Genomic Variation and Pharmacokinetics in Old Age: A Quantitative Review of Age‐ vs. Genotype‐Related Differences

Dücker, Christof; Brockmöller, Jürgen

doi:10.1002/cpt.1057

Cited by 21 publications

(28 citation statements)

References 44 publications

(77 reference statements)

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“…Although no particularly strong effects of the combined effects of age and metabolic genotype on pharmacokinetics have been demonstrated, a moderate ~1.5‐fold increase in systematic exposure of drugs is found and, in a few drugs, systemic exposure can rise 2‐fold or even more. Examples include capecitabine (due to reduced activity of dihydropyrimidine‐dehydrogenase), clomipramine (CYPD2D6/CYP2C19), codeine, ezetimibe, fluvoxamine, paroxetine, venlafaxine and zolpidem …”

Section: How Altered Human Organ Functions Affect Pharmacokineticsmentioning

confidence: 99%

“…Another important aspect of frailty is unspecific systemic inflammation, partially due to dysregulation of the immune system. Systemic inflammation may result in downregulation of cytochrome P450 enzymes, increasing the risk of individual overdose in older people …”

Section: How Frailty May Alter Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

“…Examples include capecitabine (due to reduced activity of dihydropyrimidine-dehydrogenase), clomipramine (CYPD2D6/ CYP2C19), codeine, ezetimibe, fluvoxamine, paroxetine, venlafaxine and zolpidem. 32 For metabolic capacity-limited drugs with low protein binding, such as paracetamol and theophylline, there is evidence to suggest a decreased metabolic clearance of 30-50% in older people. For metabolic capacity-limited drugs with high protein binding, such as naproxen and valproic acid, total clearance is unreliable, as changes in protein binding may obscure the true intrinsic clearance.…”

Section: Metabolic Capacitymentioning

confidence: 99%

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Prescribing medicines to older people—How to consider the impact of ageing on human organ and body functions

Maanen

Wilting

Jansen

2019

Brit J Clinical Pharma

104

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Ageing is associated with several changes in human organs, which result in altered medication pharmacokinetics and pharmacodynamics. Ageing is also associated with changes in human body functions, such as impaired vision, hearing, swallowing, motor and cognitive functions, which can affect the adequate intake and administration of drugs. As a consequence, older people, and especially patients older than 75 years, are the main users of many drugs and they frequently use 5 drugs or more long‐term (i.e. polypharmacy). All this increases the complexity of adequate drug intake, administration and adherence. However, there is a lack of evidence on the considerations that should be taken into account to ensure appropriate drug prescribing to older people. This review article summarizes the most clinically relevant changes in human organ and body functions and the consequential changes in pharmacokinetics and pharmacodynamics in older people, along with possible dosing consequences or alternatives for drugs frequently prescribed to this patient population. Recommendations are given on how ageing could be considered in clinical drug development, drug authorization and appropriate prescribing.

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Section: How Altered Human Organ Functions Affect Pharmacokineticsmentioning

confidence: 99%

Section: How Frailty May Alter Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

Section: Metabolic Capacitymentioning

confidence: 99%

See 1 more Smart Citation

Prescribing medicines to older people—How to consider the impact of ageing on human organ and body functions

Maanen

Wilting

Jansen

2019

Brit J Clinical Pharma

104

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“…Changes in platelet aggregation, which may contribute to increased ischemic events, increase as patient age increases, that is, a higher rate of ischemic events occurs due to increased platelet aggregability in the elderly [ 21 ]. Regarding the relationship between age and genomic variation, Dücker et al [ 22 ] reported that systemic exposure might be increased in elderly patients, even if their old age affects pharmacokinetics and they share the same genetic polymorphism. The authors reported that additional systemic exposure of approximately 1.5-fold occurred by age, even in the same poor metabolizer group, and more clinical events could occur [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…Regarding the relationship between age and genomic variation, Dücker et al [ 22 ] reported that systemic exposure might be increased in elderly patients, even if their old age affects pharmacokinetics and they share the same genetic polymorphism. The authors reported that additional systemic exposure of approximately 1.5-fold occurred by age, even in the same poor metabolizer group, and more clinical events could occur [ 22 ]. This might explain why comparisons of clinical outcomes among the poor, normal, and intermediate metabolizers yielded negative results in the general population analysis [ 8 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Impact of genetic variants on clinical outcome after percutaneous coronary intervention in elderly patients

