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Study on Pharmacokinetics and Pharmacodynamics of IFNα-2b PLGA Sustained-release Microspheres

Author: LuLei
Tutor: ZhongYanQiang；ZouHao
School: Second Military Medical University
Course: Pharmacy
Keywords: interferon alpha-2b PLGA microspheres ELISA pharmacokinetics human renal cell carcinoma 786-0 cell line nude mice transplantation tumor pharmacodynamics
CLC: R96
Type: Master's thesis
Year: 2006
Downloads: 190
Quote: 0
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Abstract

Interferon alpha （IFNα） is a protein with extensive antiviral, antiproliferative and immunomodulatory biological activity. It is the first recombined cytokine permitted to the clinical applications by FDA. IFNa has great effectiveness to treat various diseases, such as chronic hepatitis B, chronic hepatitis C, chronic myelocytic leukemia and renal cell carcinoma. Now, it is generally accepted that IFNa is the most effective antiviral and antitumor cytokine. Ordinarily it is applied by intramuscular and subcutaneous administration. Due to its short biological half-life （2⁶h） and quick elimination, IFNa needs to be administered frequently to meet different goals of treatment, which may bring inconvenience to patients.Therefore, in order to modify the disadvantages of traditional IFNa and decrease frequency of administration, the suitable sustained-release microspheres containing IFNa-2b were prepared using poly （lactic-co- glycolic） acid （PLGA） as carriers and the pharmacokinetics as well as the pharmacodynamics of IFNa-2b microspheres in vivo were evaluated.An enzyme linked immunosorbent assay （ELISA） method was developed to determine IFNa-2b in the serum of rats. The calibration curves were linear in each sample range with correlation coefficients above 0.99. The precision of intra-day and inter-day were evaluated by analysis of variance with the result of 3.434±2.284% and 4.381±2.603%, respectively. The average accuracy was 98.342±1.329%. The method has been successfully used to support the pharmacokinetics study of IFNa-2b PLGA microspheres in vivo.Following a single subcutaneous administration dosage of IFNa-2b microspheres or injection to rats, the blood samples were collected at given intervals according to experimental design . All collected blood samples were centrifuged to obtain serum and the concentration of IFNa-2b in serum were determined by ELISA method described as above. Pharmacokinetics parameter calculations were carried out using 3P87 software.After a single dose of IFNα-2b injection （8.8xl0⁶pg/kg 2.7x10⁵IU）, it was shown by the serum concentration-time data that the concentration of IFNa-2b in rats serum were reduced quickly, and there was little serum concentration can be detected after 12 hours. The peak serum concentration was 4042.87pg/ml which was obtained at 1h （0.042d） and the mean residence time was 1.92h （0.08d）. The AUC_0^∞ was382.382pg-d/ml.After subcutaneous administration of IFNa-2b microspheres and IFNa-2b injection microspheres by the dosage of 5.3xl07pg/kg （1.62xlO6IU）, the peak serum concentrations were 5490.22 and 25315.32 pg/ml obtained at 0.167d （4h） and 0.063d（1.5h）, respectively. The mean residence time was 6.855 and 0.099d, and the AUQ^ were 23149.018 and 2309.497pg-d/ml, respectively. The peak serum concentration of IFNa-2b by subcutaneous administration with IFNa-2b microspheres was lower than that with IFNot-2b injection （P<0.05）, Tmax and MRT of IFNa-2b microspheres were prolonged evidently compared with IFN<x-2b injection （P < 0.01）.After a single dose of IFN<x-2b microspheres （2.7xl08pg/kg 8.1xlO6IU）, it was shown by the serum concentration-time data that the concentration of IFN<x-2b in rats serum were reduced slowly, After initial burst the peak serum concentration of IFNa-2b was 12660.92pg/ml obtained at 0.167d（4h） and the mean residence time was 7.945d. The AUQ^was 76804.547pg-d/ml.In vivo/in vitro correlation studies suggested that in vitro drug release percentage was significantly correlated with in vivo drug absorption percentage.A study was set for the research of antiproliferation effect of IFNa-2b in vitro. Results of MTT assay and flow cytometry showed that IFNa-2b could inhibit the growth of renal cell carcinoma 786-0 cells and induce apoptosis of the cells in a dose-dependent manner. The antitumor effect of IFNa-2b microspheres on human renal 786-0 cell transplanted tumor was evaluated in vivo. According to the weight, the tumor-bearing nude mice were divided into three groups: the control, IFN<x-2b microspheres and IFNa-2b injection group. IFNa-2b microspheres and IFNa-2b injection were given by subcutaneous administration. The perpendicular diameter of the tumor were measured every 4 days until 28 days after tumor transplantation with a sliding caliper, and the antitumor effects were evaluated according to tumor weights calculated as （long diameter）x（short diameter）2/2. On the 28th day after adminstration, the weights of the subcutaneous tumors with the control. IFNa-2b microspheres and IFN<x-2b injection group were 141.28±29.42,68.88±5.21 and 38.74±14.04 mg, respectively. The treatment group had equivalent inhibitory effects on tumor growth compared to the control group （P < 0.01, P < 0.01）.Conclusion: Pharmacokinetic model of IFN<x-2b PLGA microspheres after subcutaneousadministration to rats was consistent with one-compartment model with 1st order kinetic elimination. The IFN<x-2b PLGA microspheres could perform sustained release in 28 days and have equivalent inhibitory effects on human renal 786-0 cell transplanted tumor growth.

Study on Pharmacokinetics and Pharmacodynamics of IFNα-2b PLGA Sustained-release Microspheres

Abstract

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