Cyclosporine -- Drug Interactions and the Influence of Patient Age

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

Disclosures

Am J Health Syst Pharm. 2000;57(17) 

In This Article

Results

One hundred patients (36 women and 64 men) who had been receiving cyclosporine for a mean ± S.D. period of 3.4 ± 2.7 years were enrolled in the study. The patients took a mean ± S.D. of 9 ± 2 medications (patients of <60 years) and 9 ± 1 medications (≥ 60 years) daily. Pertinent demographic information is presented in Table 1.

A total of 569 blood levels (an average of 5.7 per subject) were used to evaluate cyclosporine pharmacokinetics. Eighty-six percent of the patients were taking cyclosporine microemulsion (Neoral, Novartis), and 14% were taking conventional cyclosporine (Sandimmune, Novartis). Data for i.v. cyclosporine, used to determine mean bioavailability for the population, were available for 28% of the patients.

Mean population pharmacokinetic values for cyclosporine were calculated to be clearance, 0.407 L/hr/kg; volume of distribution, 4.0 L/kg; bioavailability, 31%; and half-life, 10.6 hours. The values were normalized by using ideal body weight.

The effect of 107 medications on cyclosporine pharmacokinetics was investigated. Twenty-two medications known to interact with cyclosporine were included. Significant pharmacokinetic interactions, indicated by changes in cyclosporine clearance or bioavailability upon adding, removing, or altering the dosage of a medication other than cyclosporine (p < 0.01), were detected for all 22 medications, confirming the model's ability to detect pharmacokinetic interactions (Table 2). Significant changes in cyclosporine clearance or bioavailability (p < 0.05) were detected for 12 drugs with unknown or unconfirmed interactions with cyclosporine (Table 3). Changes in cyclosporine clearance as a result of concurrent therapy with the medications listed in Tables 2 and 3 can be calculated with the following formula:

New cyclosporine clearance = baseline cyclosporine clearance + (medication dose x regression-line slope)

The regression-line slopes for the medications investigated are reported in Tables 2 and 3. The drugs and dosages associated with the previously unconfirmed or unreported changes in cyclosporine clearance are reported in Table 3. Interindividual variability in population values for cyclosporine clearance, volume of distribution, and bioavailability, reported as the mean and the 95% confidence interval, was 27% (18-33%), 41% (25-82%), and 50% (38-63%), respectively. Residual intrapatient variability was 48% (32-64%).

The impact of age and of the number of concurrent medications on cyclosporine pharmacokinetics was evaluated. Patients less than 60 years of age consumed a mean ± S.D. of 9 ± 2 medications daily, and 9 ± 1 were consumed by patients 60 or older (p > 0.05). In addition, NONMEM analysis indicated that age was not related to changes in cyclosporine clearance or bioavailability (p > 0.05).

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