Cha

Park

Joo

et al. 2021

Aging

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Elderly patients treated with percutaneous coronary intervention (PCI) have a higher risk of both ischemic and bleeding complications than younger patients. However, few studies have reported how genetic information of elderly patients treated with PCI affects clinical outcomes. We investigated the impact of genetic variants on clinical outcomes in elderly patients. Correlations between single-nucleotide polymorphisms (CYP2C19 and P2Y12 receptor gene G52T polymorphism) and clinical outcomes were analyzed in 811 elderly patients (≥75 years of age) from a prospective multicenter registry. The primary endpoint was a composite of myocardial infarction and death. Secondary endpoints were an individual event of death, cardiac death, myocardial infarction, stent thrombosis, target lesion revascularization, stroke, and major bleeding (Bleeding Academic Research Consortium ≥3). Regarding CYP2C19, patients with poor metabolizers had a significantly higher risk for the primary endpoint (hazard ratio [HR] 2.43; 95% confidence interval [95% CI] 1.12–5.24; p=0.024) and secondary endpoints (death and cardiac death). Regarding P2Y12 G52T, the TT group had a significantly higher occurrence of major bleeding than the other groups (HR 3.87; 95% CI 1.41–10.68; p=0.009). In conclusion, poor metabolizers of CYP2C19 and TT groups of P2Y12 G52T may be significant predictors of poor clinical outcomes in elderly patients.

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Risk of Opioid Overdose Associated With Concomitant Use of Oxycodone and Selective Serotonin Reuptake Inhibitors

et al. 2022

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IMPORTANCE Some selective serotonin reuptake inhibitors (SSRIs) inhibit the enzymes responsible for the metabolism of oxycodone, a potent prescription opioid. The clinical consequences of this interaction on the risk of opioid overdose have not been elucidated. OBJECTIVETo compare opioid overdose rates in patients initiating oxycodone while taking SSRIs that are potent inhibitors of the cytochrome-P450 2D6 enzyme (CYP2D6) vs SSRIs that are not. DESIGN, SETTING, AND PARTICIPANTSThis cohort study included adults who initiated oxycodone while receiving SSRI therapy between 2000 and 2020 whose data were included in 3 US health insurance databases. EXPOSURES Use of SSRIs that strongly inhibit CYP2D6 enzyme (fluoxetine or paroxetine) vs use of other SSRIs at the time of oxycodone initiation. MAIN OUTCOMES AND MEASURES Opioid overdose hospitalization or emergency department visit. Outcomes were assessed within 365 days of oxycodone initiation; in primary analyses, patients were followed up until the discontinuation of either oxycodone or their index SSRI group. Propensity score matching weights were used to adjust for confounding. Crude and weighted (adjusted) incidence rates and hazard ratios were estimated using Cox regression models, separately within each database and overall, stratifying on database. RESULTS A total of 2 037 490 initiated oxycodone while taking SSRIs (1 475 114 [72.4%] women; mean [SD] age, 50.1 [15.3] years). Most (1 418 712 [69.6%]) were receiving other SSRIs at the time of oxycodone initiation.In the primary analysis, we observed 1035 overdose events (0.05% of the study cohort). The adjusted incidence rate of opioid overdose in those using inhibiting SSRIs at the time of oxycodone initiation (9.47 per 1000 person-years) was higher than in those using other SSRIs (7.66 per 1000 person-years), indicating a greater risk of overdose among patients using CYP2D6inhibiting SSRIs (adjusted hazard ratio, 1.23; 95% CI, 1.06-1.31). Results were consistent across multiple subgroup and sensitivity analyses. CONCLUSIONS AND RELEVANCEIn this cohort study of US adults, initiating oxycodone in patients treated with paroxetine or fluoxetine was associated with a small increased risk of opioid overdose.

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Genomic Variation and Pharmacokinetics in Old Age: A Quantitative Review of Age‐ vs. Genotype‐Related Differences

Cited by 21 publications

References 44 publications

Prescribing medicines to older people—How to consider the impact of ageing on human organ and body functions

Prescribing medicines to older people—How to consider the impact of ageing on human organ and body functions

Impact of genetic variants on clinical outcome after percutaneous coronary intervention in elderly patients

Risk of Opioid Overdose Associated With Concomitant Use of Oxycodone and Selective Serotonin Reuptake Inhibitors

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