Pharmacokinetic Equivalence of a Levothyroxine Sodium Soft Capsule Manufactured Using the New Food and Drug Administration Potency Guidelines in Healthy Volunteers Under Fasting Conditions

Colucci, Philippe; D’Angelo, Pina; Mautone, Giuseppe; Scarsi, Claudia; Ducharme, Murray P.

doi:10.1097/ftd.0b013e318217b69f

Cited by 41 publications

(26 citation statements)

References 6 publications

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“…Conversely, pharmaceutical T 4 preparation is a hydrophilic sodium salt and its physico-chemical characteristics as well as that of the environment in which it dissolves, may be relevant for intestinal absorption. Softgel preparation is a new formulation of levothyroxine and consists in a pearl-shaped capsule, in which T 4 is dissolved in glycerin and has a protecting shell made of softgel gelatin [21]. This preparation has been proven to be bioequivalent to traditional T 4 in tablet form [21], but with a different dissolution profile [20].…”

Section: Introductionmentioning

confidence: 99%

“…Softgel preparation is a new formulation of levothyroxine and consists in a pearl-shaped capsule, in which T 4 is dissolved in glycerin and has a protecting shell made of softgel gelatin [21]. This preparation has been proven to be bioequivalent to traditional T 4 in tablet form [21], but with a different dissolution profile [20]. Pabla et al in fact, showed that the dissolution profile of softgel was clearly superior with the progressive increase of pH, when compared with that of other T 4 preparations from different brands [20].…”

Section: Introductionmentioning

confidence: 99%

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Thyroxine softgel capsule in patients with gastric-related T4 malabsorption

et al. 2015

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The key role of an intact gastric acid secretion for subsequent intestinal T4 absorption is supported by an increased requirement of thyroxine in patients with gastric disorders. A better pH-related dissolution profile has been described in vitro for softgel T4 preparation than for T4 tablets. Our study was aimed at comparing softgel and tablet T4 requirements in patients with gastric disorders. A total of 37 patients with gastric-related T4 malabsorption were enrolled, but only 31 (28F/3M; median age = 50 years; median T4 dose = 2.04 μg/kg/day) completed the study. All patients were in long-lasting treatment (>2 years) with the same dose of T4 tablets when treatment was switched to a lower dose of softgel T4 capsules (-17 %; p = 0.0002). Assessment of serum FT4 and TSH was carried out at baseline and after 3, 6, 12, and 18 months after the treatment switch. In more than 2/3 of patients (good-responders n = 21), despite the reduced dose of T4, median TSH values were similar at each time point (p = 0.3934) with no change in FT4 levels. In the remaining patients (poor-responders n = 10), TSH levels were significantly higher at each time point than at baseline (p < 0.0001). To note, in five of them intestinal comorbidity was subsequently detected. Comorbidity associated with poor-responders status was the only significant predictor in multivariate analysis (OR = 11.333). Doses of softgel T4 capsules lower than T4 tablet preparation are required to maintain the therapeutic goal in 2/3 of patients with impaired gastric acid secretion.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thyroxine softgel capsule in patients with gastric-related T4 malabsorption

et al. 2015

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“…Levothyroxine supplements exist in various forms, ranging from oral solutions to tablets. More recently, a soft gelatin capsule composed of an outer gelatin shell and a viscous fill has been developed by IBSA Institut Biochimique SA and proved to be bioequivalent under fasting conditions in healthy volunteers compared to already commercialized reference tablets (4).…”

Section: Introductionmentioning

confidence: 99%

When Bioequivalence in Healthy Volunteers May not Translate to Bioequivalence in Patients: Differential Effects of Increased Gastric pH on the Pharmacokinetics of Levothyroxine Capsules and Tablets

Yue¹,

Benvenga

Scarsi

et al. 2015

J Pharm Pharm Sci

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-Purpose:Clinical studies have suggested that proton pump inhibitors may decrease levothyroxine absorption and an in vitro study suggested that the effect of pH on dissolution may differ with formulation. To determine the impact of formulation on the pharmacokinetics of levothyroxine in altered gastric pH conditions, this study compared the pharmacokinetics of levothyroxine capsules and tablets, two formulations deemed bioequivalent in healthy volunteers under fasting conditions, when taken with or without esomeprazole. Methods: Two clinical studies were conducted in healthy volunteers given single dose levothyroxine (600 g) with a 45-day washout period. In Study 1 (parallel-design/two-way crossover), 16 subjects received either levothyroxine capsules or tablets, each group with or without prior administration of intravenous esomeprazole (maximum dose of 80 mg). In Study 2 (two-way crossover), 16 subjects received both capsules or tablets after intravenous esomeprazole. Blood samples were collected pre-dose and up to 24 hours post-dose. Baselineadjusted pharmacokinetic parameters were calculated: C max (maximal concentration), T max (time to C max ), AUC 0-t (area under the concentration-time curve from 0 to the last detectable concentration), AUC 0-6 and AUC 0-12 (areas under the curve from 0 to 6 and 12 hours, respectively). Analyses of variance were conducted to compare lntransformed C max and AUC. Non-parametric T max analyses were done. Results: In Study 1, esomeprazole caused a greater decrease in overall levothyroxine exposure of tablets vs. capsules (13% vs 6% for C max , 18% vs. 14% for AUC 0-6 , 17% vs. 5% for AUC 0-12 and 10% vs. 8% for AUC 0-t ). In Study 2 esomeprazole administration resulted in a 16% smaller levothyroxine exposure with tablets vs. capsules. No statistically significant differences in T max were found. Conclusions: Although both formulations are considered "bioequivalent" in healthy volunteers, they may not necessarily be bioequivalent in patients with impaired gastric pH conditions. Levothyroxine capsules may therefore be more appropriate for patients with decreased gastric acidity.

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“…The soft gel capsule contains L-T4 dissolved in glycerine in an outer gelatine shell. 22 This structure provides protection from the variations of gastric pH and could also prevent binding to other substances in the intestinal lumen, such as coffee 23 or other medicaments (for example calcium or iron salts). 21,[24][25][26][27] The liquid form is composed only of L-T4 of variable concentrations, glycerine and ethanol.…”

Section: Novel Formulations Of L-t4 and Their Potential Usementioning

confidence: 99%