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Pharmacokinetic Study of Antisense Oligodeoxynucleotides Cantide in Rhesus Monkeys

Author: WangXiuZhong
Tutor: SongHaiFeng；LiWeiPing
School: Anhui Medical University,
Course: Pharmacology
Keywords: Antisense oligonucleotide Cantide Pharmacokinetics Non- gel sieving capillary electrophoresis
CLC: R96
Type: Master's thesis
Year: 2010
Downloads: 39
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Abstract

Carcinoma TECH (Cantide), the first generation of antisense oligonucleotide drugs, structure the thio oligos deoxyribose nucleotides, and contains a 20 nucleotide sequence. Telomerase catalytic subunit hTERT mRNA targets, according to the nucleotide the complementary principle hybridization after the heteroconjugates blocking RNA template, closed hTERT expression, thereby inhibiting the activity of telomerase, resulting in tumor cell withered death, has anti-tumor effect. This study is part of a study of the Cantide preclinical study Cantide in macaques in vivo pharmacokinetic properties, in order to provide a reference for future clinical trials. The study compared the macaque Single the vd of different doses (8, 16, 24 mg · kg-1) Cantide plasma unchanged drug concentration - time change and pharmacokinetic properties; daily vd 8 mg · kg-1 and studied Cantide 1, after seven consecutive days of plasma the prototype drug concentration - time changes and pharmacokinetic properties. And at the same time on the single and multiple dosing after the plasma Cantide metabolites (n-1) and (n-2) of the drug concentration - time variation and pharmacokinetic nature preliminary observation and comparison. Rhesus monkey plasma optimization and confirmation of Cantide quantitative analysis method using a two-step solid-phase extraction (SPE) method combined with non-gel sieving capillary electrophoresis (NGCE) technology rhesus monkey plasma antisense oligonucleotide drugs Cantide in quantitative Methods of analysis Through the methods to inspect and optimize and finalize a solid phase extraction (anion exchange column sample buffer pH value of 9.0, the sample volume and elution volume were 5 mL and 3 mL) and NGCE analysis conditions (the plastic irrigation time of 30 min, the separation voltage of 24 kV). In this condition, the rhesus monkey plasma Cantide As in 1.95 ^{250μg · mL-1 range a good linear relationship, the lowest limit of quantification (LLOQ) 1.95μg · mL-1, the standard curve and QC sample the concentration of the lowest point and the rest of the deviation of each concentration point lt; 15%. Intra accuracy of 93.38% ^{1 00.71%, the relative standard deviation (intra-day RSD) of intra-lt; 10.66%; batch accuracy of 89.46% ^{1 03.46 %, relative standard deviation (inter-day RSD) of batch lt; 8.60%. Under different conditions (room temperature for 4 h, 4 ° C storage 24 h, repeated freezing and thawing, -80 ℃ save a month and stored at -80 ℃ the 7) Cantide rhesus monkey plasma stability. Methodology confirmatory results show that the method specificity, sensitivity, precision, accuracy and stability are in line with the a pharmacokinetic study requirements for Cantide in macaques in vivo pharmacokinetic studies. 2 macaque single vd different dose Cantide after prototype and its metabolites (n-1) and (n-2) of the plasma drug concentration and drug pharmacokinetics parameters macaque single of vd 8,16 and 24 mg · kg ^{-1 Cantide prototype plasma drug concentration, time to peak (Tmax) more than at the end of infusion instant were 32.50 ± 2.89,32.50 ± 2.89,28.75 ± 6.29 min. Low, medium and high dose groups peak concentration (Cmax) was 72.21 ± 8.68 (compared to the middle dose group P lt; 0.001), 110.90 ± 11.22 (compared with the high-dose group P lt; 0.05) and 150.01 ± 17.84μg · mL ^{-1 (compared with the low-dose group, P lt; 0.01) different dose group significant difference. The end of the elimination phase half-life t1 / 2 were 57.91 ± 23.64 (medium dose group compared with no statistically significant difference), 73.58 ± 25.45 (compared with the high-dose group was not statistically significant difference) and 77.94 ± 8.84 min ( compared with the low-dose group, the difference was not statistically significant). Low, medium and high dose group AUC (0-t) were 4874.46 ± 844.08 (compared to the middle dose group P lt; 0.05), 6998.54 ± 1094.18 (compared with the high-dose group P lt; 0.05), 11057.38 ± 2068.03 μg · min · mL ^{-1 (P lt; 0.01) compared with the low-dose group. Low, medium and high dose group AUC (0-inf) were 5148.73 ± 1018.81 (medium dose group compared to P lt; 0.05), 7392.22 ± 1019.76 (compared with the high-dose group, P = 0.0571), 12462.22 ± 3485.74μg · min · mL ^{-1 (compared with the low-dose group, P lt; 0.05). Each dose group dose ratio 1:2:3 ratio of AUC (0-inf) growth for 1:1.43:2.42. Low, plasma clearance rate of the high-dose group CLs were 1.60 ± 0.31 (compared to the middle dose group P lt; 0.05), 2.19 ± 0.27 (compared with the high-dose group no statistically significant difference), 2.04 ± 0.53 mL · min ^{-1 · kg ^{-1 (no statistically significant difference compared with the low-dose group). After administration of each dose group metabolite samples (n ^{-1 ) and (n-2) plasma drug concentrations and pharmacokinetic parameters between the groups results similar to the prototype drug, the same point in time metabolite concentrations were lower than the unchanged drug in plasma metabolites reach peak concentration, the clearance rate of the short-chain metabolites in the long chain of unchanged drug, macaques in vivo prototype drug constantly into metabolites immediately after the prototype drug chain shortened metabolites MRT unchanged drug prolonged terminal elimination phase half-life increases, particularly evident in the performance of the high-dose group. 3 macaques repeatedly VD 8 mg · kg ^{-1 Cantide after the prototype and its metabolites (n-1)) and (n-2) of the plasma drug concentrations and pharmacokinetic parameters macaques times vd 8 mg · kg ^{-1 Cantide after the last administration plasma concentration of unchanged drug peak time (Tmax) of 35.00 ± 7.07 min; the The peaks concentration Cmax was 58.34 ± 17.39μg · mL ^{- 1 ; the end phase half-life t1 / 2 for 57.45 ± 24.38 min, plasma clearance CLs was 1.85 ± 0.14 mL · min ^{-1 · kg ^{-1 ; AUC (0-t) to 4010.71 ± 223.81 min · μg · mL ^{-1 , AUC (0-inf) to 4335.55 ± 306.16μg · min · mL ^{-1 There was no statistically significant differences between the above parameters compared with the first dose group. After the end of the first administration of its metabolic product (n ^{-1 ), and (n-2) of the plasma drug concentrations and pharmacokinetic parameters were no statistically significant differences, suggesting that multiple administration Cantide no significant change in the body's metabolic processes in the rhesus monkey, drug metabolism and clearance process, there is no drug accumulation or induce metabolic phenomenon. The results show that, the multiple vd Cantide last administration group and the first dose groups each pharmacokinetic parameter approximation, no statistically significant difference.}}}}}}}}}}}}}}}}}}

Pharmacokinetic Study of Antisense Oligodeoxynucleotides Cantide in Rhesus Monkeys

Abstract

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