Division of Endocrinology, Boston Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
J Clin Endocrinol Metab. 2013 Feb;98(2):610-7. doi: 10.1210/jc.2012-3125. Epub 2012 Dec 21.
In the United States, generic substitution of levothyroxine (L-T(4)) by pharmacists is permitted if the formulations are deemed to be bioequivalent by the Federal Drug Administration, but there is widespread concern that the pharmacokinetic standard used is too insensitive.
We aimed to evaluate the bioequivalence of a brand-name L-T(4) (Synthroid) and an AB-rated generic formulation (Sandoz, Princeton, NJ) in children with severe hypothyroidism.
This was a prospective randomized crossover study in which patients received 8 weeks of one L-T(4) formulation followed by 8 weeks of the other.
The setting was an academic medical center.
Of 31 children with an initial serum TSH concentration >100 mU/L, 20 had congenital hypothyroidism (CH), and 11 had autoimmune thyroiditis.
The primary endpoint was the serum TSH concentration. Secondary endpoints were the free T(4) and total T(3) concentrations.
The serum TSH concentration was significantly lower after 8 weeks of Synthroid than after generic drug (P = .002), but thyroid hormone levels did not differ significantly. Subgroup analysis revealed that the difference in TSH was restricted to patients with CH (P = .0005). Patients with CH required a higher L-T(4) dose (P < .0004) and were younger (P = .003) but were not resistant to thyroid hormone; 15 of 16 CH patients had severe thyroid dysgenesis or agenesis on imaging. The response to generic vs brand-name preparation remained significant when adjusted for age.
Synthroid and an AB-rated generic L-T(4) are not bioequivalent for patients with severe hypothyroidism due to CH, probably because of diminished thyroid reserve. It would therefore seem prudent not to substitute L-T(4) formulations in patients with severe CH, particularly in those <3 yr of age. Our results may have important implications for other severely hypothyroid patients in whom precise titration of L-T(4) is necessary.
在美国，如果药剂师认为药物制剂在生物等效性方面符合联邦药物管理局的标准，就可以允许替代左旋甲状腺素（L-T（4）），但人们普遍担心所使用的药代动力学标准不够敏感。
我们旨在评估严重甲状腺功能减退症患儿的品牌左旋甲状腺素（Synthroid）和 AB 级仿制药（Sandoz，新泽西州普林斯顿）的生物等效性。
这是一项前瞻性随机交叉研究，患者接受 8 周的一种 L-T（4）制剂治疗，然后再接受 8 周的另一种制剂治疗。
学术医疗中心。
31 例初始血清 TSH 浓度>100mU/L 的患儿中，20 例患有先天性甲状腺功能减退症（CH），11 例患有自身免疫性甲状腺炎。
主要终点是血清 TSH 浓度。次要终点是游离 T（4）和总 T（3）浓度。
与使用仿制药相比，使用 Synthroid 治疗 8 周后，血清 TSH 浓度显著降低（P=0.002），但甲状腺激素水平无显著差异。亚组分析显示，TSH 的差异仅限于 CH 患者（P=0.0005）。CH 患者需要更高的 L-T（4）剂量（P<0.0004），且年龄更小（P=0.003），但对甲状腺激素无抵抗；16 例 CH 患者中有 15 例在影像学上有严重的甲状腺发育不良或发育不全。在调整年龄后，对仿制药与品牌药的反应仍有显著差异。
对于因 CH 而患有严重甲状腺功能减退症的患者，Synthroid 和 AB 级仿制药 L-T（4）在生物等效性方面并不等效，这可能是由于甲状腺储备减少所致。因此，对于严重 CH 患者，尤其是年龄<3 岁的患者，不建议替代 L-T（4）制剂。我们的结果可能对其他需要精确滴定 L-T（4）的严重甲状腺功能减退症患者具有重要意义。
