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- What is Already Known about this Subject
- What this Study Adds
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Clearance is the most important pharmacokinetic parameter to consider in clinical practice because it determines steady-state drug concentration at a given maintenance dose. Elderly people, defined as those over 65 years of age, are the largest users of drugs and the most susceptible to adverse drug reactions (ADRs) . Decreased clearance resulting in high drug concentrations is a major cause of ADRs. In particular, it is estimated that metabolic clearance by cytochrome P450 enzymes (CYP) is approximately 30–50% lower in older compared with younger people [2-5].
Studies with high hepatic extraction ratio (EH) drugs (‘flow-limited’) consistently show decreased clearance in the elderly as a result of decreased hepatic blood flow. The literature is also consistent for low EH drugs (‘capacity-limited’) with low protein binding (PB), for which decreases in clearance largely reflect reduced intrinsic clearance by the liver (CLint.liver). However, data for capacity-limited drugs with high PB are inconsistent, with studies showing decreased, unchanged, and even increased clearance in the elderly.
A possible reason for this inconsistency is variable consideration of renal function in studies that use urinary drug : metabolite ratios and urinary recovery of metabolites to measure differences in metabolic clearance i.e. these indices of enzyme activity are potentially confounded by the effect of renal function [6, 7]. Another plausible explanation is the use of total drug concentration (bound + free drug) to estimate clearance (referred to as ‘total drug clearance’) [2, 8]. If clearance is exclusively metabolic, decreases in total drug clearance from reduced CLint.liver may be masked by increases in the free fraction in blood, which may occur for some, but not all drugs, in the elderly [9, 10]. This is illustrated hypothetically in Figure 1. However, when the clearance of capacity-limited drugs with high PB is estimated from free drug concentrations, ‘free drug clearance’ is reduced in the elderly to a similar degree as total clearance (30–50%) for drugs with other EH and PB characteristics . This is because the free clearance of capacity-limited drugs with high PB is exclusively dependent on CLint.liver and not confounded by changes in binding protein concentrations (note that ‘free drug clearance’, ‘whole liver intrinsic clearance’, ‘free metabolic clearance’ and ‘hepatic intrinsic clearance’ are used inter-changeably in the literature). Thus, although total drug clearance is a valid measure for examining changes in clearance for flow-limited drugs and capacity-limited drugs with low PB, it has limitations when applied to capacity-limited drugs with high PB .
Figure 1. How total drug clearance can decrease, increase or remain unchanged following decreases in whole liver intrinsic clearance
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In vitro-in vivo extrapolation (IVIVE) coupled with physiological-based pharmacokinetic (PBPK) modelling and simulation is used widely to predict the metabolic clearance of drugs . Simcyp®, an IVIVE-PBPK programme, predicts clearance across populations and not just in individuals [12-14]. Inter-individual variability in clearance may be assessed rapidly for new drug candidates, thus aiding the appropriate selection of drugs and dosing regimens for clinical studies . Given that Simcyp® is used routinely in the pharmaceutical industry, the validity of its performance in predicting clearance in different populations (e.g. poor metabolizers, paediatrics, the elderly etc.) is an important consideration when evaluating in silico data during preclinical drug development. However, an assessment of Simcyp® in predicting metabolic drug clearance with increasing adult age has not been conducted.
Thus, the primary aim of this study was to determine the effect of increasing adult age on predicted metabolic drug clearance using IVIVE-PBPK models in Simcyp®. The secondary aims were to investigate the effect of gender on predicted metabolic drug clearance, and to compare the predicted clearances with observed clearances from human pharmacokinetic studies.
