醋酸特立帕肽性質(zhì)、用途與生產(chǎn)工藝
特立帕肽是一種合成的34肽，為人甲狀旁腺素PTH的1-34氨基酸片段，該片段是含有84個(gè)氨基酸的內(nèi)源性甲狀旁腺素PTH具有生物活性的N-末端區(qū)域。本品的免疫學(xué)和生物學(xué)特性與內(nèi)源性甲狀旁腺素PTH以及牛甲狀旁腺素PTH(bPTH)完全相同。
醋酸特立帕肽可用于臨床的有促進(jìn)骨形成的治療骨質(zhì)疏松癥的藥物，可更早增加骨形成，其幅度大于骨吸收，對(duì)骨重建平衡有積極的作用，它可以增加骨密度，改善骨微結(jié)構(gòu)和強(qiáng)度，并減少骨折的發(fā)生。
特立帕肽皮下注射后吸收及消除速度都很快，皮下注射本品20 μg，達(dá)峰時(shí)間(tmax)為30 min，半衰期(t1/2 )為60 min，靜脈注射血清半衰期為5 min，絕對(duì)生物利用度95%。90%藥物經(jīng)腎臟清除。
醋酸特立帕肽常見(jiàn)不良反應(yīng)包括頭暈、背痛、惡心和下肢痙攣等，多為一過(guò)性；少見(jiàn)的不良反應(yīng)包括心律失常、耳聾等。目前認(rèn)為不良反應(yīng)發(fā)生與患者年齡和給藥劑量之間無(wú)明顯關(guān)系。
醋酸特立帕肽可通過(guò)抑制成骨細(xì)胞凋亡、激活骨襯細(xì)胞和增強(qiáng)成骨細(xì)胞分化來(lái)介導(dǎo)骨代謝。通過(guò)調(diào)節(jié)腺苷酸環(huán)化酶-環(huán)磷酸腺苷-蛋白激酶A傳導(dǎo)通路間歇性刺激成骨細(xì)胞、骨襯細(xì)胞和骨髓基質(zhì)干細(xì)胞表面PHT-Ⅰ受體，促進(jìn)成骨細(xì)胞的分化、延長(zhǎng)成骨細(xì)胞壽命；通過(guò)磷酸酯C-胞漿鈣離子-蛋白激酶C信號(hào)傳導(dǎo)通路，刺激成骨細(xì)胞系增殖；通過(guò)抑制PPARγ的反式激活活性，減少基質(zhì)細(xì)胞向脂肪細(xì)胞系分化，使成骨細(xì)胞數(shù)量增加；通過(guò)調(diào)節(jié)細(xì)胞因子間接調(diào)節(jié)骨的成長(zhǎng)，例如可以誘導(dǎo)iGF-1與成骨細(xì)胞結(jié)合，從而促進(jìn)骨的形成；通過(guò)Wnt信號(hào)通路調(diào)節(jié)骨形成的過(guò)程，從而增加骨的形成。
禮來(lái)公司甲狀旁腺激素復(fù)泰奧（特立帕肽）最早批準(zhǔn)用于絕經(jīng)后婦女骨質(zhì)疏松 癥，初期或性腺機(jī)能減退的男性骨質(zhì)疏松癥患者，后來(lái)再次增加新適應(yīng)癥用于 在具有骨折高風(fēng)險(xiǎn)的治療與持久性、全身性糖皮質(zhì)激素治療有關(guān)的骨質(zhì)疏松。
2011年復(fù)泰奧（特立帕肽）在全球銷售額達(dá)到9.51億美元。在中國(guó)市場(chǎng)，2011 年由禮來(lái)（法國(guó)）公司開(kāi)始進(jìn)口。
Teriparatide (Human parathyroid hormone-(1-34)) 是 PHT 的激動(dòng)劑，其在 HEK293 細(xì)胞中的 IC50 值為 2 nM。
Trabecular bone calcium and dry weight of the distal femur increased significantly in Teriparatide-treated animals. The increase in trabecular calcium compared with vehicle control occurred as early as 1 week after initiation of treatment with a 35% and 45% increase, respectively, for 10 μg/kg and 40 μg/kg Teriparatide. Similar results were observed for trabecular dry weight. After 4 weeks of treatment with 10 mg/kg or 40 mg/kg Teriparatide, trabecular calcium increased significantly by 70% and 123%, respectively, compared with the vehicle and by 73%.
The 4-week Teriparatide administration increase the pore ratio, number, and density as well as the cortical area, thickness, and bone mineral content (BMC), without significant influencing the volumetric bone mineral density (BMD). The 4-week Teriparatide administration + 8-week vehicle administration decrease the pore ratio, number, and density as well as the cortical area and thickness, compared with the 4-week Teriparatide administration, but the pore ratio, cortical area, and thickness are still higher compared with the 12-week vehicle administration. The 4-week Teriparatide administration + 8-week higherdose IBN administration increase the cortical area, thickness, BMC, and volumetric
BMD and decrease the pore ratio, but not the pore number or density, compared with the 4-week Teriparatide administration + 8-week vehicle administration.
參考質(zhì)量標(biāo)準(zhǔn)
外觀白色粉末純度(HPLC) ≥95.0%
單雜≤1.0%
醋酸根含量5.0%～12.0%
水分含量≤10.0%
肽含量≥80.0%
內(nèi)毒素≤5EU/mg
醋酸特立帕肽
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