British Journal of Clinical Pharmacology
DOI:10.1111/bcp.12587
Editors’ pick
Editors’ pick 2014 Yoon K. Loke,1* Andrew A. Somogyi,2 Albert Ferro3 & James M. Ritter3 1
2
School of Medicine, University of East Anglia, Norwich, UK, Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, 3 Adelaide, Australia Department of Clinical Pharmacology, School of Medicine (Cardiovascular Division) King’s College London, London, UK
Prescribing matters Health care professionals have their own specific areas of expertise, which is why hospitals and primary care centres rely on multi-disciplinary teams to look after patients. Since pharmacists are expert in drugs and their utilization, one could anticipate that they would contribute especially to prescribing policy and indeed the recent agenda on medicines optimization in the UK and elsewhere has been driven largely by pharmacists rather than medical prescribers. Are pharmacists also well-placed to contribute as individual prescribers? Prescribing requires more than factual knowledge about drugs, notably a knowledge of the science of medicine and the priorities of individual patients. A prescribing task may require the prescriber to weigh specific strands from a sometimes confusing network of inputs, e.g. listening to a patient, reviewing physical findings and laboratory results, considering the likely diagnosis and co-morbidities before recommending a treatment option that may (or may not - stopping a chronic medication is itself a prescribing task) include prescribing a drug. Pharmacy and medical students might consequently be expected to perform differently in pharmacology and prescribing assessments. Keijser and colleagues investigated this and found that in comparison with medical students, University of Utrecht pharmacy students had better knowledge of basic pharmacology, but not of the application of such knowledge [1]. Medical students were better at writing prescriptions. Key messages are that theoretical knowledge is no substitute for experience, and that prescribing competency (as other clinical skills) needs to be maintained through regular practice. A separate issue is the scope of prescribing. Pharmacist prescribing skills have proved particularly valuable in focused contexts such as anticoagulant prescribing, for example and also, at the other extreme of the ‘generalist-specialist’ spectrum, in the context of advice to patients with self-diagnosed minor ailments seeking over the counter remedies. 354
/
354–356
/
79:3
/
Br J Clin Pharmacol
An aim of medicines optimization is to reduce unnecessary polypharmacy. Patients who take more drugs are more likely to have adverse events and to be hospitalized. Is it polypharmacy per se that is the problem, or could it be that patients treated with multiple drugs are so managed because they are afflicted by multiple pathologies, especially ones that are serious or difficult to treat? Payne and colleagues [2] confirm the association between polypharmacy and unplanned hospitalizations, but also demonstrate that the association between polypharmacy and hospitalization is less marked in those with multiple long term conditions (perhaps indicative of some beneficial impact from ‘appropriate’ polypharmacy). In contrast, use of multiple medications in those with relatively few medical conditions seemed to carry the greatest increased risk of unplanned hospitalization. So it is unwise to use polypharmacy per se as an indicator of prescribing quality, ignoring the potential of disease severity or treatmentresistant pathology as drivers.
