British Journal of Clinical

Pharmacology

DOI:10.1111/bcp.12303

Editors pick

Editors pick 2013

Albert Ferro,1 Yoon K. Loke,2 Lionel D. Lewis,3 Andrew Somogyi,4 Adam F. Cohen5 & James M. Ritter1
1

Department of Clinical Pharmacology, School of Medicine (Cardiovascular Division) Kings College London, London, 2School of Medicine, University of
East Anglia, Norwich, UK, 3Section of Clinical Pharmacology, Department of Medicine, Dartmouth Medical School &Dartmouth-Hitchcock Medical
Center, Lebanon, NH, USA, 4Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, Australia and 5Centre for Human
Drug Research, Leiden, the Netherlands

Themed issues
This Journal continues to publish a mix of original
research and review articles on all aspects of drug action
in man in categories identified by the authors, sometimes grouped into themed issues or sections. The first
themed section of 2013 was on nutraceuticals a term
that has caused some dismay among purists, representing as it does a field awash with marketing hype for products that are chemically incompletely defined and with
little, and very often no, scientific basis. Nevertheless
there is an emerging body of evidence to support the
therapeutic use of several such products and we recall
that the founding fathers of pharmacology were prepared to use incompletely characterized extracts of
spleen, prostate or fungus (e.g. ergot) to probe physiological function and to advance therapeutics. We
explored this young branch of our discipline in this collection of articles. We wished in particular to highlight
that an evidence-based approach to such products,
underpinned by good science, can make important contributions to public health, in addition to, not instead of,
pharmaceutical therapies see for example [1].
August saw an issue on biologics. The history of these
dates back at least 200 years and includes the development of the smallpox vaccine following on from Edward
Jenners work at St Georges Hospital in London, as well as
the use of blood transfusion. Biologics have very much
come to the fore in recent years and such therapies have
mushroomed (currently approximately 30% of new drugs
licensed per annum in Europe and the USA). We
overviewed the current status of biologics in a number of
disease areas (and also an article on a potential nontherapeutic application of the future: gene doping in sport
[2]), and touched on how the conduct of early phase trials
has evolved since the supervised simultaneous megaoverdose of a whole cohort of subjects with TGN1412,
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which was so brilliantly rescued by the Northwick Park

Hospital intensivists [3].
September saw the publication of a themed section on
cancer therapeutics. Recent years have seen a revolution in
our understanding of the molecular basis of many cancers
and this has resulted in the emergence of many novel
therapeutic targets. The anti-cancer armamentarium now
includes a number of drugs targeting kinase and other
signalling pathways, and more recently Chk inhibitors and
pro-apoptotic drugs. (Chk1 is a kinase that phosphorylates
a phosphatase enzyme which plays a critical role in cell
cycle control). These were reviewed and other articles
addressed the potential of genetics in predicting anticancer drug toxicity or treatment outcome, the apparent
protective effect of bisphosphonate therapy against colon
cancer, and the pro-hypertensive effect of the vascular
endothelial growth factor receptor tyrosine kinase inhibitor, axitinib. These articles highlight the ever increasing
ways of treating cancers and the unexpected new issues
that need to be considered by prescribers using these
drugs.
Finally, in October came a themed issue on novel therapeutic approaches to chronic kidney disease. Here we
examined a number of strategies that offer the prospect of
renal protection over and above standard therapy. Some
involve drugs currently licensed for other indications but
which may additionally confer renoprotection: endothelin
receptor antagonists (licensed for pulmonary arterial
hypertension), direct renin inhibitors (licensed for systemic
hypertension), the vasopressin antagonist tolvaptan
(licensed for hyponatraemia secondary to syndrome of
inappropriate anti-diuretic hormone secretion), this latter
specifically in the context of autosomal dominant polycystic kidney disease. Others represent altogether novel
therapeutic approaches, including Rho kinase inhibitors
[4], which show promise in diabetic kidney disease and
renal sympathetic denervation therapy.
2014 The British Pharmacological Society

