Correlation Study between in Vitro Release and in Vivo Absorption of Venetoclax
YUAN Hai-jian1, JIN Jian-ming1, JIANG Jun1, LU Xiao-ping2, FENG Liang3
1. Taizhou Polytechnic College, Taizhou 225300,China; 2.Jiangsu Gravity Biological Technology Co., Ltd., Taizhou 225300,China; 3.Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica, Jiaugsu Provincial Academy of Chinese Medicine, Nanjing 210028, China
Abstract��OBJECTIVE To investigate the in-vitro release behavior of venetoclax preparations, the pharmacokinetic processes and the correlations between in-vitro release and in-vivo absorption of venetoclax in Beagle dogs. METHODS The dissolution curves of venetoclax preparations in different dissolution media were studied. HPLC method was established for the determination of venetoclax in Beagle dogs, and the pharmacokinetics were studied for commercial venetoclax tablets in Beagle dogs under fed and fasted states.The IVIVC study was carried out by linear regression of cumulative in-vitro drug release and in-vivo absorption accumulation percentage data. RESULTS The in-vitro release behavior among venetoclax formulation in 4 dissolution media were significant difference. The simple, accurate and rapid analysis method for venetoclax blood samples was established. The fed group and the fasted group AUC0���� were (32.38��5.87) and (27.70��6.32) mg��h��L-1, the concentration of peak were (4.04��0.78) and (3.72 ��0.69) ��g��mL-1, the peak time were (6.01��1.04) and (4.27��0.92) h, respectively, and there was obvious difference (P<0.05) in AUC0���� and the peak time between two group. Percentage of in-vivo absorption was in good agreement with in-vitro release in pH 6.8 0.2%SDS media. CONCLUSION The study shows that food could improve the bioavailability of venetoclax formulation; 0.2%SDS pH 6.8 media (paddle, 75 r��min-1) is the in-vivo release of venetoclax associated with the in-vitro release condition.
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YUAN Hai-jian, JIN Jian-ming, JIANG Jun, LU Xiao-ping, FENG Liang. Correlation Study between in Vitro Release and in Vivo Absorption of Venetoclax. Chinese Pharmaceutical Journal, 2017, 52(17): 1525-1530.
DEEKS E D. Venetoclax: first global approval[J]. Drugs, 2016, 76(9):1-9.
[2]
DELBRIDGE A R D, GRABOW S, STRASSER A, et al. Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies[J]. Nat Rev Cancer, 2016, 16(2):99-109.
[3]
STILGENBAUER S, EICHHORST B, SCHETELIG J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study[J]. Lancet Oncol, 2016, 17(6):768-778.
[4]
SOUER A J, LEVERSON J D, BOGHAERT E R, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets[J]. Nat Med, 2013, 19(2):202-208.
[5]
CANG S, IRAGAVAPU C, SAVOOJI J, et al. ABT-199 (Venetoclax) and BCL-2 inhibitors in clinical development[J]. J Hematol Oncol, 2015, 8(1):1-8.
[6]
BIRTALAN E, HOELIG P, LINDLEY D J, et al. Melt-extruded solid dispersions containing an apoptosis-inducing agent: US Patent Application 13/253,727[P]. 2012-5-3.
[7]
AGRAWAL A M, DUDHEDIA M S, ZIMNY E. Hot melt extrusion: development of an amorphous solid dispersion for an insoluble drug from mini-scale to clinical scale[J]. AAPS Pharm Sci Tech, 2016, 17(1):133-147.
[8]
AGRAWAL A, DUDHEDIA M, DENG W, et al. Development of tablet formulation of amorphous solid dispersions prepared by hot melt extrusion using quality by design approach[J]. AAPS Pharm Sci Tech, 2016, 17(1):214-232.
[9]
FREISE K J, JONES A K, ECKERT D, et al. Relationship of venetoclax dose and exposure to response in relapsed or refractory chronic lymphocytic leukemia and non-Hodgkin��s lymphoma subjects[J]. Cancer Res, 2016, 76(14):2045.
[10]
ROBERTS A W, DAVIDS M S, PAGEL J M, et al. Targeting BCL-2 with venetoclax in relapsed chronic lymphocytic leukemia[J]. New Engl J Med, 2015, 374(4):311-322.
[11]
ABBVIE I N C, GENETECH I N C. Venclexta(venetoclax):US prescribing information. 2016[EB/OL]. [2016-09-21]. http://www.fda.gov.
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