Drug development and use in the elderly: search for the right dose and dosing regimen
2004; Wiley; Volume: 58; Issue: 5 Linguagem: Inglês
10.1111/j.1365-2125.2004.02228.x
ISSN1365-2125
Autores Tópico(s)Pharmaceutical Economics and Policy
ResumoBritish Journal of Clinical PharmacologyVolume 58, Issue 5 p. 452-469 Free Access Drug development and use in the elderly: search for the right dose and dosing regimen Rashmi R. Shah, Corresponding Author Rashmi R. Shah Medicines and Healthcare products Regulatory Agency, Market Towers, 1 Nine Elms Lane, Vauxhall, London, UKDr Rashmi R. Shah, Senior Clinical Assessor, Medicines and Healthcare products Regulatory Agency, Market Towers, 1 Nine Elms Lane, Vauxhall, London, UK. Tel: + 44 20 7084 2349 Fax: + 44 20 7084 2323 E-mail: rashmi.shah@mhra.gsi.gov.ukSearch for more papers by this author Rashmi R. Shah, Corresponding Author Rashmi R. Shah Medicines and Healthcare products Regulatory Agency, Market Towers, 1 Nine Elms Lane, Vauxhall, London, UKDr Rashmi R. Shah, Senior Clinical Assessor, Medicines and Healthcare products Regulatory Agency, Market Towers, 1 Nine Elms Lane, Vauxhall, London, UK. Tel: + 44 20 7084 2349 Fax: + 44 20 7084 2323 E-mail: rashmi.shah@mhra.gsi.gov.ukSearch for more papers by this author First published: 28 October 2004 https://doi.org/10.1111/j.1365-2125.2004.02228.xCitations: 55 The views expressed in this paper are those of the author and do not necessarily reflect the views or opinions of the MHRA, other regulatory authorities or any of their advisory bodies. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Across the globe over the last few decades, there has been a remarkable increase in the proportion of the population which is elderly, and this trend is set to continue. Data from 10 countries that accounted for about 55% of the world population of 6079 million in the year 2000 provide an overview of this significant shift in demography. Table 1 summarizes the projections for the next 25 years. Hitherto, increases in life expectancy have been most obvious in the affluent countries; however, improvements in public health and disease control are also leading to increases in life expectancy in the less affluent countries. As a result of relatively larger increases in life expectancy at birth, significant shifts in demography are also expected in countries that are at present economically less affluent. The number of elderly people in the world is therefore expected to continue to increase for some considerable time. Interestingly, the most dramatic increases in the proportion of the population who are elderly are anticipated in countries where total populations are projected to decrease (such as Japan, Germany and Italy). Table 1. Age-related demography in 2000 and projected changes in 10 major countries Country 2000 Projections for 2025 Population (millions) Life expectancy at birth (years) Total above 80 years of age (%) Actual number of centenarians Population (millions) Life expectancy at birth (years) Total above 80 years of age (%) Actual number of centenarians USA 282 76.6 3.3 51 000 350 80.5 4.5 327 000 Japan 127 80.6 3.8 12 000 120 82.8 9.7 176 000 Germany 82 78.1 3.7 7 000 81 81.2 7.8 76 000 UK 60 77.8 4.0 10 000 64 81.1 5.6 56 000 France 59 78.8 3.7 8 000 63 81.8 6.1 69 000 Italy 58 79.1 4.0 5 000 56 81.9 7.9 73 000 China 1269 71.4 0.9 9 000 1448 77.4 2.3 128 000 India 1002 62.5 0.6 1362 70.9 1.2 Indonesia 224 68.0 0.4 300 75.0 1.5 Brazil 176 70.3 0.8 218 76.5 2.1 Total for the 10 countries 3339 1.33 4067 2.56 Source: US Census Bureau, International Data Base, August 2004. The 2001 population census of the UK revealed that since the census of 1951, the proportion of elderly population above 65 years and 85 years has increased from 16% and 0.4% respectively to 21% and 1.9%, respectively. These changes in demography will have significant effects on the economics generally as well as on the provisions for healthcare. Cardiovascular and neurological diseases and cancers are the most prevalent in the elderly. These three groups of diseases account for about 54% of the total burden of disease in Europe in terms of disability adjusted life years. Of the total gross Hospital and Community Health Services expenditure of £31.9 billion in the year 2001–2002 in the UK, 13% was expended on people aged 65–74 years, 16% on those aged 75–84 years and 10% for people aged 85 years or more. Furthermore, about 55% of the community prescriptions during 2001 in the UK were dispensed for the elderly. Cardiovascular and psychoactive drugs accounted for more than 40% of these prescriptions. In view of many age-related changes in the pharmacokinetics and pharmacodynamics of a drug, the safe and effective prescribing of medicines in the elderly will continue to present a major challenge. This review provides an overview of the issues relevant to development and clinical use of drugs