OBJECTIVE To evaluate the bioequivalence of domestic sirolimus capsules and commercially available sirolimus oral solution in healthy Chinese volunteers. METHODS Twenty-two healthy Chinese male volunteers were enrolled and orally administered 5 mg sirolimus capsules or oral solution randomly. The concentrations of sirolimus in whole blood were determined by LC-MS/MS. RESULTS The pharmacokinetic parameters of sirolimus capsules and oral solution were as following： ρmax (26.62±9.97) and (25.28±5.98) ng· mL-1；tmax (2.27±0.55) and (1.91±2.33) h；t1/2 (73.07±13.81) and (65.49±17.00) h；AUC0-t (372.3±146.2) and (368.2±275.0) ng·h·mL-1，AUC0-∞ (466.8±194.3) and (442.3±324.4) ng·h·mL-1， respectively. The relative bioavailability F0-t was (112.4±34.61)% and F0-∞ was (117.2±39.93)%. Two-sided t-test of ρmax， AUC0-t and AUC0-∞ indicated that the preparations were equivalent， and non-parametric test showed that sirolimus capsules had larger tmax than the reference preparation with a significant difference (P<0.05). CONCLUSION The domestic sirolimus capsule is bioequivalent to the marketed sirolimus oral solution with significantly different tmax.
Evaluation of Bioequivalence of Sirolimus Capsules in Healthy Chinese Male Volunteers[J]. Chinese Pharmaceutical Journal, 2012, 47(4): 296-302
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参考文献
[1] JONES K， SAADAT-LAJEVARD S， LEE T， et al. An immunoassay for the measurement of sirolimus [J]. Clin Ther， 2000， 22(suppl B)： 49-61. [2] LAM M F， YIP T P S， TSE K C， et al. Sirolimus in kidney transplantation： A pilot study in Chinese patients[J]. Hong Kong J Nephrol， 2004， 6(1)： 38-42. [3] CAMPANERO M A， CARDENAS E， SDABA B， et al. Therapeutic drug monitoring for sirolimus in whole blood of organ transplants by high-performance liquid chromatography with ultraviolet detection[J]. J Chromatography A， 2004， 1031(1-2)： 265-273. [4] RANGAN G K， NGUYEN T， MAINRA R， et al. Therapeutic role of sirolimus in non-transplant kidney disease[J]. Pharmacology & Therapeutics， 2009， 123(2)： 187-206. [5] LUKAS J C， CALVO R， ZOGRAFIDIS A， et al. Simulation of sirolimus exposures and population variability immediately post renal transplantation： importance of the patient′s CYP3A5 genotype in tailoring treatment[J]. Biopharm Drug Dispos， 2010， 31(2-3)：129-137. [6] MACDONALD A， SCAROLA J， BURKE J T， et al. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus [J]. Clin Ther， 2000， 22 (suppl B)：101-121. [7] DANSIRIKUL C， MORRIS R G， TETT S E， et al. A bayesian approach for population pharmacokinetic modeling of sirolimus [J]. Br J Clin Pharmacol， 2006， 62(4)： 420-434. [8] BRATTSTRM C， SWE J， JANSSON B， et aL. Pharmacokinetics and safety of single oral doses of sirolimus (rapamycin) in healthy male volunteers[J]. Ther Drug Monit， 2000， 22(5)： 537-544. [9] LEELAHAVANICHKUL A， AREEPIUM N， VADCHARAVIVAD S， et al. Pharmacokinetics of sirolimus in Thai healthy volunteers[J]. J Med Assoc Thai， 2005， 88 (4)： 157-162. [10] LEUNG L Y， LIM H K， ABELL M W， et al. Pharmacokinetics and metabolic disposition of sirolimus in healthy male volunteers after a single oral dose[J]. Ther Drug Monit， 2006， 28(1)：51-61. [11] ZIMMERMAN J J， PATAT A， PARKS V， et al. Pharmacokinetics of sirolimus (rapamycin) in subjects with severe hepatic impairment[J]. J Clin Pharmacol， 2008， 48(3)：285-292. [12] JIAO Z， SHI X J， LI Z D， et al. Population pharmacokinetics of sirolimus in de nove Chinese adult renal transplant patients[J]. Br J Clin Pharmacol， 2009， 68(1)： 47-60. [13] PAINE M F， LEUNG L Y， WATKINS P B. New insights into drug absorption studieswith sirolimus [J]. Ther Drug Monit， 2004， 26(5)： 463-467. [14] LE MEUR Y， DJEBLI N， SZELAG J C， et al. CYP3A5*3 influences sirolimus oral clearance in de novo and stable renal transplant recipients[J]. Clin Pharmacol Ther， 2006， 80(1)：51-60. [15] MIAO L Y， HUANG C R， HOU J Q， et al. Association study of ABCB1 and CYP3A5 gene polymor- phisms with sirolimus trough concentration and dose requirements in Chinese renal transplant reci- pients [J]. Biopharm Drug Dispos， 2008， 29(1)：1-5. [16] ETTENGER R B， GRIMM E M. Safety and efficacy of TOR inhibitors in pediatric renal transplant recipients[J]. Am J Kidney Dis， 2001， 38(4 suppl 2)： 22-28. [17] MEIER-KRIESCHE H U， KAPLAN B. Toxicity and efficacy of sirolimus： relationship to whole-blood concentrations[J]. Clin Ther， 2000， 22 (suppl B)： 93-100. [18] TEJANI A， ALEXANDER S， ETTENGER R， et al. Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune， rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis[J]. Pediatr Transplant， 2004， 8(2)： 151-160.
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