Old drugs and new: still much to understand The Journal encourages the submission of manuscripts reflecting rigorous, scientifically-based studies that are hypothesis testing, but sometimes we need to assess whether therapeutic drug interventions are appropriate and that the harm to benefit balance is leaning towards more benefit and less harm. Sometimes we also need to assess whether we are using the most appropriate biomarker. Three publications in the Journal in 2014 highlight these aspects of clinical pharmacology, beginning with the effect of shiitake mushroom consumption on gabapentin pharmacokinetics, followed by the usage, costs and harms of opioid prescribing in Australia and finally, on a suitable biomarker for dabigatran. Gabapentin is one of the few drugs approved for neuropathic pain. It © 2015 The British Pharmacological Society
Editors’ pick
has highly variable pharmacokinetics, somewhat surprisingly so, as it has negligible plasma binding and its elimination is almost entirely renal with a small component of tubular secretion via the transporter OCTN1. Toh and colleagues [3] had previously shown that shiitake mushrooms (native to much of East Asia and popular in UK supermarkets) contain ergothioneine which stimulates gabapentin transport in vitro via OCTN1, raising the possibility of a food–drug pharmacokinetic interaction. To assess this possibility subjects were studied on two occasions: control (no mushrooms) and intervention (250 g of mushrooms three times a day) with a 600 mg oral dose of gabapentin on both occasions. The content of ergothioneine in the mushrooms was quantified, as was baseline ergothioneine plasma concentration. The mushroom intervention more than doubled plasma ergothioneine concentration and the renal clearance of gabapentin increased by 19%, but gabapentin AUC was similar during each 48 h period. The gastrointestinal absorption of gabapentin is by the saturable uptake PEPT1 transporter and as Cmax is decreased by mushrooms, two opposing mechanisms (decreased absorption by PEPT1 inhibition and increased renal clearance via OCTN1) might explain the lack of effect on AUC. Although the observed changes were modest, they do suggest that dietary factors such as mushrooms may affect the pharmacokinetics of some drugs. The Journal is receptive to such scientifically based, well designed, food–drug interaction studies. The rise in opioid use for chronic non-malignant pain has concerned public health authorities, especially in the USA where there is estimated to be one death every 40 min due to opioid misuse. Pain specialists and clinical pharmacologists have highlighted the modest evidence for efficacy but clear evidence for adverse effects and illegal diversion. Other Western countries are not immune. In a comprehensive analysis of opioid prescribing, harm and costs, Blanch and colleagues [4] reviewed prescribing data from the Australian national subsidized reimbursement medicine scheme. Australia has a staggering 241 different opioid formulations available from 14 opioids. Between 1998 and 2012, there was a 15-fold increase to 7.5 million prescriptions each year (equating to a notional one prescription for every three residents in 2012!), with oxycodone the major contributor at 3 million, such that the equivalent of one in seven people per year are prescribed oxycodone. Another striking finding is that buprenorphine transdermal patch use rose from zero in 2006 to 1.2 million prescriptions in 2012. The subsidization costs rose from $8.5 M (£4.7 M) in 1998 to $270 M (£148 M) in 2012, again with oxycodone accounting for 38% of the total. What about harms? In 1998, heroin accounted for two thirds of opioid-related hospitalizations, the remaining third being attributed to ‘other’ opioids. By 2012, although the total had not changed appreciably, the two had swapped (65% other
opioids and 30% heroin). The number of accidental deaths due to pharmaceutical opioids and other illicit drugs increased from 150 to 267 with the rate of accidental poisoning increasing from 0.78 to 1.19 deaths/100,000 population. The authors concluded ‘The striking increase in opioid use and related harms in Australia is consistent with trends observed in other jurisdictions. Further, there is no evidence to suggest that these increases are plateauing. This information could in turn be communicated to prescribers to guide interventions aimed at preventing opioid dependence and consequent harms’. One could also add that we need better documentation of opioid efficacy in this setting and that dose titration needs to be better managed since opioid-induced hyperalgesia might be a major contributor to inappropriate prescribing and suboptimal efficacy. The thrombin inhibitor dabigatran is a challenging drug, with low therapeutic index, no routine laboratory monitoring (as yet) available to help optimize risk– benefit and no antidote in case of overdose. Its bioavailability is low and variable and renal function impacts on dosage. Unsurprisingly, the ‘one dose-fits all’ approach is being seriously questioned. In the past 12 months there have been over 500 publications in PubMed involving dabigatran PK and/or PD, especially in healthy volunteers. In contrast, Chin and colleagues [5] tested several coagulation assays in a ‘real-world’ setting, comparing the results with dabigatran plasma concentrations measured by LC-MS-MS. In 52 atrial fibrillation patients aged from 38 to 94 years and taking dabigatran either 110 or 150 mg twice daily, plasma dabigatran ranged from 9 to 408 μg l–1. Plasma dabigatran concentrations contributed only modestly to the variances in INR and aPTT (r2 values of < 0.54), while the standard thrombin time (TT) assay (Haemosil) was too sensitive for dabigatran concentrations, plateauing at the limiting time of 300 s above 100 μg l–1 (r2 = 0.70 over the linear portion). Incorporating the fibrinogen concentration into the TT analysis only explained 11% of the variability in TT values, whereas the nonconventional HTI αthrombin assay (a plasma-diluted thrombin time) was highly correlated (r2 = 0.95) with plasma dabigatran concentration. What, if any, test(s) to use in clinical practice depends on assay availability. The standard TT, although routinely available, is limited to the lower part of the dabigatran plasma concentration range. INR and aPTT may be normal in this lower range, and if prolonged thus suggest high dabigatran plasma concentration. Pharmacokinetic measurement in the form of therapeutic drug monitoring (TDM) while not currently routinely available could add value to a panel of pharmacodynamic clotting tests. A therapeutic means of correcting excessive anticoagulation in dabigatrantreated patients experiencing bleeding might stimulate the development of such approaches for clinical use. Br J Clin Pharmacol
/
79:3
/
355
Editors’ pick
These three studies highlight how much we still have to learn about how to use old and new drugs more effectively and safely.