in the elderly population, with particular reference to determining the right dosage and dose regimen and the regulatory requirements that facilitate this process. It also examines whether, as a result of advancing age per se, the dosing regimens in the elderly and the frail elderly might be different from those in the non-elderly. Pattern of drug usage in the elderly Before discussing the impact of any age-related changes in drug response and the current regulatory framework supporting the development of drugs in the elderly, it is worth asking whether the medications already available are used appropriately in this population. The broad aims of treatment in this group are improving morbidity and prolonging survival without any adverse effect on quality of life. A number of studies have reported on the use of inappropriate medications in the elderly while others have focused on underutilization of appropriate medications. Such prescribing patterns have important consequences in terms of frequencies of adverse drug reactions (ADRs), hospitalizations and mortality in the elderly as well as implications for healthcare and economic resources. A PubMed search by the author in February 2004, using the combination of key words 'inappropriate use of drugs' and 'elderly', retrieved 372 citations (although each citation was not individually scrutinized). In one study of 603 hospitalized patients with a mean age of 79 years, a total of 376 patients (62%) were discharged on digoxin. There was no indication for its use in 223 (37%) patients. Half of the patients in whom digoxin was not indicated were actually given the drug. Furthermore, 38 (29%) of the 132 patients without an indication and not already on digoxin were initiated on it [1]. Onder et al. have reported that during their hospital stay, 837 (14.6%) of 5734 patients (mean age 79 years) admitted to geriatric or internal medicine wards received one or more medications classified as inappropriate on the basis of Beers criteria [2]. Ticlopidine (n = 346) was the most frequently used medication, followed by digoxin (n = 174) and amitriptyline (n = 113). The particular drugs used inappropriately vary from time to time and from hospital to hospital. However, all studies reveal that a large number of drugs are prescribed inappropriately to the elderly. The most important determinant of the risk of receiving an inappropriate medication is the number of drugs being taken. One multicentre study during the period 1988 and 1997 reported 1704 ADRs in 28 411 patients consecutively admitted to participating centres [3]. In 964 cases (3.4% of all admissions), ADRs were the cause of these hospital admissions. Of these, 187 ADRs were classified as severe. The mean age of the patients was 70 ± 16 years. In 397 frail elderly inpatients (46.4% were aged ≥ 75 years), Hanlon et al. reported that 365 patients had at least one medication rated as inappropriate [4]. Some of the most common problems involved expensive drugs (70.0%) and impractical (55.2%) or incorrect directions for use (37.5%). Other problems related to dose and interactions. In this study, 169 patients were taking drugs for which there was no indication. A wide range of drug classes was implicated in inappropriate use. These included cardiovascular (10.77%), gastrointestinal (9.12%), central nervous system (4.22%), respiratory (4.11%), hormones (4.01%), blood products (3.36%) and antimicrobials (2.56%) among others. In terms of number of patients involved, the most common drug classes used inappropriately were gastric (50.6% of patients), cardiovascular (47.6%) and central nervous system (23.9%) drugs. In contrast to inappropriate use, there is also a serious problem of underutilization of appropriate medications. 'Statin' therapy is known to be associated with reduced mortality in all age groups, including very elderly individuals, with significant coronary artery disease. Elderly patients were significantly less likely to receive 'statins' than younger patients (< 65 years 28.0%, 65–79 years 21.1%, and ≥ 80 years 19.8%) [5]. Similar underuse of 'statin' was reported in another study of 622 eligible patients with previously established coronary artery disease and hyperlipidaemia. Only 230 (37%) of these patients had received these hypolipidaemic drugs [6]. One of the studies has provided further worrisome evidence showing that the elderly > 65 years old as well as females were less likely to be prescribed aspirin, β-blocker and a statin in the secondary prevention of ischaemic heart disease in primary care [7]. The concern from these observations arises from the fact that older patients receive a greater absolute risk reduction than younger individuals, and yet they were less likely to receive a 'statin' therapy. A study on the use of lipid-lowering drugs in the UK revealed similar trends. Although the use of 'statins' had increased over time, 