ABSTRACT
Sirolimus, a novel immunosuppressive drug, has been used in kidney transplant recipients to minimize calcineurine inhibitor (CNI) and steroid toxicities. Likewise CNI, Sirolimus's pharmacokinetics have both inter and intra-individual pharmacokinetic variations. Due to ethnic differences, the recommended oral loading dose of 6 mg and oral maintenance dose of 2 mg per day for Caucasian patients and oral loading dose of 10 mg and oral maintenance dose of 5 mg per day for African-American patients may not be appropriate for Asian recipients. We, therefore conducted the pharmacokinetic study of sirolimus in Thai population, aimed to delineate the appropriate sirolimus dose for further clinical use. The study was performed in 12 healthy Thai volunteers. After an over night fasting, a single oral dose of 6 mg sirolimus was given. The complete pharmacokinetic study was done by UVhigh performance liquid chromatography (HPLC-UV) to measure the whole blood sirolimus level at 0.5 hour after the dose (C0.5) and then C1, C1.5, C2, C2.5, C3, C4, C6, C8, C12, and C24 hours. A complete area under the concentration time curve from 0-24 hours (AUC(0-24 hr)) was calculated by using the trapezoidal rule. The mean (+/- SD) time to maximal concentration (Tmax) was 1.45 +/- 0.5 hr (range 1-3 hrs). The maximal (Cm) and minimal plasma concentration (Ctroug) for sirolimus were 25.3 +/- 6.1 ng/ml (range 18.10 - 40 ng/ml) and 4.47 +/- 0.57 ng/ml (range 2.90 - 7.20) ng/ml respectively. The AUC(0-24 hr) were 187.9 +/- 48.2 ng * hr/ml (range 151.3 - 294.8 ng * hr/ml). Sirolimus level at 4 hr post-dose had the best of correlation with AUC(0-24 hr) (Pearson correlation = 0.76, p < 0.007). One volunteer had a very high sirolimus level. This subject's pharmacokinetic data showed AUC(0-24 hr) of 256 ng * hr/ml and Cmax of 40 ng/ml. In conclusion, the oral loading dose of 6 mg of sirolimus in Thai volunteers did not achieve the recommended therapeutic level (5-10 ng/ml) in most subjects. There are differences in pharmacokinetics of sirolimus between Thais and Caucasians.