Themed issues 2104 saw the publication of two themed issues, ‘addiction’ in February and ‘pharmacogenomics and pharmacoepigenetics’ in April. Substance addiction, which includes dependence on tobacco and alcohol as well as on illicit substances, presents a large societal burden from a number of viewpoints. Smoking and alcohol-related diseases account for the main portion of health care expenditure in the UK and other industrialized nations and dependence on other drugs, in particular opioids (see above), continues to be an important cause of much crime and misery. Addiction medicine has been relatively starved of financial support, both in terms of clinical service provision for addicts and of research funding, yet the potential for health and financial gains by tackling the problem effectively is huge. The themed issue gave an up-to-date overview of many important areas where pharmacotherapy has made a real difference to the treatment of addictions, and also gave some important insights into novel potential therapies. Genetics and genomics have been of intense research interest in the last decade, both from the point of view of understanding disease pathophysiology and of targeting therapies more effectively and on an individual basis, the business of pharmacogenetics and pharmacogenomics. While long-hailed as the harbingers of ‘personalized medicine’, this goal has proved far more elusive than originally anticipated, in large part because of the previously under-recognized complexity not only of the genetic determinants of treatment response but also of gene–environment interactions. It has also become clear that the epigenetic contribution to variations in gene expression, determined by factors such as DNA
356
/
79:3
/
Br J Clin Pharmacol
methylation, histone acetylation and microRNA interaction, add an extra dimension to the nuances of gene expression. The relevance of epigenetics to drug response and toxicity remains poorly understood and is fertile ground for future research. The themed issue outlined the state of the art in major clinical areas where pharmacogenetics plays a substantial role, and also examined areas where it is less well established and its possible future role remains to be established. It also looked at modern approaches to analyzing the vast amount of data that come from genetic/epigenetic/genomic studies, requiring advanced computational modelling to inform practical regulatory decision making.
REFERENCES 1 Keijsers CJ, Brouwers JR, de Wildt DJ, Custers EJ, Ten Cate OT, Hazen AC, Jansen PA. A comparison of medical and pharmacy students’ knowledge and skills of pharmacology and pharmacotherapy. Br J Clin Pharmacol 2014; 78: 781–8. doi:10.1111/bcp.12396. 2 Payne RA, Abel GA, Avery AJ, Mercer SW, Roland MO. Is polypharmacy always hazardous? A retrospective cohort analysis using linked electronic health records from primary and secondary care. Br J Clin Pharmacol 2014; 77: 1073–82. doi: 10.1111/bcp.12292. 3 Toh DSL, Limenta LMG, Yee JY, Wang L-Z, Goh B-C, Murray M, Lee EJD. Effect of mushroom diet on pharmacokinetics of gabapentin in healthy Chinese subjects. Br J Clin Pharmacol 2014; 78: 129–34. 4 Blanch B, Pearson S-A, Haber PS. An overview of the patterns of prescription opioid use, costs and related harms in Australia. Br J Clin Pharmacol 2014; 78: 1159–66. 5 Chin PKL, Patterson DM, Zhang M, Jensen BP, Wright DFB, Barclay ML, Begg EJ. Coagulation assays and plasma fibrinogen concentrations in real-world patients with atrial fibrillation treated with dabigatran. Br J Clin Pharmacol 2014; 78: 630–8.
