Pharmacokinetic (PK) interaction study of sirolimus (SRL) and cyclosporine (CSA)

Abstract

SRL (Rapamune®) is an effective immunosuppressant currently marketed worldwide for the prophylaxis of renal allograft rejection. The interaction between SRL 5 mg (oral solution) and CsA 300 mg (Neoral® capsules) when administered simultaneously and 2 hours apart was assessed in a randomized, open-label, 5-period crossover study in 33 healthy male subjects (age 19-43 years, weight 58–89 kg). The subjects received a single oral dose of SRL alone (A), CsA alone (B), SRL and CsA together (C), SRL 2 hours after CsA (D), or SRL 2 hours before CsA (E). Whole blood SRL was assayed by HPLC with mass spectrometric detection (HPLC/MS/MS), and whole blood CsA by immunoassay. Geometric least-squares (GLS) mean ratios and 90% confidence intervals (CIs) were computed for treatment comparisons. Reference treatments for equivalence tests were either A (SRL alone) or B (CsA alone). A GLS mean ratio between 80% to 125% showed equivalence. CsA significantly increased SRL Cmax and AUC during simultaneous administration (by 117% and 183%, respectively) and when SRL was administrated 2 hours after CsA (by 126% and 141%, respectively). CsA did not affect SRL PK when SRL was administrated 2 hours before CsA. SRL did not affect the PK of CsA, regardless of the timing of administration.Table In conclusion, CsA significantly increased SRL whole blood exposure when SRL and CsA were administered simultaneously and when SRL was given 2 hours after CsA. However, no significant PK interaction was observed when SRL was administered 2 hours before CsA. Clinical Pharmacology & Therapeutics (2004) 75, P33–P33; doi: 10.1016/j.clpt.2003.11.126 Table 1. GLS mean ratios (90% CI)* for whole blood SRL and CsA PK parameters SRL CsA C vs A D vs A E vs A C vs B D vs B E vs B * Equivalence Window = 80% to 125%. Cmax 217 (196–241) 226 (204–251) 98 (88- 109) 105 (96–115) 97 (89–116) 93 (86–102) AUC 283 (257–311) 241 (219- 265) 99 (90–109) 105 (100–110) 101 (96–106) 94 (89–99) t1/2 87 (82–91) 87 (83–92) 97 (92–103) 95 (90–100) 104 (99–109) 99 (94–104)