33% of these patients were still receiving only an equivalent of < 20 mg simvastatin daily. In 1998, the odds ratios for receiving a 'statin' therapy were 1 in the age band 55–64 years, 0.64 in the age band 65–74 years and 0.16 in the age band 75–84 years. This age effect was similar in those with and those without a major comorbidity [8]. Similarly, underuse of effective medicines in the elderly has been reported with antihypertensive drugs [9] and antiplatelet or anticoagulant therapy [7, 10, 11]. β-Blockers following acute myocardial infarction (AMI) [7, 12] are also underused but this seems to have improved recently [13]. Underinvestigation and undertreatment of chronic heart failure have been shown to persist. Failure to treat elderly patients with angiotensin converting enzyme (ACE) inhibitors is associated with a mortality that appears to be greater than that seen in the placebo arms of large clinical trials of ACE inhibitor therapy [14, 15]. Jackson et al. have provided a number of reasons for suboptimal prescribing [16] while others have commented on improving quality of prescribing and access of the elderly to the medications [17]. While underprescribing is a problem that can be remedied through physician education, noncompliance by patients themselves continues to present a challenge in the care of not only the elderly but also their younger counterparts. Persistence with 'statin' therapy in older patients declines substantially over time, with the greatest drop occurring in the first 6 months of starting treatment [18, 19]. With regard to the use of β-blockers, patients not discharged on β-blockers are unlikely to be started on them as outpatients. For patients who are discharged on β-blockers after AMI, there is a significant decline in use after discharge [20]. Age-related changes in pharmacology Pharmacokinetics and pharmacodynamics of a drug are the two determinants of its dose–response relationship, both of which exhibit large interindividual variability. This variability arises from their modulation by factors such as age, gender, comedications or comorbidity (e.g. renal or hepatic dysfunction). There may be age-related up- or downregulation of pharmacological targets responsible for the pharmacodynamic effects of a drug. This variability also arises from genetic influences that regulate the expression of drug-metabolizing enzymes or the responsiveness of various pharmacological targets. The presence of variant alleles often exerts influences that usually far exceed those due to the other covariates stated above. Contrary to what is often claimed, there is little evidence to demonstrate that age per se has a major effect on the pharmacology of a drug. Table 2 summarizes the prevalence of various covariates that influence the pharmacokinetics of a drug in the elderly relative to young adults. Therefore, any age-related differences in the prevalence of these covariates may be expected to give rise to age-related changes in the pharmacology of the drug when the group is evaluated as a whole. Unless these changes are taken into account when prescribing, they may impact adversely on dose–response relationship and therefore, on the clinical efficacy, safety and risk–benefit of a drug. Table 2. Relative prevalence of various covariates that influence the pharmacokinetics Covariate Young adults Elderly Liver disease/CYP3A4 + ++ Genetics/CYP2D6 + + Genetics/CYP2C9/19 + + Renal disease + +++ Cardiac disease – ++ Polypharmacy + ++++ Age-related changes in pharmacokinetics One of the earliest, and perhaps the most striking, example of a drug that provided alarming evidence of age-related changes in its pharmacokinetics was benoxaprofen. Benoxaprofen was a novel nonsteroidal anti-inflammatory drug (NSAID) introduced in 1980. The drug was launched amidst massive publicity and its marketing was 'explosive'. The resulting uptake of the drug in clinical practice was overwhelming. Not surprisingly, reports of serious ADRs (photosensitivity and hepatotoxicity in this case) began to appear at an alarming rate. Benoxaprofen-induced hepatic injury was typically a progressive painless jaundice (cholestasis with little or no necrosis) and usually associated with nephrotoxicity. Its incidence was estimated to be about 2–4% and the mortality rate high. By August 1982, there were 61 fatalities reported and the marketing authorization of the drug was suspended immediately. Age was identified as a risk factor. Subsequent studies in otherwise healthy individuals showed that the half-life of benoxaprofen was of the order of 110 h in the elderly [21, 22] in contrast to 16–35 h in young adults [22, 23]. Renal insufficiency did not induce major changes in pharmacokinetic parameters in one study [24] while another reported a correlation between creatinine clearance and elimination half-life and plasma clearance of benoxaprofen [25]. Of the administered