Copyright of British Journal of Clinical Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
DOI:10.1111/bcp.12587
Editors’ pick
Editors’ pick 2014 Yoon K. Loke,1* Andrew A. Somogyi,2 Albert Ferro3 & James M. Ritter3 1
2
School of Medicine, University of East Anglia, Norwich, UK, Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, 3 Adelaide, Australia Department of Clinical Pharmacology, School of Medicine (Cardiovascular Division) King’s College London, London, UK
Prescribing matters Health care professionals have their own specific areas of expertise, which is why hospitals and primary care centres rely on multi-disciplinary teams to look after patients. Since pharmacists are expert in drugs and their utilization, one could anticipate that they would contribute especially to prescribing policy and indeed the recent agenda on medicines optimization in the UK and elsewhere has been driven largely by pharmacists rather than medical prescribers. Are pharmacists also well-placed to contribute as individual prescribers? Prescribing requires more than factual knowledge about drugs, notably a knowledge of the science of medicine and the priorities of individual patients. A prescribing task may require the prescriber to weigh specific strands from a sometimes confusing network of inputs, e.g. listening to a patient, reviewing physical findings and laboratory results, considering the likely diagnosis and co-morbidities before recommending a treatment option that may (or may not - stopping a chronic medication is itself a prescribing task) include prescribing a drug. Pharmacy and medical students might consequently be expected to perform differently in pharmacology and prescribing assessments. Keijser and colleagues investigated this and found that in comparison with medical students, University of Utrecht pharmacy students had better knowledge of basic pharmacology, but not of the application of such knowledge [1]. Medical students were better at writing prescriptions. Key messages are that theoretical knowledge is no substitute for experience, and that prescribing competency (as other clinical skills) needs to be maintained through regular practice. A separate issue is the scope of prescribing. Pharmacist prescribing skills have proved particularly valuable in focused contexts such as anticoagulant prescribing, for example and also, at the other extreme of the ‘generalist-specialist’ spectrum, in the context of advice to patients with self-diagnosed minor ailments seeking over the counter remedies. 354
/
354–356
/
79:3
/
Br J Clin Pharmacol
An aim of medicines optimization is to reduce unnecessary polypharmacy. Patients who take more drugs are more likely to have adverse events and to be hospitalized. Is it polypharmacy per se that is the problem, or could it be that patients treated with multiple drugs are so managed because they are afflicted by multiple pathologies, especially ones that are serious or difficult to treat? Payne and colleagues [2] confirm the association between polypharmacy and unplanned hospitalizations, but also demonstrate that the association between polypharmacy and hospitalization is less marked in those with multiple long term conditions (perhaps indicative of some beneficial impact from ‘appropriate’ polypharmacy). In contrast, use of multiple medications in those with relatively few medical conditions seemed to carry the greatest increased risk of unplanned hospitalization. So it is unwise to use polypharmacy per se as an indicator of prescribing quality, ignoring the potential of disease severity or treatmentresistant pathology as drivers.