Editors pick

Therapeutic matters
Dosing regimens need to be adjusted according to renal
function, so it is no surprise that clinical pharmacologists
have a keen interest in the comparative performance of
different formulae for estimating the glomerular filtration
rate (GFR). In a study of 16 older patients, Drenth-Van
Mareen and colleagues found that the CockcroftGault
equation based on ideal body weight is the most reliable
option [5]. However, caution is required since misclassification of chronic kidney disease potentially occurred in
up to one in four patients, even with the best performing
formula.
Errors in classification also occur when computerized
diagnostic codes (recorded by general practitioners) are
used to identify suicide and self-harm. Thomas and colleagues found that only just over a quarter of suicides
(identified from the gold standard national statistics database) were correctly identified using diagnostic codes in
the Clinical Practice Research Database, and that the
general practice codes also grossly underestimated the
incidence of self-harm [6]. Data linkage of general practice
records with government mortality databases will help to
address these gaps, which are particularly important for
pharmaco-epidemiological research into drug-related selfharm and suicide.
Research may also shake some therapeutic preconceptions. Melatonin, a non-prescription drug widely used for
sleep problems, was investigated in patients receiving
chronic haemodialysis (a procedure that can interfere with
sleep) by Rusccher and colleagues [7]. These authors found
some benefit from 3 month melatonin treatment, but no
demonstrable improvement in quality of life or sleep with
use up to 12 months. The case for long term use of
melatonin remains unproven.

First in man (FIM) studies of new

chemical entities and biologics:
are we maximizing the
information obtained?
First in man (FIM) studies of novel chemical entities and
biologics are among the most challenging and exciting
aspects of translational research. During 2013 the Journal
received and published several such studies. These reports
detail escalating single and multiple dose regimens,
providing what is likely to be the richest dataset of the
drug concentration profile and its pharmacodynamic
(pharmacotoxic) effects.
Baluom and colleagues [8] report early phase clinical
development studies of fostamatinib (a methylenephosphate prodrug) which is converted by intestinal
phosphatases to its active metabolite R940406 (R406), an
ATP mimetic and inhibitor (Ki 30 nM) of spleen tyrosine
kinase (SYK). SYK antagonism blocks immunoglobulin

(Ig)E and IgG-mediated activation of Fc receptor and

B-cell receptor signalling, with potential as a novel antiinflammatory agent [9]. Disappointingly, phase III studies
of fostamatanib as second line disease modifying therapy
in rheumatoid arthritis were negative, but SYK inhibition
has other potential applications.
Sirtuins are a class of deacetylases that play an
important role in numerous physiological pathways.
There are seven mammalian sirtuin isoforms, the best
characterized being sirtuin1 (SIRT1). A comprehensive
understanding of the biological role of SIRT1 has yet to be
determined, but the pharmacological potential of SIRT1
modulation is apparent since it has more than 70 known
sub-cellular protein substrates including p53, PGC1a,
FOXO, ACS1 and p65-NFkB, as well as a host of other
nuclear and cytosolic proteins with significant roles
in disease. Hoffman and colleagues [10] describe a FIM
investigation of SRT2104, a first in class, highly selective
small molecule activator of the NAD+-dependent
deacetylase, SIRT1. These investigators describe a FIM
single and repeat dose escalation study and a crossover
study that determined the effect of gender, prandial
status and formulation on SRT2104 pharmacokinetics. A
radioactive microtracer study is also described which
defined the systemic clearance, bioavailability and preliminary human metabolism of SRT2104. The findings
of these studies were encouraging and a validated
biomarker for SIRT1 activation that could be related to
SRT2104 pharmacokinetics is clearly needed.
Interleukin-13 (IL-13) is a Th2 pro-inflammatory
cytokine implicated in the pathophysiology of asthma.
Hodsman and colleagues [11] report FIM studies of a
recombinant humanized anti-IL-13 IgG1monoclonal antibody (GSK679586), a potential treatment for asthma. In the
asthmatics exhaled nitric oxide (FeNO), a marker of pulmonary inflammation, decreased relative to baseline values at
2 and 8 weeks after a second GSK679586 infusion and this
decrease was most pronounced at the higher GSK679586
doses.
Clinical pharmacologists should promote the need to
discover as much as possible about a therapeutic agent
from FIM studies and whenever possible develop a mechanistic PKPD model. This approach is elegantly described
by Ali and colleagues [12] in the case of GSK1482160, a
P2X7 allosteric receptor modulator.

