Editors’ pick

Editors’ pick 2013Albert Ferro,1 Yoon K. Loke,2 Lionel D. Lewis,3 Andrew Somogyi,4 Adam F. Cohen5 & James M. Ritter1

1Department of Clinical Pharmacology, School of Medicine (Cardiovascular Division) King’s 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 originalresearch and review articles on ‘all aspects of drug actionin man’ in categories identified by the authors, some-times grouped into themed issues or sections. The firstthemed section of 2013 was on ‘nutraceuticals’ – a termthat has caused some dismay among purists, represent-ing as it does a field awash with marketing hype for prod-ucts that are chemically incompletely defined and withlittle, and very often no, scientific basis. Neverthelessthere is an emerging body of evidence to support thetherapeutic use of several such products and we recallthat the founding fathers of pharmacology were pre-pared to use incompletely characterized extracts ofspleen, prostate or fungus (e.g. ergot) to probe physi-ological function and to advance therapeutics. Weexplored this young branch of our discipline in this col-lection of articles. We wished in particular to highlightthat an evidence-based approach to such products,underpinned by good science, can make important con-tributions to public health, in addition to, not instead of,pharmaceutical therapies – see for example [1].

August saw an issue on biologics. The history of thesedates back at least 200 years and includes the develop-ment of the smallpox vaccine following on from EdwardJenner’s work at St George’s Hospital in London, as well asthe use of blood transfusion. Biologics have very muchcome to the fore in recent years and such therapies havemushroomed (currently approximately 30% of new drugslicensed per annum in Europe and the USA). Weoverviewed the current status of biologics in a number ofdisease areas (and also an article on a potential non-therapeutic application of the future: gene doping in sport[2]), and touched on how the conduct of early phase trialshas evolved since the supervised simultaneous mega-overdose of a whole cohort of subjects with TGN1412,

which was so brilliantly rescued by the Northwick ParkHospital intensivists [3].

September saw the publication of a themed section oncancer therapeutics. Recent years have seen a revolution inour understanding of the molecular basis of many cancersand this has resulted in the emergence of many noveltherapeutic targets. The anti-cancer armamentarium nowincludes a number of drugs targeting kinase and othersignalling pathways, and more recently Chk inhibitors andpro-apoptotic drugs. (Chk1 is a kinase that phosphorylatesa phosphatase enzyme which plays a critical role in cellcycle control). These were reviewed and other articlesaddressed the potential of genetics in predicting anti-cancer drug toxicity or treatment outcome, the apparentprotective effect of bisphosphonate therapy against coloncancer, and the pro-hypertensive effect of the vascularendothelial growth factor receptor tyrosine kinase inhibi-tor, axitinib. These articles highlight the ever increasingways of treating cancers and the unexpected new issuesthat need to be considered by prescribers using thesedrugs.

Finally, in October came a themed issue on novel thera-peutic approaches to chronic kidney disease. Here weexamined a number of strategies that offer the prospect ofrenal protection over and above standard therapy. Someinvolve drugs currently licensed for other indications butwhich may additionally confer renoprotection: endothelinreceptor antagonists (licensed for pulmonary arterialhypertension), direct renin inhibitors (licensed for systemichypertension), the vasopressin antagonist tolvaptan(licensed for hyponatraemia secondary to syndrome ofinappropriate anti-diuretic hormone secretion), this latterspecifically in the context of autosomal dominant polycys-tic kidney disease. Others represent altogether noveltherapeutic approaches, including Rho kinase inhibitors[4], which show promise in diabetic kidney disease andrenal sympathetic denervation therapy.

British Journal of ClinicalPharmacology

DOI:10.1111/bcp.12303

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Therapeutic matters

Dosing regimens need to be adjusted according to renalfunction, so it is no surprise that clinical pharmacologistshave a keen interest in the comparative performance ofdifferent formulae for estimating the glomerular filtrationrate (GFR). In a study of 16 older patients, Drenth-VanMareen and colleagues found that the Cockcroft–Gaultequation based on ideal body weight is the most reliableoption [5]. However, caution is required since misclas-sification of chronic kidney disease potentially occurred inup to one in four patients, even with the best performingformula.

