Immunotherapy in Elderly Transplant Recipients A Guide to Clinically Significant Drug Interactions

Currently, >50% of candidates for solid organ transplantation in Europe and the US are aged >50 years while approximately 15% of potential recipients are aged >= 65 years. Elderly transplant candidates are characterized by specific co-morbidity profiles that compromise graft and patient outcome after transplantation. The presence of coronary artery or peripheral vascular disease, cerebrovascular disease, history of malignancy, chronic obstructive lung disease or diabetes mellitus further increases the early post-transplant mortality risk in elderly recipients, with infections and cardiovascular complications as the leading causes of death. Not only are elderly patients more prone to developing drug-related adverse effects, but they are also more susceptible to pharmacokinetic and pharmacodynamic drug interactions because of polypharmacy. The majority of currently used immunosuppressant drugs in organ transplantation are metabolized by cytochrome P450 (CYP) or uridine diphosphate-glucuronosyltransferases and are substrates of the multidrug resistance (MDR)-1 transporter P-glycoprotein, the MDR-associated protein 2 or the canalicular multispecific organic anion transporter, which predisposes these immunosuppressant compounds to specific interactions with commonly prescribed drugs. In addition, important drug interactions between immunosuppressant drugs have been identified and require attention when choosing an appropriate immunosuppressant drug regimen for the frail elderly organ recipient. An age-related 34% decrease in total body clearance of the calcineurin inhibitor ciclosporin was observed in elderly renal recipients (aged >65 years) compared with younger patients, while older recipients also had 44% higher intracellular lymphocyte ciclosporin concentrations. Similarly, using a Bayesian approach, an inverse relationship was noted between sirolimus clearance and age in stable kidney recipients. Ciclosporin and tacrolimus have distinct pharmacokinetics, but both are metabolized by intestinal and hepatic CYP3A4/3A5 and transported across the cell membrane by P-glycoprotein. The most common drug interactions with ciclosporin are therefore also observed with tacrolimus, but the two drugs do not interact identically when administered with CYP3A inhibitors or inducers. The strongest effects on calcineurin-inhibitor disposition are observed with azole antifungals, macrolide antibacterials, rifampicin, calcium channel antagonists, grapefruit juice, St John's wort and protease inhibitors. Drug interactions with mycophenolic acids occur mainly through inhibition of their enterohepatic recirculation, either by interference with the intestinal flora (antibacterials) or by limiting drug absorption (resins and binders). Rifampicin causes a reduction in mycophenolic acid exposure probably through induction of uridine diphosphate-glucuronosyltransferases. Proliferation signal inhibitors (PSIs) such as sirolimus and everolimus are substrates of CYP3A4 and P-glycoprotein and have a macrolide structure very similar to tacrolimus, which explains why common drug interactions with PSIs are comparable to those with calcineurin inhibitors. Ciclosporin, in contrast to tacrolimus, inhibits the enterohepatic recirculation of mycophenolic acids, resulting in significantly lower concentrations and hence risk of underexposure. Therefore, when switching from tacrolimus to ciclosporin and vice versa or when reducing or withdrawing ciclosporin, this interaction needs to be taken into account. The combination of ciclosporin with PSIs requires dose reductions of both drugs because of a synergistic interaction that causes nephrotoxicity when left uncorrected. Conversely, when switching between calcineurin inhibitors, intensified monitoring of PSI concentrations is mandatory. Increasing age is associated with structural and functional changes in body compartments and tissues that alter absorptive capacity, volume of distribution, hepatic metabolic function and renal function and ultimately drug disposition. While these age-related changes are well-known, few specific effects of the latter on immunosuppressant drug metabolism have been reported. Therefore, more clinical data from elderly organ recipients are urgently required.