Cyclosporine -- Drug Interactions and the Influence of Patient Age

Jennifer Lill, Larry A. Bauer, John R. Horn, and Philip D. Hansten


Am J Health Syst Pharm. 2000;57(17) 

In This Article

Abstract and Introduction

Cyclosporine-drug interactions in adult transplant patients and the impact of age were studied.

The medical records of transplant patients receiving cyclosporine therapy were identified. Data on patient demographics, cyclosporine dosages, dosage form, blood trough concentrations, clinical laboratory test values, and concurrent medications were collected. One-compartment models for oral and i.v. administration were used to fit cyclosporine concentration data to population pharmacokinetic and statistical models. Nonlinear mixed-effect modeling (NONMEM) software was used. The influence of covariates, including but not limited to concomitant medications and age, on cyclosporine pharmacokinetics was evaluated.

The records of 100 patients (36 women and 64 men) were reviewed. A mean ± S.D. of 9 ± 2 and 9 ± 1 medications per day were consumed by patients <60 and ≥60 years old, respectively. Mean population pharmacokinetic values of 0.407 L/hr/kg for clearance, 4.0 L/kg for volume of distribution, 31% for bioavailability, and 10.6 hours for half-life were determined on the basis of 569 blood cyclosporine levels. Twelve medications (sertraline, losartan, valsartan, quinine, atorvastatin, simvastatin, pravastatin, fluvastatin, alendronate, digoxin, acyclovir, and oxycodone) with previously unconfirmed pharmacokinetic interactions with cyclosporine were identified as interacting. There was no correlation between age and interactions.

Patients taking cyclosporine were at risk for pharmacokinetic drug interactions when cyclosporine was used in combination with sertraline, losartan, valsartan, quinine, atorvastatin, simvastatin, pravastatin, fluvastatin, alendronate, digoxin, acyclovir 2 , and oxycodone. Transplant patients 60-75 years of age had cyclosporine- drug interactions similar to those in younger patients.

Cyclosporine was introduced into clinical practice in the early 1980s as an effective immunosuppressant. Since that time, cyclosporine has been found to interact with many drugs; the interaction results in either elevated or subtherapeutic blood cyclosporine concentrations. Elevated cyclosporine levels have been linked to nephrotoxicity, neurotoxicity, and an increased risk of infection, while subtherapeutic levels have been associated with acute and chronic rejection of transplanted tissue.[1,2,3,4,5]

Pharmacokinetic interactions involving cyclosporine appear to be mediated primarily by modifications in its gastrointestinal absorption and by alterations in its metabolism associated with changes in cytochrome P-450 3A4 (CYP3A4) activity related to induction of, inhibition of, or competition for this isoenzyme. CYP3A4 participates in the metabolism of approximately 60% of available medicinal agents, creating the potential for frequent cyclosporine drug interactions.[3,6]

Although numerous pharmacokinetic interactions involving cyclosporine mediated by CYP3A4 have been characterized, a significant percentage remain unidentified or have not been fully investigated.[3,6,7] Furthermore, there has been minimal investigation of cyclosporine-drug interactions in persons 60 years of age or older, which hinders clinical management of older patients after organ transplantation. Thus, there is a need to further describe interactions involving cyclosporine in the elderly and to explore how aging influences these interactions.

Limited studies indicate that recipients of kidney and liver transplants who are in the age range of 56-72 years have short-term patient and graft outcomes similar to those of their younger counterparts.[8,9] Advanced age in and of itself is therefore no longer a contraindication to transplantation.[10] In fact, the percentage of kidney, heart, and liver transplants performed in patients older than 65 increased nearly 100% from January 1994 to December 1998.[11] This increase in solid-organ transplantation in the elderly makes it necessary to fully investigate alterations in cyclosporine pharmacokinetics in older patients -- who, in general, appear to be at greater risk of interactions. Elderly individuals are hospitalized because of drug interactions two to three times as frequently as persons in other age groups.[12] Drug interactions account for approximately 22% of the adverse drug events experienced by elderly patients.[13] The mechanisms contributing to the increased risk of drug interactions in older patients have not been fully elucidated. Changes in physiology, receptor sensitivity, and metabolic capacity and the practice of polypharmacy in this population appear to contribute.[13] Given the prevalence of cyclosporine-drug interactions and the expanding use of cyclosporine in the elderly, it is necessary to identify medications that alter cyclosporine pharmacokinetics in this population.

This study was designed to identify unreported or unconfirmed cyclosporine- drug interactions in adult transplant patients and to determine if the observed interactions were influenced by aging.


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