Old drugs new tricks

While we are keen to publish the latest in clinical pharmacology, including FIM studies (see above), studies of drugs
that have been on the market for decades can reveal new
insights of potential therapeutic or functional importance.
Four 2013 publications highlight this old drugs new
tricks phenomenon, demonstrating the potential value of
good clinical pharmacology studies on old drugs that
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Editors pick

advance our knowledge of mechanisms of drug action and

how to optimize therapeutics.
The effect of grapefruit juice on oral drug exposure
highlighted a drug interaction that has major clinical
importance given the advisory warning stickers that are
placed on patients medicines. Other juices may also interact, in this case apple juice and drugs which are substrates
of the organic anion transporting polypeptide transporters OATP2B1 and 1A2 located on the apical membrane of
enterocytes [13]. Jeon and colleagues conducted a three
phase crossover study in 12 healthy Korean subjects given
50 mg atenolol as a single tablet on each occasion. Apple
juice (1200 ml) reduced the exposure to oral atenolol
by about 80% and 600 ml by about 50%. The SCLO2B1
c.1457C>T polymorphism had no influence on the
decrease in exposure, but systolic blood pressure was less
reduced by both apple juice doses. Although the precise
mechanism needs further investigation (altered OATP
function by pH, sugary water, substrate specificity), the
study highlights that apple juice can substantially affect
drug absorption and is perhaps best avoided when taking
specific oral medications.
Platinum-based chemotherapy produces several
severe adverse effects (nephrotoxicity, ototoxicity, neurotoxicity, haematological and gastrointestinal toxicities)
related to its mechanism of action. These limit its use in
cancer patients and consequently impact on patient
response and overall survival. The nucleotide excision
repair (NER) pathway is implicated in being the major
cellular defence mechanism against the efficacy and,
importantly, toxicity of these drugs. An upstream gene of
the pathway, elF3, is the largest subunit of eukaryotic
translation initiation factor 3, which is overexpressed in
many malignancies and its expression level is related to
platinum sensitivity. Two C > T mis-sense mutations
(Arg438Lys and Arg803Lys) have been identified in Han
Chinese people and although their functional effects
are unclear, they could be contributing to these platinum toxicities. In a study in 282 patients with non-small
cell lung carcinoma receiving cisplatin- or carboplatinbased chemotherapy, Xu and colleagues [14] investigated 22 SNPs in the elF3 gene using discovery and
validation patient sets. Severe ototoxicity was significantly related to T carriers with an odds ratio of 4.41
(95% CI 1.5, 12.9). The study highlighted the major
barriers/limitations when investigating the specific role
of germline genetic polymorphisms in chemotherapyinduced toxicity. These include co-administration of multiple chemotherapeutic drugs, dosage, multiple gene
pathways, phenotype quantification and the well recognized patient and environmental influences. Whether the
T allele of elF3 can be used as a predictive tool to identify those patients likely to have more toxicities to
platinum-based drugs will require much more investigation, but these types of candidate gene studies remain
useful pointers.
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Topical vs. oral administration of non-steroidal antiinflammatory drugs (NSAIDs) reduces the incidence and
severity of harmful effects but can be equally effective for
soft tissue pain and inflammation. Diclofenac is formulated
as a gel and is available without prescription, but concerns
remain regarding its COX2 inhibition. Hence, there is the
need to evaluate other NSAIDs. The tissue rather than
plasma pharmacokinetics of these topical formulations are
the optimal bioavailability assessment, but which tissue is
the subject of debate. Kai and colleagues conducted
a pharmacokinetic study in 16 patients scheduled to
undergo anterior cruciate ligament reconstruction [15].
Oral flurbiprofen (as tablets) was given to seven patients
twice daily and, flurbiprofen as a proprietary tape (immediate release transdermal delivery) on the medial and
lateral aspects of the knee at 14 and 2 h prior to surgery to
another nine patients, with blood, subcutaneous fat, sartorius muscle, tendon and peri-osteal tissue and drilledbone tissue collected for flurbiprofen concentration
assessment. Whereas the transdermal : oral concentration
ratio was about 6 for fat, tendon and muscle, it was only 2
for peri-osteal tissue and 0.5 for bone. Somewhat surprising was that the plasma concentration for the transdermal
formulation was 40% that of plasma. Although these
values were only at one time point, they indicate that a
substantial amount of the drug can diffuse into the blood
stream and that just sampling one tissue (for example the
tendon) may lead one to conclude erroneously that other
local tissues, such as the peri-osteum, will have the same
pharmacokinetic profile.
Allopurinol has stood the test of time (it is listed twice
in the WHO list of Essential Medicines), having been
discovered and investigated in the mid 1950s by Nobel
laureates Gertrude Elion and George Hitchings. It was
approved in 1966 for hyperuricaemia, but still holds some
secrets, including what factors determine the substantial
inter-individual variation in responsiveness to this drug.
Graham and colleagues [16] tackled this by examining
doseresponse relationships in patients with gout, using a
modelling approach with plasma urate as the response
metric. It is under-appreciated that for individuals there is
a plasma urate concentration beyond which the value
cannot be reduced further by allopurinol, the apparent
resistant plasma urate concentration. By collating data
from two patient cohorts (total 47 patients), these authors
developed an equation that relates dose, plasma urate
concentration before and during allopurinol treatment to
steady-state and ID50 (allopurinol dose to reduce the
inhibitable plasma urate concentration by 50%). The equation fitted the data with an r2 of 0.74. Somewhat surprisingly creatinine clearance did not improve the fit, but the
authors rightly argue that it should nonetheless be used to
determine the starting dose. They confirmed that a higher
baseline plasma urate requires a higher maintenance dose
and (less well appreciated) that not everyone needs the
usual fixed dose of 300 mg daily.