Errors in classification also occur when computerizeddiagnostic codes (recorded by general practitioners) areused to identify suicide and self-harm. Thomas and col-leagues found that only just over a quarter of suicides(identified from the ‘gold standard’ national statistics data-base) were correctly identified using diagnostic codes inthe Clinical Practice Research Database, and that thegeneral practice codes also grossly underestimated theincidence of self-harm [6]. Data linkage of general practicerecords with government mortality databases will help toaddress these gaps, which are particularly important forpharmaco-epidemiological research into drug-related self-harm and suicide.

Research may also shake some therapeutic preconcep-tions. Melatonin, a non-prescription drug widely used forsleep problems, was investigated in patients receivingchronic haemodialysis (a procedure that can interfere withsleep) by Rusccher and colleagues [7]. These authors foundsome benefit from 3 month melatonin treatment, but nodemonstrable improvement in quality of life or sleep withuse up to 12 months. The case for long term use ofmelatonin remains unproven.

First in man (FIM) studies of newchemical entities and biologics:are we maximizing theinformation obtained?

First in man (FIM) studies of novel chemical entities andbiologics are among the most challenging and excitingaspects of translational research. During 2013 the Journalreceived and published several such studies. These reportsdetail escalating single and multiple dose regimens,providing what is likely to be the richest dataset of thedrug concentration profile and its pharmacodynamic(pharmacotoxic) effects.

Baluom and colleagues [8] report early phase clinicaldevelopment studies of fostamatinib (a methylene-phosphate prodrug) which is converted by intestinalphosphatases to its active metabolite R940406 (R406), anATP mimetic and inhibitor (Ki 30 nM) of spleen tyrosinekinase (SYK). SYK antagonism blocks immunoglobulin

(Ig)E and IgG-mediated activation of Fcγ receptor andB-cell receptor signalling, with potential as a novel anti-inflammatory agent [9]. Disappointingly, phase III studiesof fostamatanib as second line disease modifying therapyin rheumatoid arthritis were negative, but SYK inhibitionhas other potential applications.

Sirtuins are a class of deacetylases that play animportant role in numerous physiological pathways.There are seven mammalian sirtuin isoforms, the bestcharacterized being sirtuin1 (SIRT1). A comprehensiveunderstanding of the biological role of SIRT1 has yet to bedetermined, but the pharmacological potential of SIRT1modulation is apparent since it has more than 70 knownsub-cellular protein substrates including p53, PGC1a,FOXO, ACS1 and p65-NFkB, as well as a host of othernuclear and cytosolic proteins with significant rolesin disease. Hoffman and colleagues [10] describe a FIMinvestigation of SRT2104, a first in class, highly selectivesmall molecule activator of the NAD+-dependentdeacetylase, SIRT1. These investigators describe a FIMsingle and repeat dose escalation study and a crossoverstudy that determined the effect of gender, prandialstatus and formulation on SRT2104 pharmacokinetics. Aradioactive microtracer study is also described whichdefined the systemic clearance, bioavailability and pre-liminary human metabolism of SRT2104. The findingsof these studies were encouraging and a validatedbiomarker for SIRT1 activation that could be related toSRT2104 pharmacokinetics is clearly needed.

Interleukin-13 (IL-13) is a Th2 pro-inflammatorycytokine implicated in the pathophysiology of asthma.Hodsman and colleagues [11] report FIM studies of arecombinant humanized anti-IL-13 IgG1monoclonal anti-body (GSK679586), a potential treatment for asthma. In theasthmatics exhaled nitric oxide (FeNO), a marker of pulmo-nary inflammation, decreased relative to baseline values at2 and 8 weeks after a second GSK679586 infusion and thisdecrease was most pronounced at the higher GSK679586doses.

Clinical pharmacologists should promote the need todiscover as much as possible about a therapeutic agentfrom FIM studies and whenever possible develop a mecha-nistic PK–PD model. This approach is elegantly describedby Ali and colleagues [12] in the case of GSK1482160, aP2X7 allosteric receptor modulator.