- Top of page
- What is Already Known about this Subject
- What this Study Adds
- Competing Interests
This is the first study to investigate systematically the effect of increasing adult age on predicted metabolic drug clearance. IVIVE-PBPK using Simcyp® predicted a weight-normalized metabolic drug clearance 20–40% lower in elderly compared with younger adults. Although simulation data should always be interpreted in the context of the limitations of IVIVE approaches, this result is generally consistent with the changes reported in clinical studies for drugs eliminated by CYP enzymes (see discussion on specific drugs below) [2-5]. Age-related changes in QH, LW and the hepatic endothelium are considered to be primarily responsible for decreased metabolic clearance with age rather than changes in CYP activity or expression . This decline with age is replicated in the functions for extrapolation factors in Simcyp® – MPPGL, LW and QH. As these are physiological parameters, the clearance of any drug eliminated exclusively via CYP will be affected similarly by increasing adult age in Simcyp®. Indeed, Figures 2 and 3 show comparable percentage decreases in CLPT and CLPF for each probe drug. Clearance predictions for drugs metabolized by multiple CYP enzymes will therefore be insensitive to the fraction of drug metabolized by each enzyme (fmCYP). Thus, the current status of Simcyp® in predicting 20–40% lower metabolic clearance in elderly people is independent of drug-specific physiochemical parameters, the CYP enzymes responsible for metabolism, and their fractional contributions to clearance (e.g. specific fmCYP values).
Simulated CLPT and CLPF decreased with increasing adult age until approximately 65–70 years (Figures 2 and 3). The lack of further decreases in predicted clearances after this age appears to result from plateauing of the MPPGL decrease (Figure 4). The exact reason why MPPGL fails to decrease further with advancing age is unknown. However, this pattern may simply reflect bias in the mean MPPGL derived from liver samples in those >65 years, since they may be relatively healthy individuals who have outlived their counterparts.
IVIVE-PBPK modelling of CLPT in elderly vs. young males and females was compared with clinical data that describe the clearance of caffeine, S-warfarin, desipramine and midazolam, but such a comparison was not possible for S-mephenytoin (Table 2). In each of these cases, comparisons were limited by the small sample sizes in the clinical studies. For example, the only study to investigate the effects of age on caffeine clearance showed slightly higher total clearance in elderly men, although this difference was not statistically significant . In contrast, when clearance data from separate studies in young and elderly men are compared, a modest decrease in total caffeine clearance with ageing is found (14.9%) [19, 25]. However, this approach introduces additional sources of uncertainty and provides unconvincing evidence for a negative correlation between increasing adult age and caffeine clearance. Interestingly, the effects of adult age on caffeine CLPT resemble clinical data with theophylline, another capacity-limited CYP1A2-selective probe with low PB. Clinical data show that the total clearance of theophylline is significantly decreased in the elderly (22–35%)  despite increases in the fraction unbound (20–25%) . When theophylline is studied in Simcyp®, CLPT decreases to a similar degree as shown in clinical studies (21%, simulations not shown). Thus, the effects of increasing adult age on the clearance of drugs predominantly metabolized by CYP1A2 may require consideration on a case-by-case basis.
Clinical data on S-mephenytoin clearance are scarce. The decrease in CLPT shown here (39%) is consistent with lower recovery of 4-hydroxymephenytoin (35%) and a decreased S : R enantiomeric ratio (25%) in the urine of patients ≥50 years [26, 27], although the effect of changes in renal function may contribute to this result. In the eight studies that report changes in total S-warfarin clearance with ageing, most found a significant decrease with age, although in two of the studies this was only a trend [2, 22]. The majority of these studies were not designed to investigate specifically changes in clearance with age and data are not available to allow for a direct comparison with the Simcyp® data generated here. However, for the studies in which multiple regression analysis or population pharmacokinetic modelling was used on populations of 39–306 patients, the decline in S-warfarin clearance with age was reported to be 0.3-1% per year , which roughly translates to a 14–45% decline between the young and elderly age groups used in the Simcyp® simulations. For one recent study that specifically investigated the influence of adult age on warfarin clearances , it was possible to stratify the results as shown in Table 2. This analysis showed a significant decrease (48%) in total S-warfarin clearance in women but an increase (27%), although not statistically significant, in men. When females and males were combined, a modest decrease in total S-warfarin clearance was found between the young and the elderly (<15%, data not shown). Since the CLPT of S-warfarin was decreased by 36%, this falls within the range of reported studies, although it may slightly over-predict the effects of adult age on decreased total clearance of CYP2C9 substrates (note that sub-analysis of CYP2C9 genotype was not conducted). There are two small clinical studies showing decreased total desipramine and midazolam clearance with age [20, 21], and Simcyp® was moderately successful in reproducing the observed % decreases (Table 2).