Editors pick

What do we publish and what

would we like to publish?
A clinical pharmacology journal serves many masters. The
editors receive papers of diverse categories and have to
balance the content of the journal. At the end of the year it
is possible to see what was chosen, first by the editorial
selection and subsequently by our peer reviewers.
If one describes clinical pharmacology as a translational specialty, dealing with methodology to investigate
and develop new and old medicines one would expect
that papers on translational drug development, PKPD
relationships and pharmacodynamics would top the list of
categories. Table 1 (based on figures till October 31 2013)
shows this is not the case. We deliberately publish many
reviews (this year about 25%) on wide-ranging subjects
and these allow the editors to choose, especially in the
commissioned reviews.
However, the other categories strongly reflect what we
receive and what passes peer review. The editors subsequently allocate priority but are still largely constrained by
the supply. The statistics in Table 1 show that our authors
still work in the traditional area of how humans handle the
medicine (commonly named pharmacokinetics, PK) and
submit this work to us. We hope that as time passes they
will also submit progressively more of the work they carry
out to determine what the drug does to the subject (pharmacodynamics, PD) or more integrative aspects (PKPD
and physiologically based pharmacokinetics, PBPK) and
clinically relevant areas (clinical trials, mechanisms of drug
harms, important interactions and so on). There is little
doubt that the development of new medicines and the

Table 1
Distribution of articles by category in 2013 (1st Jan31st Oct)

Article category

Number

Percentage

Review
Pharmacokinetics (PK)

67
28

24.7
10.3

Letter
Clinical trials

26
23

9.6
8.5

Drug safety
Drug interactions

14
13

5.2
4.8

PKPD relationships
Pharmacoepidemiology

11
10

4.1
3.7

Supplement article
Pharmacodynamics (PD)

10
9

3.7
3.3

Pharmacogenetics
Methods in clinical pharmacology

8
7

3.0
2.6

Paediatric clinical pharmacology

Commentary

7
6

2.6
2.2

Systematic review
Meta-analysis

6
4

2.2
1.5

Therapeutics
Drugs in pregnancy and lactation

4
3

1.5
1.1

Translational research

1.1

evaluation of existing ones in increasingly complicated

diseases is only possible in a multidimensional and multidisciplinary approach in which all data are being used optimally. We hope that the experimental content of the
journal will in future reflect these trends more accurately,
and will actively encourage our authors to submit their
work in these areas.

