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Themed issues

  1. Top of page
  2. Themed issues
  3. Therapeutic matters
  4. First in man (FIM) studies of new chemical entities and biologics: are we maximizing the information obtained?
  5. Old drugs – new tricks
  6. What do we publish and what would we like to publish?
  7. References

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 Jenner's work at St George's 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 non-therapeutic 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 mega-overdose of a whole cohort of subjects with TGN1412, 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 anti-cancer 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.

Therapeutic matters

  1. Top of page
  2. Themed issues
  3. Therapeutic matters
  4. First in man (FIM) studies of new chemical entities and biologics: are we maximizing the information obtained?
  5. Old drugs – new tricks
  6. What do we publish and what would we like to publish?
  7. References

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 Cockcroft–Gault 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 self-harm 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?

  1. Top of page
  2. Themed issues
  3. Therapeutic matters
  4. First in man (FIM) studies of new chemical entities and biologics: are we maximizing the information obtained?
  5. Old drugs – new tricks
  6. What do we publish and what would we like to publish?
  7. References

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 methylene-phosphate 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 Fcγ receptor and B-cell receptor signalling, with potential as a novel anti-inflammatory 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 PK–PD 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

  1. Top of page
  2. Themed issues
  3. Therapeutic matters
  4. First in man (FIM) studies of new chemical entities and biologics: are we maximizing the information obtained?
  5. Old drugs – new tricks
  6. What do we publish and what would we like to publish?
  7. References

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 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, elF3α, 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 carboplatin-based chemotherapy, Xu and colleagues [14] investigated 22 SNPs in the elF3α 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 chemotherapy-induced 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 elF3α 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.

Topical vs. oral administration of non-steroidal anti-inflammatory 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 drilled-bone 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 dose–response 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.

What do we publish and what would we like to publish?

  1. Top of page
  2. Themed issues
  3. Therapeutic matters
  4. First in man (FIM) studies of new chemical entities and biologics: are we maximizing the information obtained?
  5. Old drugs – new tricks
  6. What do we publish and what would we like to publish?
  7. References

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, PK–PD 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.

Table 1. Distribution of articles by category in 2013 (1st Jan–31st Oct)
Article categoryNumberPercentage
Review6724.7
Pharmacokinetics (PK)2810.3
Letter269.6
Clinical trials238.5
Drug safety145.2
Drug interactions134.8
PK–PD relationships114.1
Pharmacoepidemiology103.7
Supplement article103.7
Pharmacodynamics (PD)93.3
Pharmacogenetics83.0
Methods in clinical pharmacology72.6
Paediatric clinical pharmacology72.6
Commentary62.2
Systematic review62.2
Meta-analysis41.5
Therapeutics41.5
Drugs in pregnancy and lactation31.1
Translational research31.1

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 (PK–PD 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 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. Top of page
  2. Themed issues
  3. Therapeutic matters
  4. First in man (FIM) studies of new chemical entities and biologics: are we maximizing the information obtained?
  5. Old drugs – new tricks
  6. What do we publish and what would we like to publish?
  7. 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: 677696.
  • 2
    Gould D. Gene doping: gene delivery for olympic victory. Br J Clin Pharmacol 2013; 76: 292298.
  • 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: 551559.
  • 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: 616623.
  • 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: 145157.
  • 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 of life and sleep in haemodialysis patients (Melody study): a randomized controlled trial. Br J Clin Pharmacol 2013; 76: 668679.
  • 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: 186196.
  • 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: 118128.
  • 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.
  • 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: 172179.
  • 14
    Xu X, Han L, Duan L, Zhao Y, Yang H, Zhou B, Ma R, Yuan R, Zhou H, Liu Z. Association between elF3α polymorphism and severe toxicity caused by platinum-based chemotherapy in non-small cell lung cancer patients. Br J Clin Pharmacol 2013; 75: 516523.
  • 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.
  • 16
    Graham GG, Kannangara DRW, Stocker SL, Portek I, Pile KD, Indraratna PL, Datta I, Williams KM, Day RO. Understanding the dose–response relationship of allopurinol: predicting the optimal dosage. Br J Clin Pharmacol 2013; 76: 932938.