Drug Interactions with Levothyroxine Therapy in Patients with Hypothyroidism: Observational Study in General Practice

Trifirò, Gianluca; Parrino, Fabrizio; Sultana, Janet; Giorgianni, Francesco; Ferrajolo, Carmen; Bianchini, Elisa; Medea, Gerardo; Benvenga, Salvatore; Cricelli, Iacopo; Cricelli, Claudio; Lapi, Francesco

doi:10.1007/s40261-015-0271-0

Cited by 31 publications

(35 citation statements)

References 33 publications

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“…Sachmechi et al also showed that chronic use of PPIs (in their case lansoprazole) in hypothyroid patients resulted in statistically significant changes in thyrotropin levels which could necessitate adjustments in levothyroxine dosage (10). The drug interaction between PPIs and LT4 has also been recently reported by two epidemiological studies (11,12).…”

Section: Introductionmentioning

confidence: 90%

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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Section: Introductionmentioning

confidence: 90%

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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“…Contrary to a previous nationwide report in which the authors analyzed HSD records on LT4 number of prescriptions during potential DDIs regardless of the type of LT4 formulation [45], we explored the differential effects of DDIs on LT4 liquid and tablet users choosing the PDD variation as preferred outcome best reflecting the actual therapeutic regimen. Furthermore, we improved on previous work, taking into account a number of confounders that may variously interfere with treatment effect on TSH variability, such as age, gender and diverse comorbidities, along with performing a statistical analysis which accounts for dependent pairwise data [39].…”

Section: Discussionmentioning

confidence: 99%

“…In line with prior investigations, we excluded estrogen-progestin combinations because the pharmacological effects of one hormone on TSH may be counter-balanced by the other [44], potentially leading to unexpected TSH fluctuations. We also excluded medications with proven minor clinical relevance [45,46].…”

Section: Exposure Assessmentmentioning

confidence: 99%

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Drug interactions in users of tablet vs. oral liquid levothyroxine formulations: a real-world evidence study in primary care

et al. 2017

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Purpose Several medications may interact with levothyroxine (LT4) intestinal absorption or metabolism, thus reducing its bioavailability. We investigated the variability of thyroid stimulating hormone (TSH) levels and prescribed daily dosages (PDDs) of LT4 before and during potential drug-drug interactions (DDIs) in users of tablets vs. oral liquid LT4 formulations. Methods By using the Italian general practice Health Search Database (HSD), we retrospectively selected adult patients with at least one LT4 prescription from 2012 to 2015 and at least 1 year of clinical history recorded. The incident prescription of interacting medications (e.g., proton pump inhibitors, calcium or iron salts) was the index date. Analysis was carried out using a self-controlled study design. Results Overall, 3965 users of LT4 formed the study cohort (84.1% women, mean age 56 ± 16.5 years). TSH variability on the entry date was greater among liquid LT4 users than in those prescribed with tablets as shown by the difference between 75th and 25th centile, which were 3.01 and 3.8, respectively. The incidence rate ratio (IRR) for TSH variability did not differ between groups, before and during exposure to DDIs. In contrast, PDDs less likely increased during the exposure to DDI with oral liquid LT4 compared with tablets (IRR = 0.84; 95% CI: 0.77-0.92), especially in patients with post-surgical hypothyroidism (IRR = 0.75; 95% CI: 0.64-0.85). Conclusions In clinical practice, the use of oral liquid LT4 is not associated with increased PDDs, compared with tablets formulation, during exposure to DDIs. These results support the need for individualizing LT4 formulation to prescribe, especially in patients with various comorbidities and complex therapeutic regimens.

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“…It has been reported that oral absorption of levothyroxine may be hindered by certain foods, coffee beverages, and drugs [1,5,9,[17][18][19][20][21][22]. There is also evidence indicating that hypothyroid patients treated with levothyroxine gel caps may experience less thyroid hormone fluctuation than with treatment using levothyroxine tablets [23][24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

The Economic Impact of Changing Levothyroxine Formulations in Difficult-to-Treat Hypothyroid Patients: An Evidence-Based Model

Elmor¹,

Sandulli²,

Carter³

2017

Pharmacoeconomics

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Objective: To determine the budget impact of incorporating levothyroxine gel caps in the treatment plan of patients diagnosed with hypothyroidism who experience multiple levothyroxine dose or formulation changes annually due to inadequate efficacy or tolerability.Methods: Cost estimates of levothyroxine formulations were obtained. Estimated utilization patterns and costs of physician services, laboratory tests, ancillary healthcare services, and lost productivity were quantified based on published literature and government/public sources. The patient population was based on epidemiology reports and estimates from the American Association of Clinical Endocrinology and the American Thyroid Association. All calculations of economic outcomes were determined using a budget impact model constructed in a MS Excel platform.Results: The economic model demonstrated for a population of 500,000 persons, there are 23,000 (4.6%) people with hypothyroidism, of which 18,400 (80.0%) receive pharmacologic treatment, including 17,480 (95.0%) that receive levothyroxine. The proportion of patients requiring ≥ 1 dosage changes annually is 31.4%, producing 5,489 "hard-to-treat" patients. Similarly, the proportion of patients requiring ≥ 2 dosage changes annually is 8.0% or 1,398 "harder-to-treat" patients. Using evidence-based data of the tolerability and absorption characteristics of levothyroxine gel caps, changing 20.0% of the target cohort to the gel cap formulation produced annual net cost savings of $542,901 in direct medical costs and $564,650 in lost productivity for "hard-to-treat" patients and savings of $409,107 in direct medical costs and $441,926 in lost productivity for "harder-to-treat" patients. Conclusions:Consideration of switching levothyroxine product from a tablet to a gel cap formulation is justified on an economic and therapeutic basis for hypothyroid patients at risk of subadequate drug efficacy or tolerability as measured by the need for one or more annual levothyroxine dosage or formulation adjustments.

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Drug Interactions with Levothyroxine Therapy in Patients with Hypothyroidism: Observational Study in General Practice

Cited by 31 publications

References 33 publications

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

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

Drug interactions in users of tablet vs. oral liquid levothyroxine formulations: a real-world evidence study in primary care

The Economic Impact of Changing Levothyroxine Formulations in Difficult-to-Treat Hypothyroid Patients: An Evidence-Based Model

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