Old drugs – new tricks

While we are keen to publish the latest in clinical pharma-cology, including FIM studies (see above), studies of drugsthat have been on the market for decades can reveal newinsights of potential therapeutic or functional importance.Four 2013 publications highlight this ‘old drugs – newtricks’ phenomenon, demonstrating the potential value ofgood clinical pharmacology studies on old drugs that

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advance our knowledge of mechanisms of drug action andhow to optimize therapeutics.

The effect of grapefruit juice on oral drug exposurehighlighted a drug interaction that has major clinicalimportance given the advisory warning stickers that areplaced on patients’ medicines. Other juices may also inter-act, in this case apple juice and drugs which are substratesof the organic anion transporting polypeptide transport-ers OATP2B1 and 1A2 located on the apical membrane ofenterocytes [13]. Jeon and colleagues conducted a threephase crossover study in 12 healthy Korean subjects given50 mg atenolol as a single tablet on each occasion. Applejuice (1200 ml) reduced the exposure to oral atenololby about 80% and 600 ml by about 50%. The SCLO2B1c.1457C>T polymorphism had no influence on thedecrease in exposure, but systolic blood pressure was lessreduced by both apple juice doses. Although the precisemechanism needs further investigation (altered OATPfunction by pH, sugary water, substrate specificity), thestudy highlights that apple juice can substantially affectdrug absorption and is perhaps best avoided when takingspecific oral medications.

Platinum-based chemotherapy produces severalsevere adverse effects (nephrotoxicity, ototoxicity, neuro-toxicity, haematological and gastrointestinal toxicities)related to its mechanism of action. These limit its use incancer patients and consequently impact on patientresponse and overall survival. The nucleotide excisionrepair (NER) pathway is implicated in being the majorcellular defence mechanism against the efficacy and,importantly, toxicity of these drugs. An upstream gene ofthe pathway, elF3α, is the largest subunit of eukaryotictranslation initiation factor 3, which is overexpressed inmany malignancies and its expression level is related toplatinum sensitivity. Two C > T mis-sense mutations(Arg438Lys and Arg803Lys) have been identified in HanChinese people and although their functional effectsare unclear, they could be contributing to these plati-num toxicities. In a study in 282 patients with non-smallcell lung carcinoma receiving cisplatin- or carboplatin-based chemotherapy, Xu and colleagues [14] investi-gated 22 SNPs in the elF3α gene using discovery andvalidation patient sets. Severe ototoxicity was signifi-cantly related to T carriers with an odds ratio of 4.41(95% CI 1.5, 12.9). The study highlighted the majorbarriers/limitations when investigating the specific roleof germline genetic polymorphisms in chemotherapy-induced toxicity. These include co-administration of mul-tiple chemotherapeutic drugs, dosage, multiple genepathways, phenotype quantification and the well recog-nized patient and environmental influences. Whether theT allele of elF3α can be used as a predictive tool to iden-tify those patients likely to have more toxicities toplatinum-based drugs will require much more investiga-tion, but these types of candidate gene studies remainuseful pointers.

Topical vs. oral administration of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the incidence andseverity of harmful effects but can be equally effective forsoft tissue pain and inflammation. Diclofenac is formulatedas a gel and is available without prescription, but concernsremain regarding its COX2 inhibition. Hence, there is theneed to evaluate other NSAIDs. The tissue rather thanplasma pharmacokinetics of these topical formulations arethe optimal ‘bioavailability’ assessment, but which tissue isthe subject of debate. Kai and colleagues conducteda pharmacokinetic study in 16 patients scheduled toundergo anterior cruciate ligament reconstruction [15].Oral flurbiprofen (as tablets) was given to seven patientstwice daily and, flurbiprofen as a proprietary tape (imme-diate release transdermal delivery) on the medial andlateral aspects of the knee at 14 and 2 h prior to surgery toanother nine patients, with blood, subcutaneous fat, sar-torius muscle, tendon and peri-osteal tissue and drilled-bone tissue collected for flurbiprofen concentrationassessment. Whereas the transdermal : oral concentrationratio was about 6 for fat, tendon and muscle, it was only 2for peri-osteal tissue and 0.5 for bone. Somewhat surpris-ing was that the plasma concentration for the transdermalformulation was 40% that of plasma. Although thesevalues were only at one time point, they indicate that asubstantial amount of the drug can diffuse into the bloodstream and that just sampling one tissue (for example thetendon) may lead one to conclude erroneously that otherlocal tissues, such as the peri-osteum, will have the samepharmacokinetic profile.

