Cyclosporin Pharmacokinetics in the Elderly

Abstract

Cyclosporin is an immunosuppressant used in organ transplantation and selected autoimmune diseases such as rheumatoid arthritis. In both these indications, the elderly represent an important and growing segment of the patient population. Cyclosporin is primarily eliminated via biotransformation by cytochrome P450 (CYP)3A in the gut wall and liver. Additionally, P-glycoprotein (mdr-1) located in the gastrointestinal epithelium can affect affect blood drug concentrations after oral administration of cyclosporin, presumably by counter-transporting the drug from the systemic circulation back into the gastrointestinal lumen. Theoretically, age-related alterations in either of these pathways could affect cyclosporin disposition in the elderly. These general pharmacological considerations together with the narrow therapeutic index of cyclosporin between minimally immunosuppressive concentrations and those associated with adverse events, underscore the need for dedicated pharmacokinetic studies in the elderly. Single dose studies have demonstrated that cyclosporin pharmacokinetics are not different in healthy elderly individuals compared with healthy young adults, nor is the between-subject variability in pharmacokinetic parameters more heterogenous in healthy elderly individuals. Similarly, there were no apparent differences in cyclosporin disposition in elderly patients with rheumatoid arthritis compared with healthy young and elderly individuals. Whether pharmacokinetic variability may be increased in elderly patients has not been rigorously addressed and requires investigation in a larger patient population for a definitive conclusion. A population pharmacokinetic study of cyclosporin in organ transplant patients, including elderly allograft recipients up to 75 years of age, did not identify age as a covariable influencing cyclosporin pharmacokinetics. Hence, the available pharmacokinetic data in the elderly do not reveal any major differences from the disposition characterised in younger individuals. It is generally recognised that the elderly are more prone to drug-related adverse experiences and are at greater risk for drug-drug interactions secondary to polypharmacy. The former factor may underlie, in part, the increased incidence of renal adverse events reported in patients with rheumatoid arthritis over 65 years of age receiving cyclosporin. Clinical experience with cyclosporin in elderly organ transplant recipients has not revealed a tolerability profile remarkably different from those in younger patients. Polypharmacy may have specific relevance for elderly patients treated with cyclosporin since this agent is a substrate of both CYP3A and P-glycoprotein, both of which are important in the elimination of many commonly used drugs. This implies that the clinician prescribing cyclosporin for an elderly patient must exercise a heightened awareness for potential drug-drug interactions which could affect the pharmacokinetics of cyclosporin. Based on the available cyclosporin pharmacokinetic data in adults, no age-r...

Aging Biology and Geriatric Clinical Pharmacology

“…The clearance of drugs that undergo phase II metabolism [e.g., mizolastine (Lebrun-Vignes et al, 2001)] is unchanged in old age, whereas drugs that undergo phase I metabolism [e.g., ropinirole (Kaye and Nicholls, 2000), citalopram (Gutierrez and Abramowitz, 2000), rabeprazole (Swan et al, 1999), argatroban (Swan and Hursting, 2000)] have reduced clearance in older people. On the other hand, a review of pharmacokinetics found that aging in volunteers and subjects with rheumatoid arthritis was not associated with any significant change in cyclosporin pharmacokinetics; although, clearance was lower in older renal transplant recipients (Kovarik and Koelle, 1999). However, cyclosporin metabolism is dependent on both CYP3A4 and P-glycoprotein and the effects of aging on P-glycoprotein are not known.…”

Reduced Elimination of Cyclosporine A in Elderly (>65 Years) Kidney Transplant Recipients

“…The difference in CL/F was 34% and is one important reason why elderly patients reach therapeutic concentrations with lower doses than younger patients. Factors of importance are lower liver mass and reduced liver blood flow in elderly patients (19). In coherence with the lower CL/F in elderly patients, increased terminal elimination half-life was observed in this group and the volume of distribution was somewhat decreased compared with younger patients (Pϭ0.4); however, the exact mechanism for the observed decrease in clearance is not known.…”

Management of Chronic Spontaneous Urticaria in the Elderly

“…Elderly patients should be monitored with particular care, since a decline in renal function also occurs with aging. Most available pharmacokinetic data in the elderly do not reveal any major differences from the drug disposition detected in younger individuals [54]. A more recent pharmacokinetic study in elderly kidney transplant patients has, however, demonstrated that the clearance of cyclosporine decreased with increasing age and that old patients had a significantly larger proportion of the whole blood cyclosporine concentration located in T lymphocytes [55].…”