dose of benoxaprofen, only 13.9% is recovered in the urine over a 24-h period. However, since renal clearance accounts for 33% of total clearance, benoxaprofen kinetics may be influenced by severe renal impairment [24]. Terodiline is a more recent example of a drug with similar age-related differences in its half-life. The mean half-life of terodiline was 131 h (range 63–237) in the elderly in contrast to only 57 h (range 35–72) in young adults [26]. It was originally marketed in Sweden in 1965 as an antianginal drug. However, severe urinary retention proved to be a frequent side-effect and it was therefore re-developed in the late 1980s for the treatment of urinary incontinence. Approved in July 1986, it was withdrawn from the market in September 1991 following 69 reports of serious cardiac arrhythmias associated with its use. This included torsade de pointes (TdP), a unique form of polymorphic ventricular tachycardia associated with prolongation of the QTc interval. An analysis of predisposing factors in the 69 reports identified an age of > 75 years as one of the potential risk factors. There are very few drugs for which such striking differences in half-lives between the elderly and the non-elderly have been demonstrated in absence of any obvious cause. However, the presence of various modulating factors could explain the observed age-related differences in the pharmacokinetics of other drugs [27, 28]. Age-related changes in pharmacokinetics due to impaired drug clearance are a frequent cause of, and major contributor to, drug toxicity in the elderly. Drug distribution may be altered in the elderly. The relative lipid content increases markedly with age. Body fat increases from 19% at the age of 25 to 35% at the age of 70 years in males and from 33% to 49%, respectively, in females [29]. Total body water content and lean body mass also fall with advancing age. The effect of these changes is to decrease the volume of distribution of polar (water-soluble) drugs such as cimetidine and morphine and to increase that of nonpolar (lipid-soluble) drugs such as benzodiazepines. Increase in volume of distribution often results in retention and prolonged half-lives of the drugs concerned. For most drugs, however, these age-related changes in body composition do not have a significant effect on volume of distribution [30]. Serum albumin decreases from 4% in younger adults to 3.5% in those over 80 years old [31]. The concentration of α1-acid glycoprotein that is responsible for binding many basic drugs tends to increase with age [32]. Changes in plasma proteins can be clinically significant for drugs with a narrow therapeutic index. However, the effect of age on protein binding is generally unpredictable. Total serum haloperidol levels have been reported to show a linear relationship with daily dose with no difference in the total haloperidol level per daily dose between the elderly and younger adults [33]. However, in this study of 59 patients aged 50–88 years, the free fraction increased with age. No doubt, there are a few other similar examples. In contrast, plasma protein binding of celecoxib or diclofenac was unaffected by age [34]. Alterations in plasma protein binding that occur in the elderly are generally not attributed to age, but rather to physiological and pathophysiological changes or disease states that may occur more frequently in the elderly. In general, only a few drugs show a change of more than 50% in their free fraction in the elderly. The activity of some drug-metabolizing enzymes responsible for phase I oxidation may be impaired in old age. Phase II conjugation reactions appear to be much less susceptible. Overall, it is estimated that drug-metabolizing capacity is reduced by approximately 30% after the age of 70 years [35]. Other studies have suggested that specific activities of phase I drug-metabolizing enzymes are not reduced with age per se and that there is no change in the enzyme affinity for their substrates [36]. Rather, an important contribution to reduced hepatic elimination of drugs comes from reduction in liver size and blood flow with advancing age [36, 37]. Metabolism could also be impaired due to the presence of liver disease. Normal liver function is an important determinant of the activity of CYP3A4 that metabolizes a large number of drugs widely used clinically. It is an enzyme that is highly susceptible to liver disease. This is in contrast to CYP2D6, which is relatively refractory to liver disease. The susceptibility of other major CYP drug-metabolizing enzymes appears to be intermediate between that of CYP3A4 and CYP2D6 [38–41]. Intercurrent stresses such as community-acquired pneumonia, a fracture or hip replacement surgery have been shown to reduce the activity of aspirin esterase in older patients [42, 43]. For many of the alleged age-related changes in protein binding, fat content and drug