REFERENCES
1 Lidder S, Webb AJ. Vascular effects of dietary nitrate (as
found in green leafy vegetables and beetroot) via the
nitrate-nitrite-nitric oxide pathway. Br J Clin Pharmacol
2013; 75: 67796.
2 Gould D. Gene doping: gene delivery for olympic victory.
Br J Clin Pharmacol 2013; 76: 2928.
3 Eastwood D, Bird C, Dilger P, Hockley J, Findlay L, Poole S,
Thorpe SJ, Wadhwa M, Thorpe R, Stebbings R. Severity of
the TGN1412 trial disaster cytokine storm correlated with
IL-2 release. Br J Clin Pharmacol 2013; 76: 299315.
4 Komers R. Rho kinase inhibition in diabetic kidney disease.
Br J Clin Pharmacol 2013; 76: 5519.
5 Drenth-van Maanen AC, Jansen PA, Proost JH, Egberts TC,
van Zuilen AD, van der Stap D, van Marum RJ. Renal
function assessment in older adults. Br J Clin Pharmacol
2013; 76: 61623.
6 Thomas KH, Davies N, Metcalfe C, Windmeijer F, Martin RM,
Gunnell D. Validation of suicide and self-harm records in the
Clinical Practice Research Datalink. Br J Clin Pharmacol 2013;
76: 14557.
7 Russcher M, Koch BC, Nagtegaal JE, van Ittersum FJ,
Pasker-de Jong PC, Hagen EC, van Dorp WT, Gabrels B,
Wildbergh TX, van der Westerlaken MM, Gaillard CA,
Ter Wee PM. Long term effects of melatonin on quality of
life and sleep in haemodialysis patients (Melody study): a
randomized controlled trial. Br J Clin Pharmacol 2013; 76:
66879.
8 Baluom M, Grossbard EB, Mant T, Lau DT. Pharmacokinetics
of fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, in
healthy human subjects following single and multiple oral
dosing in three phase I studies. Br J Clin Pharmacol 2013; 76:
7888.
9 Braselmann S, Taylor V, Zhao H, Wang S, Sylvain C, Baluom
M, Qu K, Herlaar E, Lau A, Young C, Wong BR, Lovell S, Sun T,
Park G, Argade A, Jurcevic S, Pine P, Singh R, Grossbard EB,
Payan DG, Masuda ES. R406, an orally available spleen
tyrosine kinase inhibitor blocks Fc receptor signaling and
reduces immune complex-mediated inflammation.
J Pharmacol Exp Ther 2006; 319: 9981008.
10 Hoffmann E, Wald J, Lavu S, Roberts J, Beaumont C, Haddad
J, Elliott P, Westphal C, Jacobson E. Pharmacokinetics and
tolerability of SRT2104, a first-in-class small molecule
activator of SIRT1, after single and repeated oral
administration in man. Br J Clin Pharmacol 2013; 75: 18696.
Br J Clin Pharmacol

/ 77:2

231

Editors pick

11 Hodsman P, Ashman C, Cahn A, De Boever E, Locantore N,

Serone A, Pouliquen I. A phase 1, randomized,
placebo-controlled, dose-escalation study of an anti-IL-13
monoclonal antibody in healthy subjects and mild
asthmatics. Br J Clin Pharmacol 2013; 75: 11828.

14 Xu X, Han L, Duan L, Zhao Y, Yang H, Zhou B, Ma R, Yuan R,

Zhou H, Liu Z. Association between elF3 polymorphism
and severe toxicity caused by platinum-based
chemotherapy in non-small cell lung cancer patients. Br J
Clin Pharmacol 2013; 75: 51623.

12 Ali Z, Laurijssens B, Ostenfeld T, McHugh S, Stylianou A,

Scott-Stevens P, Hosking L, Dewit O, Richardson JC, Chen C.
Pharmacokinetic and pharmacodynamic profiling of a P2X7
receptor allosteric modulator GSK1482160 in healthy human
subjects. Br J Clin Pharmacol 2013; 75: 197207.

15 Kai S, Kondo E, Kawaguchi Y, Kitamura N, Yasuda K.

Flurbiprofen concentration in soft tissues is higher after
topical application than after oral administration. Br J Clin
Pharmacol 2013; 75: 799804.

13 Jeon H, Jang I-J, Lee SH, Ohashi K, Kotegawa T, Ieiri I, Cho

J-Y, Yoon SH, Shin S-G, Yu K-S, Lim KS. Apple juice greatly
reduces systemic exposure to atenolol. Br J Clin Pharmacol
2013; 75: 1729.

232

/ 77:2

Br J Clin Pharmacol

16 Graham GG, Kannangara DRW, Stocker SL, Portek I, Pile KD,

Indraratna PL, Datta I, Williams KM, Day RO. Understanding
the doseresponse relationship of allopurinol: predicting the
optimal dosage. Br J Clin Pharmacol 2013; 76: 9328.