Old drugs and new: still much to understand The Journal encourages the submission of manuscripts reflecting rigorous, scientifically-based studies that are hypothesis testing, but sometimes we need to assess whether therapeutic drug interventions are appropriate and that the harm to benefit balance is leaning towards more benefit and less harm. Sometimes we also need to assess whether we are using the most appropriate biomarker. Three publications in the Journal in 2014 highlight these aspects of clinical pharmacology, beginning with the effect of shiitake mushroom consumption on gabapentin pharmacokinetics, followed by the usage, costs and harms of opioid prescribing in Australia and finally, on a suitable biomarker for dabigatran. Gabapentin is one of the few drugs approved for neuropathic pain. It © 2015 The British Pharmacological Society
Editors’ pick
has highly variable pharmacokinetics, somewhat surprisingly so, as it has negligible plasma binding and its elimination is almost entirely renal with a small component of tubular secretion via the transporter OCTN1. Toh and colleagues [3] had previously shown that shiitake mushrooms (native to much of East Asia and popular in UK supermarkets) contain ergothioneine which stimulates gabapentin transport in vitro via OCTN1, raising the possibility of a food–drug pharmacokinetic interaction. To assess this possibility subjects were studied on two occasions: control (no mushrooms) and intervention (250 g of mushrooms three times a day) with a 600 mg oral dose of gabapentin on both occasions. The content of ergothioneine in the mushrooms was quantified, as was baseline ergothioneine plasma concentration. The mushroom intervention more than doubled plasma ergothioneine concentration and the renal clearance of gabapentin increased by 19%, but gabapentin AUC was similar during each 48 h period. The gastrointestinal absorption of gabapentin is by the saturable uptake PEPT1 transporter and as Cmax is decreased by mushrooms, two opposing mechanisms (decreased absorption by PEPT1 inhibition and increased renal clearance via OCTN1) might explain the lack of effect on AUC. Although the observed changes were modest, they do suggest that dietary factors such as mushrooms may affect the pharmacokinetics of some drugs. The Journal is receptive to such scientifically based, well designed, food–drug interaction studies. The rise in opioid use for chronic non-malignant pain has concerned public health authorities, especially in the USA where there is estimated to be one death every 40 min due to opioid misuse. Pain specialists and clinical pharmacologists have highlighted the modest evidence for efficacy but clear evidence for adverse effects and illegal diversion. Other Western countries are not immune. In a comprehensive analysis of opioid prescribing, harm and costs, Blanch and colleagues [4] reviewed prescribing data from the Australian national subsidized reimbursement medicine scheme. Australia has a staggering 241 different opioid formulations available from 14 opioids. Between 1998 and 2012, there was a 15-fold increase to 7.5 million prescriptions each year (equating to a notional one prescription for every three residents in 2012!), with oxycodone the major contributor at 3 million, such that the equivalent of one in seven people per year are prescribed oxycodone. Another striking finding is that buprenorphine transdermal patch use rose from zero in 2006 to 1.2 million prescriptions in 2012. The subsidization costs rose from $8.5 M (£4.7 M) in 1998 to $270 M (£148 M) in 2012, again with oxycodone accounting for 38% of the total. What about harms? In 1998, heroin accounted for two thirds of opioid-related hospitalizations, the remaining third being attributed to ‘other’ opioids. By 2012, although the total had not changed appreciably, the two had swapped (65% other
opioids and 30% heroin). The number of accidental deaths due to pharmaceutical opioids and other illicit drugs increased from 150 to 267 with the rate of accidental poisoning increasing from 0.78 to 1.19 deaths/100,000 population. The authors concluded ‘The striking increase in opioid use and related harms in Australia is consistent with trends observed in other jurisdictions. Further, there is no evidence to suggest that these increases are plateauing. This information could in turn be communicated to prescribers to guide interventions aimed at preventing opioid dependence and consequent harms’. One could also add that we need better documentation of opioid efficacy in this setting and that dose titration needs to be better managed since opioid-induced hyperalgesia might be a major contributor to inappropriate prescribing and suboptimal efficacy. The thrombin inhibitor dabigatran is a challenging drug, with low therapeutic index, no routine laboratory monitoring (as yet) available to help optimize risk– benefit and no antidote in case of overdose. Its bioavailability is low and variable and renal function impacts on dosage. Unsurprisingly, the ‘one dose-fits all’ approach is being seriously questioned. In the past 12 months there have been over 500 publications in PubMed involving dabigatran PK and/or PD, especially in healthy volunteers. In contrast, Chin and colleagues [5] tested several coagulation assays in a ‘real-world’ setting, comparing the results with dabigatran plasma concentrations measured by LC-MS-MS. In 52 atrial fibrillation patients aged from 38 to 94 years and taking dabigatran either 110 or 150 mg twice daily, plasma dabigatran ranged from 9 to 408 μg l–1. Plasma dabigatran concentrations contributed only modestly to the variances in INR and aPTT (r2 values of < 0.54), while the standard thrombin time (TT) assay (Haemosil) was too sensitive for dabigatran concentrations, plateauing at the limiting time of 300 s above 100 μg l–1 (r2 = 0.70 over the linear portion). Incorporating the fibrinogen concentration into the TT analysis only explained 11% of the variability in TT values, whereas the nonconventional HTI αthrombin assay (a plasma-diluted thrombin time) was highly correlated (r2 = 0.95) with plasma dabigatran concentration. What, if any, test(s) to use in clinical practice depends on assay availability. The standard TT, although routinely available, is limited to the lower part of the dabigatran plasma concentration range. INR and aPTT may be normal in this lower range, and if prolonged thus suggest high dabigatran plasma concentration. Pharmacokinetic measurement in the form of therapeutic drug monitoring (TDM) while not currently routinely available could add value to a panel of pharmacodynamic clotting tests. A therapeutic means of correcting excessive anticoagulation in dabigatrantreated patients experiencing bleeding might stimulate the development of such approaches for clinical use. Br J Clin Pharmacol
/
79:3
/
355
Editors’ pick
These three studies highlight how much we still have to learn about how to use old and new drugs more effectively and safely.