metabolism, the evidence is modest and not consistent. By comparison, age-related deterioration in renal function is more critical and well characterized. It results in accumulation of many drugs and/or their metabolites that are cleared predominantly by the renal route. Glomerular filtration rate declines with age, with a mean of 35% reduction in older people compared with their younger counterparts [44]. Renal tubular function also declines with resulting impairment of excretion of drugs by active tubular secretion. Unexpectedly, however, renal disease also influences the activity of drug-metabolizing enzymes. Animal studies in chronic renal failure have shown a major downregulation (40–85%) of hepatic cytochrome P450-mediated metabolism by specific CYP enzymes. Phase II reactions such as acetylation and glucuronidation are also involved, with the activity of some enzymes induced and others inhibited [45]. Animal studies have also suggested the presence of circulating uraemic factor(s) in the serum that downregulates the activity of CYP enzymes by 30–35% secondary to reduced gene expression [46, 47]. End-stage renal disease is associated with inhibition of hepatic enzymes exhibiting genetic polymorphisms such as N-acetyltransferase-2 (NAT-2), which is responsible for the rapid and slow acetylator phenotypes. This inhibition is reversed by transplantation [45, 48]. There is substantial evidence suggesting that it may be possible to remove by dialysis the inhibitory factors circulating in the serum in end-stage renal disease patients [45]. Patients with end-stage renal disease are at an increased risk of drug toxicity due to reduced activity of the CYP3A enzyme pathway [49]. Similarly, CYP2D6 activity in man is also compromised in parallel with deterioration of renal function [50]. In patients with end-stage renal disease, the plasma S/R warfarin ratio is 50% higher than in control group (0.82 vs. 0.55; P < 0.03). There was no correlation between warfarin dose and plasma S/R warfarin ratio. This probably reflects a decrease in CYP2C9 activity [51]. The effect of moderate renal insufficiency on hepatic drug metabolism is not as well characterized and requires investigation. Age-related pharmacokinetic changes in perspective When age-related changes in pharmacokinetics are put in perspective, it is evident that gender, ethnicity or the genotype of a patient frequently has a far greater effect. CYP3A4 is responsible for the metabolism of nearly 50% of drugs metabolized by oxidation. The activity of this enzyme appears to be unaffected by age over the range of 27–83 years, suggesting that any age-related changes in the clearance of CYP3A4 substrates are secondary to changes in liver blood flow, size, or drug-binding and distribution with ageing [52]. Even the presence of food in the stomach can markedly alter the pharmacokinetics of some drugs. Age-related changes in pharmacokinetics are typically investigated in a panel of subjects aged ≥ 65 years and who are otherwise healthy – a population that is not easy to find. Subjects who have renal or hepatic impairment are excluded from randomization and the influence of these two variables is investigated in separate studies. The pharmacokinetic parameters in this elderly panel are compared with those from a younger panel (about 30–40 years of age). It is neither possible nor intended to generalize, but in broad terms, the mean data from a number of drugs show that changes in pharmacokinetics due to age per se are very modest (of the order of 20–40%) when compared with the influences of other covariates such as food, gender, comorbidity, comedications and genetic factors (of the order of 50–300%). There are of course exceptions to this. Age-related changes in pharmacodynamics Only recently has interindividual variability in pharmacodynamic response to drugs attracted academic, regulatory and clinical interest. It is generally acknowledged that at a given drug concentration, the elderly are more susceptible to certain pharmacological effects [53, 54]. These include anticholinergic, dopaminergic and proarrhythmic effects. It is probable that there is age-related up- or downregulation in the pharmacological responsiveness of the corresponding pharmacological targets. With advancing age, there are changes in central neurochemical transmission. For example, pre- and postsynaptic neurochemical markers of the central cholinergic system decline [55] while dopamine D2 receptor subtypes decrease [56] and dopamine D1 receptor subtypes increase [57]. The concentrations of noradrenaline in the hypothalamus decline [58] whereas responses to serotonergic drugs vary with advancing age. Although the total brain serotonin declines with age, the change is much less evident in the hindbrain [59, 60]. There is a significant reduction with age not only in the 5-HT1D and 5-HT2 serotonin receptor sites but also in 5-HT2 