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in Japan. Clin. Pharmacol. Ther. 88, 487–491 (2010). Pharmaceuticals and Medical Devices Agency. New 5 years goals for FY2007–FY2011 [in Japanese] (2007). Pharmaceuticals and Medical Devices Agency. Annual Report FY2008 (2009). Uyama, Y., Shibata, T., Nagai, N., Hanaoka, H., Toyoshima, S. & Mori, K. Successful bridging strategy based on ICH E5 guideline for drugs approved in Japan. Clin. Pharmacol. Ther. 78, 102–113 (2005). Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour, and Welfare. Basic Principles on Global Clinical Trials. Notification no. 0928010 (2007). Ichimaru, K., Toyoshima, S. & Uyama, Y. Effective global drug development strategy for obtaining regulatory approval in Japan in the context of ethnicity-related drug response factors. Clin. Pharmacol. Ther. 87, 362–366 (2010). The International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005). Myrand, S.P. et al. Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and thirdgeneration Japanese populations: comparison with Korean, Chinese, and Caucasian populations. Clin. Pharmacol. Ther. 84, 347–361 (2008). Uzu, S. Japan’s Regulatory Initiative to Promote Global Clinical Development. 2010 China–Japan Symposium on Global Clinical Trials and Ethnic Factors, Beijing, China (2010). Pharmaceuticals and Medical Devices Agency. MHLW/PMDA participated in China–Japan– Korea Working Group on Clinical Trials, Director-General Meeting on Pharmaceutical Affairs, and Clinical Trial Symposium 2009, held in Beijing [press release] (22 December 2009). Goodsaid, F.M. et al. Voluntary exploratory data submissions to the US FDA and the EMA: experience and impact. Nat. Rev. Drug Discov. 9, 435–445 (2010). Dieterle, F. et al. Renal biomarker qualification submission: a dialog between the FDA-EMEA and Predictive Safety Testing Consortium. Nat. Biotechnol. 28, 455–462 (2010). Critical Path Institute. Critical Path Institute’s Predictive Safety Testing Consortium (PSTC) announces first-ever biomarker qualification decision by the Pharmaceuticals and Medical Devices Agency (PMDA) [press release] (21 June 2010). International Conference on Harmonisation. Draft Consensus Guideline. Genomic Biomarkers Related to Drug Response: Context, Structure, and Format of Qualification Submissions (E16) (10 June 2009).
Understanding Forgiveness: Minding and Mining the Gaps Between Pharmacokinetics and Therapeutics LG Osterberg1, J Urquhart2,3 and TF Blaschke1,3 The usual objective during long-term pharmacotherapy is, in large part, to maintain continuity of action of the prescribed drug(s). Continuity of action arises from the continuity of execution of a prescribed dosing regimen that is pharmacologically sound in dose quantity and interval between successive doses. Interruptions in dosing can interrupt drug action, but the consequences vary according to length of interruption, drug, drug formulation, length of the patient’s prior exposure to the drug, and the disease being treated. Interruptions in ambulatory patients’ dosing occur for varying lengths of time and with varying incidence. A comprehensive overview of these interruptions has been provided by Vrijens et al.,1 who reported electronically compiled dosing history data from 21 studies of 43 recently introduced, once-daily antihypertensive drugs in 4,783 patients during their first year of treatment. Only 5% of the patients maintained continuous daily dosing throughout the year. About 50% of the patients completely discontinued dosing during the year, and, on any given day, 8–10% of patients who were still engaged with the dosing regimen omitted that day’s dose. Many of those dose omissions involved single doses, but others were part of variously long runs of sequentially omitted doses. The incidence of dose omissions is highest when single doses are omitted, lower when two or three sequential doses are omitted, and lowest when more than three sequential doses are omitted (see Figure 3 in ref. 1). In individual patients, these findings translate into episodically occurring lapses in dosing of