For low EH drugs with high PB, total drug clearance does not reliably assess changes in clearance and free drug clearance is preferred . As shown in Figure 1, this is because decreased CLint.liver may be masked by increased fub (from decreased binding proteins) when total drug concentration is used to estimate drug clearance. In this study, the percentage decreases in CLPT were similar (27 to 39%) for all probes which have different EH and PB characteristics. Therefore, minor increases in the predicted fub of caffeine, S-warfarin, S-mephenytoin and midazolam did not significantly affect the relationship between decreased CLPT and increasing adult age (note that the non-significant increases in predicted fub, along with the small decrease for desipramine, are consistent with clinical data [19-22]). Clinical comparisons of free drug clearance between young and elderly people are limited. Of the five drugs studied here, sufficient data are available only for caffeine and S-warfarin. The free clearance of S-warfarin decreases by 0.4% per year in the absence of statistically significant decreases in PB , and the simulations of CLPF are consistent with this trend (Figure 3). Here, the free clearance of caffeine was accurately predicted in the young (CLPF = 2.3 vs. clinical = 2.14 ml min−1 kg−1 ), but the decrease in simulated caffeine free clearance with age did not correspond with the increase observed in elderly non-smoking men (CLPF = 1.6 vs. clinical = 2.55 ml min−1 kg−1 ).
Gender difference in drug metabolism is a controversial topic that has been extensively reviewed in the literature [28-32]. In the simulations, women generally had higher CLPT than men (Figure 2). This results from differences between women and men in the physiological parameters that determine IVIVE of metabolic clearance, although analysis of these differences was not undertaken here (see Chetty et al. for more on this topic ). Most investigators concur that a small but statistically significant increase in the size adjusted clearance of CYP3A substrates, including midazolam, occurs in women . Similarly for S-mephenytoin, women have significantly lower S : R enantiomeric ratios in urine (35%) as a result of greater CYP2C19 activity . However, for the other CYP-selective probes studied here, increased CLPT in women is not supported by available clinical data. For example, a recent population pharmacokinetic analysis of S-warfarin in predominantly older patients showed men to have 12% higher clearance than women . Our sub-analysis of the elderly in Jensen et al.  showed a trend of an even greater difference, although the opposite gender difference for S-warfarin is seen in the young (Table 2). Lower CYP1A2 and CYP2D6 activities in women have also been suggested [20, 25]. It must be emphasized, however, that many studies on gender difference in clearance are problematic, as many are underpowered to consider large inter-individual variability in clearance, they employ different probes with varying degrees of selectivity, they use total drug concentration to estimate clearance in the absence of PB information, and urinary drug : metabolite ratios are measured to assess differences in metabolic clearance without considering the impact of renal function [6, 7]. Therefore, there are no simple answers on whether particular CYPs differ significantly between men and women. We noted that large numbers of virtual subjects (n = 100 and 1000) were required to show statistically significant gender differences in predicted metabolic drug clearance (data not shown). Thus, in the absence of superior clinical studies, it is difficult to assess accurately the current performance of Simcyp® in predicting gender differences in the clearances of caffeine, S-mephenytoin and desipramine.
In conclusion, the primary aim of this study was to investigate the effect of increasing adult age on predicted metabolic drug clearance. IVIVE-PBPK using Simcyp® predicted 20–40% lower weight-normalized metabolic drug clearance in the elderly. This is generally consistent with limited clinical data for four out of five drugs studied here and the broader literature on drugs metabolized by CYP enzymes [2-5]. Decreased metabolic clearance with increasing adult age was similar for probe drugs of major CYP enzymes with different EH and PB characteristics. Observed decreases in predicted drug clearance with age were attributable to the physiological changes of ageing. IVIVE-PBPK modelling and simulation may be used with increasing confidence to predict metabolic drug clearance in the elderly and to inform clinical study design.