Themed issues 2104 saw the publication of two themed issues, ‘addiction’ in February and ‘pharmacogenomics and pharmacoepigenetics’ in April. Substance addiction, which includes dependence on tobacco and alcohol as well as on illicit substances, presents a large societal burden from a number of viewpoints. Smoking and alcohol-related diseases account for the main portion of health care expenditure in the UK and other industrialized nations and dependence on other drugs, in particular opioids (see above), continues to be an important cause of much crime and misery. Addiction medicine has been relatively starved of financial support, both in terms of clinical service provision for addicts and of research funding, yet the potential for health and financial gains by tackling the problem effectively is huge. The themed issue gave an up-to-date overview of many important areas where pharmacotherapy has made a real difference to the treatment of addictions, and also gave some important insights into novel potential therapies. Genetics and genomics have been of intense research interest in the last decade, both from the point of view of understanding disease pathophysiology and of targeting therapies more effectively and on an individual basis, the business of pharmacogenetics and pharmacogenomics. While long-hailed as the harbingers of ‘personalized medicine’, this goal has proved far more elusive than originally anticipated, in large part because of the previously under-recognized complexity not only of the genetic determinants of treatment response but also of gene–environment interactions. It has also become clear that the epigenetic contribution to variations in gene expression, determined by factors such as DNA
356
/
79:3
/
Br J Clin Pharmacol
methylation, histone acetylation and microRNA interaction, add an extra dimension to the nuances of gene expression. The relevance of epigenetics to drug response and toxicity remains poorly understood and is fertile ground for future research. The themed issue outlined the state of the art in major clinical areas where pharmacogenetics plays a substantial role, and also examined areas where it is less well established and its possible future role remains to be established. It also looked at modern approaches to analyzing the vast amount of data that come from genetic/epigenetic/genomic studies, requiring advanced computational modelling to inform practical regulatory decision making.
REFERENCES 1 Keijsers CJ, Brouwers JR, de Wildt DJ, Custers EJ, Ten Cate OT, Hazen AC, Jansen PA. A comparison of medical and pharmacy students’ knowledge and skills of pharmacology and pharmacotherapy. Br J Clin Pharmacol 2014; 78: 781–8. doi:10.1111/bcp.12396. 2 Payne RA, Abel GA, Avery AJ, Mercer SW, Roland MO. Is polypharmacy always hazardous? A retrospective cohort analysis using linked electronic health records from primary and secondary care. Br J Clin Pharmacol 2014; 77: 1073–82. doi: 10.1111/bcp.12292. 3 Toh DSL, Limenta LMG, Yee JY, Wang L-Z, Goh B-C, Murray M, Lee EJD. Effect of mushroom diet on pharmacokinetics of gabapentin in healthy Chinese subjects. Br J Clin Pharmacol 2014; 78: 129–34. 4 Blanch B, Pearson S-A, Haber PS. An overview of the patterns of prescription opioid use, costs and related harms in Australia. Br J Clin Pharmacol 2014; 78: 1159–66. 5 Chin PKL, Patterson DM, Zhang M, Jensen BP, Wright DFB, Barclay ML, Begg EJ. Coagulation assays and plasma fibrinogen concentrations in real-world patients with atrial fibrillation treated with dabigatran. Br J Clin Pharmacol 2014; 78: 630–8.
Copyright of British Journal of Clinical Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