varying lengths. The focus of this Commentary is on the quantitative dimensions of the way in which these lapses in dosing influence drug action. When dosing stops permanently, drug actions fade with a time course that is drug-, disease-, and formulation-specific. Exceptions are drugs that have rebound effects upon abrupt cessation, but these, too, eventually fade. The result is epitomized in the saying attributed to former US Surgeon General C. Everett Koop: “Drugs don’t work in patients who don’t take them.” But what are the consequences of episodic, temporary lapses in dosing? From the pharmacokinetic perspective, most drugs in today’s pharmacopoeia have plasma half-lives of 12 hours or less. When the dosing of these drugs is interrupted, their concentrations in plasma will, by the second day of lapsed dosing, have fallen far below the range prevailing during continuous dosing. In association therewith, some drugs’ actions will have fallen to unmeasurable levels or ceased altogether. Other drugs’ actions, however, will continue
1Department of Medicine, Stanford University School of Medicine, Stanford, California, USA; 2AARDEX
Group, Sion, Switzerland; 3Department of Bioengineering and Therapeutic Sciences and Center for Drug Development Sciences, University of California, San Francisco, San Francisco, California, USA. Correspondence: LG Osterberg (
[email protected]) doi:10.1038/clpt.2010.171
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perspec tives for periods of time substantially beyond the disappearance of drug from plasma. Examples are omeprazole, clopidogrel, and aspirin and warfarin. A pertinent characteristic of a drug or a drug formulation has been called “forgiveness.”2 In symbolic terms, forgiveness (F) is the difference between the medication’s postdose duration of beneficial action (D) and the prescribed dosing interval (I): F = D – I. In the examples cited above, relatively long forgiveness is due to a prolonged pharmacodynamic effect, such as permanent inactivation of a receptor or enzyme, the regeneration of which occurs slowly. Another method to increase forgiveness is to extend the plasma half-life. Irrespective of mechanistic bases by which gaps in dosing result in gaps in drug action, however, gaps in dosing may have substantial consequences for clinical outcomes. In characterizing the forgiveness of a medication, which should be part of its labeling, it seems most appropriate to define the 5th or lower percentile of forgiveness in the population of treated patients. Unlike the mean value of forgiveness, the 5th or lower percentile defines a duration of drug action on which the vast majority of patients can depend and on which evidence-based instructions can be provided for what to do if one or more doses are missed. The labels’ dosing instructions for oral steroidal contraceptives exemplify this approach (see, e.g., ref. 3), the aim of which is to minimize consequences of missed doses and define the best return to correct dosing. Forgiveness is dose-dependent, so one method of extending a pharmaceutical’s forgiveness is to increase the dose. This approach is obviously limited by dosedependent toxicity, as illustrated by the greater forgiveness but higher likelihood of intravascular thrombotic events of the original high-dose oral contraceptive (OC) “pill,” compared with the post-1970, low-dose OC pill.4 Extending the forgiveness of a drug should therefore not always be the ultimate goal, particularly when done through increasing drug half-life or strength in a high-risk drug already being dosed near its limits of toxicity. How does one predict the impact on drug action of episodically omitted doses? Quantitative answers to this question for some drugs have come from a study 458
design that, when judged ethical, calls for the controlled, blinded substitution of placebo for active drug, with frequent measurements of drug action to determine how long it takes, after the last-taken dose of active drug, for the drug’s actions to become unmeasurable. This study design, known as placebosubstitution-for-active (PSA), originated in the OC field after the 1970 reduction in the estrogen dose in OC pills. Five placebo substitution studies carried out during the 1980s determined the duration of the steroidal blockade of ovulation following a last-taken low-dose OC pill. The results stimulated first efforts to write evidencebased instructions for patients on what to do if they miss one or more pills,4 and serve as the pioneering example of “mining the gaps” between pharmacokinetics and therapeutics. In 1990, the PSA design was used to compare the postdose durations of action of two once-daily β-blockers, atenolol and betaxolol.5 This study showed that the widely used β-blocker atenolol maintained its hypotensive action for a mean value of only ~30 hours