Allopurinol has stood the test of time (it is listed twicein the WHO list of Essential Medicines), having beendiscovered and investigated in the mid 1950s by Nobellaureates Gertrude Elion and George Hitchings. It wasapproved in 1966 for hyperuricaemia, but still holds somesecrets, including what factors determine the substantialinter-individual variation in responsiveness to this drug.Graham and colleagues [16] tackled this by examiningdose–response relationships in patients with gout, using amodelling approach with plasma urate as the responsemetric. It is under-appreciated that for individuals there isa plasma urate concentration beyond which the valuecannot be reduced further by allopurinol, the ‘apparentresistant plasma urate concentration’. By collating datafrom two patient cohorts (total 47 patients), these authorsdeveloped an equation that relates dose, plasma urateconcentration before and during allopurinol treatment tosteady-state and ID50 (allopurinol dose to reduce theinhibitable plasma urate concentration by 50%). The equa-tion fitted the data with an r2 of 0.74. Somewhat surpris-ingly creatinine clearance did not improve the fit, but theauthors rightly argue that it should nonetheless be used todetermine the starting dose. They confirmed that a higherbaseline plasma urate requires a higher maintenance doseand (less well appreciated) that not everyone needs the‘usual’ fixed dose of 300 mg daily.

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What do we publish and whatwould we like to publish?

A clinical pharmacology journal serves many masters. Theeditors receive papers of diverse categories and have tobalance the content of the journal. At the end of the year itis possible to see what was chosen, first by the editorialselection and subsequently by our peer reviewers.

If one describes clinical pharmacology as a transla-tional specialty, dealing with methodology to investigateand develop new and old medicines one would expectthat papers on translational drug development, PK–PDrelationships and pharmacodynamics would top the list ofcategories. Table 1 (based on figures till October 31 2013)shows this is not the case. We deliberately publish manyreviews (this year about 25%) on wide-ranging subjectsand these allow the editors to choose, especially in thecommissioned reviews.

However, the other categories strongly reflect what wereceive and what passes peer review. The editors subse-quently allocate priority but are still largely constrained bythe supply. The statistics in Table 1 show that our authorsstill work in the traditional area of how humans handle themedicine (commonly named pharmacokinetics, PK) andsubmit this work to us. We hope that as time passes theywill also submit progressively more of the work they carryout to determine what the drug does to the subject (phar-macodynamics, PD) or more integrative aspects (PK–PDand physiologically based pharmacokinetics, PBPK) andclinically relevant areas (clinical trials, mechanisms of drugharms, important interactions and so on). There is littledoubt that the development of new medicines and the

evaluation of existing ones in increasingly complicateddiseases is only possible in a multidimensional and multi-disciplinary approach in which all data are being used opti-mally. We hope that the experimental content of thejournal will in future reflect these trends more accurately,and will actively encourage our authors to submit theirwork in these areas.

REFERENCES

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2 Gould D. Gene doping: gene delivery for olympic victory.Br J Clin Pharmacol 2013; 76: 292–8.

3 Eastwood D, Bird C, Dilger P, Hockley J, Findlay L, Poole S,Thorpe SJ, Wadhwa M, Thorpe R, Stebbings R. Severity ofthe TGN1412 trial disaster cytokine storm correlated withIL-2 release. Br J Clin Pharmacol 2013; 76: 299–315.

