric mean Cmax of moxifloxacin using a linear mixed effects model. The concentration-effect slopes of the two populations were also compared. Equivalence was concluded if the 2-sided 90% confidence interval of the difference in ΔΔQTcF was contained within -5 ms to +5 ms limits and the ratio of the slopes was between 0.5 and 2.ResultsThere were no statistically significant differences between the two populations studied, Japanese versus Caucasians, respectively, for moxifloxacin Cmax (3.27 ± 0.6 vs 2.98 ± 0.7 µg/mL), ΔΔQTcF (9.63 ± 1.15 vs 11.46 ± 1.19 ms at Cmax of 3.07 µg/mL) and concentration-response slopes (2.58 ± 0.62 vs 2.34 ± 0.64 ms/µg/mL). The difference in the two ΔΔQTcF of -1.8 (90% CI -4.6, 0.9) and the ratio of the two slopes (1.1) were within pre-specified equivalence limits.Conclusions Moxifloxacin-induced QTc prolongations did not differ significantly between the Japanese and Caucasian subjects. However, before our findings are more widely generalized, further studies in other populations and with other QT-prolonging drugs are needed to clarify whether inter-ethnic differences in QT-sensitivity exist and whether ethnicity of the study population may affect the outcome of a TQT study.
    British Journal of Clinical Pharmacology 05/2015; DOI:10.1111/bcp.12684
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    ABSTRACT: AimDespite promising preclinical findings regarding clinical utility of farnesyltransferase inhibitors (FTI), such as lonafarnib, success of clinical trials is limited. A multi-center AGO-OVAR-15 phase II trial reported an unfavorable effect of lonafarnib on the outcome of patients with advanced ovarian cancer. This study was performed as a genetic subgroup analysis of the AGO-OVAR-15, which investigated the utility of the promoter polymorphism rs11623866 of the farnesyltransferase ß-subunit gene (FNTB) in predicting the clinical effectiveness of lonafarnib.Methods The influence of rs11623866 (c.-609G > C) on FNTB promoter activity was investigated by electrophoretic-mobility-shift assay, luciferase-reporter assay and RT-qPCR. A total of 57 out of 105 patients from AGO-OVAR-15 trial, treated with carboplatin and paclitaxel ± lonafarnib, was genotyped for rs11623866 by restriction fragment length polymorphism analysis. Genotype-dependent survival analysis was performed by Kaplan-Meier analysis.ResultsThe presence of the G allele was associated with increased FNTB promoter activity compared to the C allele. An unfavorable effect of lonafarnib was limited to patients, carrying a GG genotype (HRPFS 6.2, 95%CI = 2.01-19.41, p = 0.002; HROS 9.6, 95%CI = 1.89-48.54, p = 0.006). Median PFS for patients with GG genotype in the lonafarnib treated arm was 10 months, whereas median PFS without FTI-treatment was 40 months. Median OS in the lonafarnib-treated group was 19 months, whereas median OS was not reached in the untreated group.Conclusions Discrepancies between preclinical success and clinical failure may be due to the patients’ genetic variability of FNTB. Therefore, our results may encourage retrospective evaluation of FNTB polymorphisms in previous FTI-studies, especially those reporting positive FTI-response.
    British Journal of Clinical Pharmacology 05/2015; DOI:10.1111/bcp.12688