Pharmacokinetic Alterations in the Elderly; You’re Not Too Young to Understand

Renal transplantation reduces mortality in elderly patients by more than 50%, however, challenges are magnified in elderly renal transplant recipients (RTR) when managing their pharmacotherapy regimen. 

Aging is associated with changes in several pharmacokinetics parameters including absorption, distribution, metabolism, and excretion. Developing an effective pharmacotherapeutic plan for elderly transplant recipients requires a clear understanding of the principles of pharmacokinetics and how a specific drug’s handling may be altered with age (Table ). 

Below, few of the specifics of pharmacokinetics of maintenance immunosuppressants in elderly:

Calcineurin Inhibitors (CNI): Several studies evaluated cyclosporin and tacrolimus in elderly RTR. Results show that CNI trough concentrations are 50% higher, Cmax and AUC are also higher, and mandate a dose reduction. These differences in concentration and exposure can be attributed to the good oral absorption, and a reduction in intestinal and hepatic metabolism and elimination. 

mToR inhibitors: Many studies of the mToR inhibitors included a pharmacokinetic subgroup analyses of the elderly. In these studies, there was no association seen between age and drug clearance. 

Antimetabolites: the elderly demonstrate lower mycophenolic acid (MPA) trough concentrations, Cmax and AUC compared to younger RTR. This is likely due to reduced MPA bioavailability of MPA in older patients. Another reason to explain the lower exposure to MPA in the elderly is that MPA is highly protein bound, yet there is a reduction in protein binding sites in the older population, which increased the free fraction of MPA making it more available for glucuronidation and clearance.  

Corticosteroids: there is little data on alteration of corticosteroid pharmacokinetics in elderly RTR; however, decisions can be made based on speculated changes. Prednisolone is extensively metabolized in the liver with significant intra- and inter-individual variability, and mainly binds to albumin. Age-related reductions in metabolism and elimination will likely result in an increased exposure to prednisolone and methylprednisolone. 

Belatacept has been studied in older population, and these analyses found that age-related changes, such as changes in renal function and albumin, did not affect exposure to belatacept. 

In sum, age broadly impacts immune responses as well the pharmacokinetics of the maintenance immunosuppressants, in particular CNI and MMF. There are some data to help aid in the creation of an immunosuppressant protocol in the older transplant recipient, but more specific studies of this patient population are needed. 

Dema Alissa, B.Sc. Pharm., SSC_PhP, MBA 

Felix Krenzien, MD 

Steven Gabardi, PharmD, FAST, FCCP, BCPS

Falls and dialysis

The recent death of the actor Gary Coleman after a fall in his home brought to mind the issue of falls in dialysis patients. Gary was best known for playing the role of Arnold in the TV show Different Strokes. He had congenital nephrotic syndrome and had two renal transplants, in 1973 and 1984. Over the last few years he had been on regular hemodialysis. He had dialysis on the morning of his fall and one of his friends reported that he had been feeling very weak after the session. Unfortunately, he fell at home that afternoon and suffered a head injury from which he did not recover.

There are only a few papers that directly address the issue of falls in dialysis patients. One study prospectively followed 308 dialysis patients of all ages for 8 weeks and found that 13% of patients fell at least once with 80% of the falls occurring at home. In the 12 months after the close observation period ended, 4% of patients suffered a fall-related fracture. Falls were independently associated with polypharmacy, increasing age, diabetes, use of anti-depressants and, unsurprisingly, failing functional tests at the beginning of the study period.

Another study divided 78 dialysis patients into younger (less than 65yrs) and older age groups and followed them for 6 months. Rates of dizziness (80%), pre-syncope (50%) and syncope (20-30%) were similar in the two groups but falls were much commoner in the older cohort (38% v 4%). The rate of falls in the older patients was 1.76/patient/year, which is higher than the rate recorded for elderly nursing home residents.

These falls are not without serious consequences, the rate of hip fractures is 3-4 times higher in dialysis patients than in the general population. Some of this risk is related to reduced bone mineral density but some is related to the increased risk of falls. The one-year mortality for hip fracture in dialysis patients is 40-60%.

So what can we do to prevent falls in our patients? The first thing is to identify patients at risk, particularly those who have a history of previous falls. Avoid overly aggressive fluid removal and reduce the number of medications the patients are taking if possible. Randomized trails have demonstrated the effectiveness of a multidisciplinary approach to falls in non-dialysis patients. This includes review of medications, strength and gait testing with targeted training, assessment of the home environment and measuring visual acuity. These strategies are likely to be effective in dialysis patients also and could help reduce the morbidity associated with falls in this vulnerable population.

PD vs HD in the elderly

Patients over 65 tend not to choose peritoneal dialysis for a host of reasons, not the least of which is PD is underutilized in the US in general. However, a recent study suggests that PD may be preferable to HD in the elderly, at least for those with the cognitive and functional ability to perform PD.

The BOLDE (Broadening Outcomes for Long-term Dialysis in the Elderly) trial out of the UK looked at health-related quality of life measures in PD vs HD patients over 65. Results have not yet been published but were recently presented at the Annual Dialysis Conference in Seattle in March. Using a cross-sectional design, the study matched PD and HD patients (age, gender, time on dialysis) and compared health related quality of life via several validated assessment tools. Mean age was 73, most were men (70%), and ~25% lived alone in both groups. Patients in both groups were on dialysis for on average about 2.5 years. Education level was similar in both groups. Disease intrusiveness scores were lower in PD than in HD patients (22.0 in PD vs. 26.0 in HD) as assessed by the Illness and Intursiveness Rating Scale. The study also found that depressive symptoms were less common in the PD group, as were common dialysis-associated symptoms (headaches, dry mouth, taste changes, dizziness, and unsteadiness), with the exception of lower extremity edema, which was more common in patients with PD. For more details see the author's presentation data here and a review article here.

With the aging of the population, modality choice in the elderly will be a decision encountered more frequently, and at the very least this study should lead us to seriously entertain, if not encourage, PD in the elderly population. Further, as many of you know, Centers for Medicare and Medicaid Services (CMS) will be implementing the bundle payment system in January 2011. In short, dialysis treatments in the US will be reimbursed with one lump some that will cover all the costs of the treatment, including labs, medications etc. Reimbursement for home dialysis will be comparable to in-center dialysis, providing some incentive to increase the use of home modalities which are generally cheaper. Taken in this context, PD enthusiasm in general should increase, both for quality of life and, for better or worse, financial, reasons.