4 Komers R. Rho kinase inhibition in diabetic kidney disease.Br J Clin Pharmacol 2013; 76: 551–9.

5 Drenth-van Maanen AC, Jansen PA, Proost JH, Egberts TC,van Zuilen AD, van der Stap D, van Marum RJ. Renalfunction assessment in older adults. Br J Clin Pharmacol2013; 76: 616–23.

6 Thomas KH, Davies N, Metcalfe C, Windmeijer F, Martin RM,Gunnell D. Validation of suicide and self-harm records in theClinical Practice Research Datalink. Br J Clin Pharmacol 2013;76: 145–57.

7 Russcher M, Koch BC, Nagtegaal JE, van Ittersum FJ,Pasker-de Jong PC, Hagen EC, van Dorp WT, Gabreëls B,Wildbergh TX, van der Westerlaken MM, Gaillard CA,Ter Wee PM. Long term effects of melatonin on quality oflife and sleep in haemodialysis patients (Melody study): arandomized controlled trial. Br J Clin Pharmacol 2013; 76:668–79.

8 Baluom M, Grossbard EB, Mant T, Lau DT. Pharmacokineticsof fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, inhealthy human subjects following single and multiple oraldosing in three phase I studies. Br J Clin Pharmacol 2013; 76:78–88.

9 Braselmann S, Taylor V, Zhao H, Wang S, Sylvain C, BaluomM, 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 spleentyrosine kinase inhibitor blocks Fc receptor signaling andreduces immune complex-mediated inflammation.J Pharmacol Exp Ther 2006; 319: 998–1008.

10 Hoffmann E, Wald J, Lavu S, Roberts J, Beaumont C, HaddadJ, Elliott P, Westphal C, Jacobson E. Pharmacokinetics andtolerability of SRT2104, a first-in-class small moleculeactivator of SIRT1, after single and repeated oraladministration in man. Br J Clin Pharmacol 2013; 75: 186–96.

Table 1Distribution of articles by category in 2013 (1st Jan–31st Oct)

Article category Number Percentage

Review 67 24.7Pharmacokinetics (PK) 28 10.3

Letter 26 9.6Clinical trials 23 8.5

Drug safety 14 5.2Drug interactions 13 4.8

PK–PD relationships 11 4.1Pharmacoepidemiology 10 3.7

Supplement article 10 3.7Pharmacodynamics (PD) 9 3.3

Pharmacogenetics 8 3.0Methods in clinical pharmacology 7 2.6

Paediatric clinical pharmacology 7 2.6Commentary 6 2.2

Systematic review 6 2.2Meta-analysis 4 1.5

Therapeutics 4 1.5Drugs in pregnancy and lactation 3 1.1

Translational research 3 1.1

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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-13monoclonal antibody in healthy subjects and mildasthmatics. Br J Clin Pharmacol 2013; 75: 118–28.

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 P2X7receptor allosteric modulator GSK1482160 in healthy humansubjects. Br J Clin Pharmacol 2013; 75: 197–207.

13 Jeon H, Jang I-J, Lee SH, Ohashi K, Kotegawa T, Ieiri I, ChoJ-Y, Yoon SH, Shin S-G, Yu K-S, Lim KS. Apple juice greatlyreduces systemic exposure to atenolol. Br J Clin Pharmacol2013; 75: 172–9.

14 Xu X, Han L, Duan L, Zhao Y, Yang H, Zhou B, Ma R, Yuan R,Zhou H, Liu Z. Association between elF3α polymorphismand severe toxicity caused by platinum-basedchemotherapy in non-small cell lung cancer patients. Br JClin Pharmacol 2013; 75: 516–23.

15 Kai S, Kondo E, Kawaguchi Y, Kitamura N, Yasuda K.Flurbiprofen concentration in soft tissues is higher aftertopical application than after oral administration. Br J ClinPharmacol 2013; 75: 799–804.

16 Graham GG, Kannangara DRW, Stocker SL, Portek I, Pile KD,Indraratna PL, Datta I, Williams KM, Day RO. Understandingthe dose–response relationship of allopurinol: predicting theoptimal dosage. Br J Clin Pharmacol 2013; 76: 932–8.

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