Wednesday, December 9, 2015

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

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