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Pharmacokinetic Interactions between Sirolimus and Microemulsion Cyclosporine When Orally Administered Jointly and 4 Hours Apart in Healthy Volunteers

From the Department of Clinical Pharmacology, Wyeth Research, Collegeville, Pennsylvania (Dr. Zimmerman, Ms. Harper, Dr. Getsy) and the Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Buffalo, New York (Dr. Jusko).

Sirolimus (RAPA) and cyclosporine (CsA) are immunosuppressive compounds that are being used concomitantly in renal transplant patients. Both drugs are dosed orally, have common intestinal and hepatic metabolism and intestinal transport mechanisms, and thus offer potential for pharmacokinetic drug interactions. A single-dose, open-label, four-period, four-treatment, randomized crossover study was completed in 15 male and 6 female volunteers. Each subject received a 10-mg oral dose of RAPA alone (Rapamune Oral Solution), a 300-mg oral dose of CsA alone (3 x 100-mg Neoral Soft Gelatin Capsules), RAPA and CsA jointly, and CsA followed by RAPA delayed by 4 hours. Blood samples were collected for either 144 hours (RAPA) or 48 hours (CsA) and analyzed by either liquid chromatography/tandem mass spectrometry (RAPA) or radioimmunoassay (CsA). RAPA bioavailability was markedly increased by CsA when given jointly, with C_max,t_max, and AUC being increased 116%, 92%, and 230%, respectively. However, when RAPA was administered 4 hours after CsA, increases in RAPA C_max, t_max, and AUC were only 37%, 58%, and 80%, respectively. CsA did not affect t_1/2 or mean residence time (MRT) by either mode of combined administration. RAPA did not significantly affect CsA bioavailability after either joint or delayed combined administrations. It was concluded that CsA markedly increases the bioavailability of RAPA, which may be attributed to a large intestinal and hepatic first-pass effect, rather than altered elimination. RAPA did not affect the bioavailability of CsA.

Key Words: Sirolimus • rapamycin • cyclosporine • pharmacokinetics • drug interactions • P-glycoprotein • CYP3A4 • immunosuppression

Address for reprints: James J. Zimmerman, PhD, Clinical Pharmacology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426.

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