after the last-taken dose. In contrast, betaxolol maintained its hypotensive action for longer than 48 hours, which was the limit of data collection. The most important result was the brevity of atenolol’s antihypertensive action after a missed once-daily dose. A question not considered was the statistical distribution of individual patients’ duration of action of atenolol, so as to estimate, e.g., the 5th or lower percentile, which is perhaps less than 24 hours. A striking result of applying the PSA protocol arose from the work of Rosenbaum et al.,6 who carried out a 5- to 8-day placebo substitution study in patients who were being treated for depression with fluoxetine, sertraline, or paroxetine. The authors used several validated instruments, including the Hamilton-D Rating Scale for Depression, as a measure of drug action. In the patients previously treated with fluoxetine—the selective serotonin reuptake inhibitor with the longest halflife—the Hamilton-D scores remained unchanged before and after the period of placebo administration, whereas the group of patients previously treated with paroxetine had increases in their Hamilton-D
Rating Scales after the period of placebo administration. In addition, patients previously treated with paroxetine experienced more somatic and psychological symptoms of distress during the placebo substitution period than patients in the sertraline or fluoxetine groups. This surprisingly fast loss of paroxetine’s antidepressant action indicates that this agent is subject to interruptions in efficacy as a result of the more commonly occurring dose omissions. This observation may account for some of the controversy about the effectiveness and safety of paroxetine that could arise from its exceptionally slender forgiveness. In the treatment of HIV-AIDS patients, Vanhove et al.7 gave the first alert that gaps in antiretroviral (ARV) drug dosing are not infrequent and are followed by increases in viral load and emergence of drug-resistant virus. Vrijens et al.8 used ARV dosing histories of 35 HIV+ patients to model the probabilities that, during gaps in dosing, viral load would rise. Recently, Podsadecki et al. showed how short, spontaneously occurring gaps in ARV drug dosing result in transient “blips” in viral load.9 These and other studies exemplify how “mining the gaps” can define the limits of ARV drug exposure needed for control of viral load. Thiazide diuretics provide a moleculespecific degree of forgiveness in the treatment of hypertension. Wide variations in forgiveness prevail within the thiazide class, as illustrated by the appreciably longer duration of the antihypertensive actions of chlorthalidone than of hydrochlorothiazide.10 Substantial evidence from several randomized controlled trials show that atenolol, with its short forgiveness, was no better than placebo in reducing cardiovascular events, thus resulting in its removal from practice guidelines as a first-line treatment of hypertension.11 Could different values of forgiveness explain why some medications are more effective in real-life use than others? In the largest comparative trial of antihypertensive drugs, chlorthalidone proved to be superior to amlodipine, lisinopril, or doxazosin in reducing cardiovascular events.12 In this and other large trials, returned pill counts and histories were cited as evidence of adherence by trial subjects. Such data have repeatedly
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perspec tives been shown to overestimate patients’ adherence,2 and of course cannot show, because of the sparse rate of data gathering, the details about lapses of varying lengths in dosing. One is left to consider the extent to which the data reported by Vrijens et al.,1 described earlier, are exemplary of the dosing patterns that prevailed in large drug trials such as ALLHAT.12 In the treatment of most chronic diseases, forgiveness increases in therapeutic importance and clinical explanatory power as a patient’s dosing history is increasingly interrupted by episodic lapses in dosing of varying lengths, creating pharmacokinetically corresponding gaps of low or undetectable concentrations of drug in plasma. The incidence and varying lengths of gaps in dosing have only come to light as richly sampled dosing histories have become available from large numbers of patients in a diversity of therapeutic settings. As suggested by the findings in Vrijens et al.1 and the data at http://www. iadherence.org, gaps are not isolated responses to exceptional therapeutic situations but an integral part of the landscape of long-term pharmacotherapy for chronic disease. Thus, drugs that can safely forgive 2- to 3-day gaps in dosing can, everything else being equal, bring added therapeutic value to long-term pharmacotherapy. ACKNOWLEDGMENT The authors acknowledge Bernard Vrijens for his critique of this Commentary. CONFLICT OF INTEREST L.G.O. and T.F.B. have consulted for Proteus Biomedical. J.U. is chairman and chief scientist and a minority shareholder in AARDEX Group. © 2010 ASCPT