serotonin binding affinity in the frontal cortex [61]. Autonomic reflexes are significantly altered in the older population. β-Adrenoreceptor sensitivity declines with age [62], particularly with regard to inotropic and chronotropic responses. The anticholinergic effects of some antidepressants and neuroleptic drugs are often responsible for agitation, confusion, and delirium in the elderly. The use of heterocyclic antidepressants in the elderly is frequently limited by anticholinergic and/or cardiovascular side-effects. This has resulted in a significant change in the pattern of antidepressant use in the elderly from tricyclic antidepressants to selective serotonin reuptake inhibitors (SSRIs) that are devoid of anticholinergic effects. Apart from antidepressants, the use of antiarrhythmic therapy in the elderly is also complicated by their anticholinergic properties. Similarly, tardive dyskinesia has been strongly associated in the elderly with the use of older typical neuroleptics with high affinity (blockade) for the dopamine D2 receptor. Not surprisingly, the elderly are more sensitive to the autonomic and extrapyramidal effects of neuroleptics. Newer atypical antipsychotics, while showing similar efficacy to conventional antipsychotics, induce lower rates of motor disturbances [63] and are now the preferred class in the elderly. TdP is a potentially fatal ventricular tachycardia induced by a number of non-antiarrhythmic drugs that prolong the QTc interval. Cardiac disease, especially cardiac failure, is a major risk factor since potassium channels are often downregulated in diseased myocardium. Apart from the higher prevalence of cardiac failure in the elderly, it has been shown that a significant correlation exists between ageing and prolongation of the QTc interval [64]. Not surprisingly, age is one of the risk factors for drug-induced TdP. Pharmacogenetics and the elderly Although not widely appreciated, genetic factors may play as important a role in the elderly as they may in the younger population. A number of drug-metabolizing enzymes are expressed polymorphically in the population [65]. The impact of these polymorphisms in the safe and effective use of drugs in the elderly is most evident during induction of anticoagulation with warfarin that is metabolized predominantly by CYP2C9 [66]. Available data support the view that although the CYP2C9* 3/CYP2C9* 3 genotype is associated with dramatic over-anticoagulation soon after the introduction of oral anticoagulants, overdose during the maintenance period is mostly related to environmental factors [67]. It is also recognized that interindividual variability in warfarin sensitivity also originates from environmental factors. In one study, age and CYP2C9 genotype accounted for 12% and 10% of the variation in warfarin dose requirements, respectively [68]. CYP2D6 polymorphism is responsible for the metabolism of a large number of cardiovascular and psychoactive drugs and is therefore of particular relevance to the use of drugs in the elderly. Studies beginning in 1977 have shown that any given population may be divided into two phenotypes – extensive metabolizers (EMs) or poor metabolizers (PMs) – depending on their ability to mediate CYP2D6-dependent hydroxylation of the (now obsolete) antihypertensive drug debrisoquine [69]. Advances in molecular genetics over the last decade have allowed CYP2D6 metabolic capacity to be assigned by direct genotyping of the patients. This polymorphism results from autosomal recessive inheritance, in a simple Mendelian fashion, of variant alleles at a single locus. Those individuals who carry two CYP2D6 inactivating alleles are phenotypic PMs. Within the EMs, there are two subgroups of particular interest at either extreme of the EM population distribution. One subgroup, termed the ultrarapid metabolizers (UMs), is comprised of individuals possessing multiple copies of the alleles (CYP2D6* 1 and CYP2D6* 2) responsible for normal metabolic capacity [70]. The presence of two specific CYP2D6 alleles, CYP2D6* 35 and CYP2D6* 41, is also thought to confer ultrarapid metabolizing capacity even in the absence of gene duplication [71]. The other subgroup, termed the intermediate metabolizers (IMs), is comprised of a heterozygous genotype ('gene-dose effect'). UMs metabolize drugs so avidly that despite being prescribed high doses, they attain very low concentrations of the parent drug and high levels of rapidly accumulating metabolites while IMs display a modest impairment in drug-metabolizing capacity. The pharmacokinetic consequences arising from CYP2D6 polymorphism are shown in Table 3. Table 3. Pharmacokinetic consequences of CYP2D6 polymorphism Pharmacokinetic parameter Consequences for the PM relative to EM Bioavailability 2–5-fold Systemic exposure Cmax 2–6-fold AUC 2–5-fold Half-life 2–6-fold Metab
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