1. Vrijens, B., Vincze, G., Kristanto, P., Urquhart, J. & Burnier M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ 336, 1114–1117 (2008). 2. Urquhart, J. Pharmacodynamics of variable patient compliance: implications for pharmaceutical value. Adv. Drug Deliv. Rev. 33, 207–219 (1998). 3. Ortho Tri-Cyclen Tablets and Ortho Cyclen Tablets (norgestimate/ethinyl estradiol) [physician’s package insert]. Ortho-McNeil, pp 32–34 (1998). 4. Guillebaud, J. The forgotten pill—and the paramount importance of the pill-free week. Br. J. Fam. Planning 12, 35–43 (1987). 5. Johnson, B.F. & Whelton, A. A study design for comparing the effects of missing daily doses of
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antihypertensive drugs. Am. J. Ther. 1, 260–267 (1994). Rosenbaum, J.F., Fava, M., Hoog, S.L., Ascroft, R.C. & Krebs, W.B. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol. Psychiatr. 44, 77–87 (1998). Vanhove, G.F., Schapiro, J.M., Winters, M.A., Merigan, T.C. & Blaschke, T.F. Patient compliance and drug failure in protease inhibitor monotherapy. JAMA 276, 1955–1956 (1996). Vrijens, B., Goetghebeur, E., de Klerk, E., Rode, R., Mayer, S. & Urquhart, J. Modelling the association between adherence and viral load in HIV-infected patients. Stat. Med. 24, 2719–2731 (2005). Podsadecki, T.J., Vrijens, B.C., Tousset, E.P., Rode, R.A. & Hanna, G.J. Decreased adherence to
antiretroviral therapy observed prior to transient human immunodeficiency virus type 1 viremia. J. Infect. Dis. 196, 1773–1778 (2007). 10. Ernst, M.E. et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension 47, 352–358 (2006). 11. Wiysonge, C.S. et al. β-blockers for hypertension. Cochrane Database Syst. Rev. CD002003 (2007). 12. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 288, 2981–2997 (2002).
See COMMENTARY page 461
Neuroenhancement: Wisdom of the Masses or “False Phronesis”? D Larriviere1 and MA Williams2 Neuroenhancement (NE) refers to the use of prescription medications by healthy persons to boost their cognitive skills. This growing phenomenon represents a potential market not only for pharmaceutical manufacturers but also for physicians who might enter the potentially lucrative specialty of so-called cosmetic neurology. But before the medical establishment gears up to supply drugs to produce wisdom for the masses, we should ask whether the wisdom of the masses in regard to NE is wisdom at all.
The practice of otherwise normal, healthy persons licitly or illicitly obtaining prescription medications such as methylphenidate or modafinil to enhance their memory and cognitive skills has been referred to as neuroenhancement (NE). In the last decade alone, there has been an increase in NE to the point that at least one-third of students at some colleges have used such drugs illegally, almost always obtaining them from friends or other students.1,2 Students see nothing wrong with it. “We’re not getting high off it. We are doing it to do better in school. So, no,
I don’t feel bad or anything,” said one student interviewed on the topic.2 And NE is not limited to students. A 2008 survey of Nature readers found that 1 in 5 of 1,400 respondents from 60 countries had used such drugs to stimulate their focus, concentration, or memory, and 80% of them thought that healthy adults should be able to take the drugs if they want to.3 How did they obtain these drugs? Unlike students, more than 50% of these respondents said they were given prescriptions.3 The wisdom of the masses would seem to ask how there could be anything wrong
1Department of Neurology, University of Virginia, Charlottesville, Virginia, USA; 2The Sandra and Malcolm
Berman Brain & Spine Institute, Department of Neurology, Sinai Hospital of Baltimore, Baltimore, MD. Correspondence: D Larriviere (
[email protected]) doi:10.1038/clpt.2010.140
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