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.

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 mg) 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. Baseline-adjusted pharmacokinetic parameters were calculated: Cmax (maximal concentration), Tmax (time to Cmax), AUC0-t (area under the concentration-time curve from 0 to the last detectable concentration), AUC0-6 and AUC0-12 (areas under the curve from 0 to 6 and 12 hours, respectively). Analyses of variance were conducted to compare ln-transformed Cmax and AUC. Non-parametric Tmax analyses were done. RESULTS In Study 1, esomeprazole caused a greater decrease in overall levothyroxine exposure of tablets vs. capsules (13% vs 6% for Cmax, 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 Tmax 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.

[1]  G. Trifirò,et al.  Drug Interactions with Levothyroxine Therapy in Patients with Hypothyroidism: Observational Study in General Practice , 2015, Clinical Drug Investigation.

[2]  G. Leese,et al.  Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS) , 2015, Clinical endocrinology.

[3]  C. Vito,et al.  Thyroxine softgel capsule in patients with gastric-related T4 malabsorption , 2015, Endocrine.

[4]  S. Benvenga,et al.  Tablet levothyroxine (L-T4) malabsorption induced by proton pump inhibitor; a problem that was solved by switching to L-T4 in soft gel capsule. , 2014, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[5]  F. Guillén-Grima,et al.  The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. , 2014, The Journal of clinical endocrinology and metabolism.

[6]  S. Benvenga.  When thyroid hormone replacement is ineffective? , 2013, Current opinion in endocrinology, diabetes, and obesity.

[7]  S. Benvenga,et al.  A Review of the Pharmacokinetics of Levothyroxine for the Treatment of Hypothyroidism. , 2013, European endocrinology.

[8]  Hiroki Shimura,et al.  [Epidemiology of thyroid disease]. , 2012, Nihon rinsho. Japanese journal of clinical medicine.

[9]  H. Gharib,et al.  Hypothyroidism: etiology, diagnosis, and management. , 2012, The Medical clinics of North America.

[10]  M. Ducharme,et al.  Pharmacokinetic Equivalence of a Levothyroxine Sodium Soft Capsule Manufactured Using the New Food and Drug Administration Potency Guidelines in Healthy Volunteers Under Fasting Conditions , 2011, Therapeutic drug monitoring.

[11]  J. Hershman,et al.  Conditions and drugs interfering with thyroxine absorption. , 2009, Best practice & research. Clinical endocrinology & metabolism.

[12]  F. Akhlaghi,et al.  A comparative pH-dissolution profile study of selected commercial levothyroxine products using inductively coupled plasma mass spectrometry. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[13]  F. Jamali,et al.  Pharmacokinetics of meloxicam administered as regular and fast dissolving formulations to the rat: influence of gastrointestinal dysfunction on the relative bioavailability of two formulations. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[14]  E. Pearce,et al.  The effect of famotidine, esomeprazole, and ezetimibe on levothyroxine absorption. , 2008, Thyroid : official journal of the American Thyroid Association.

[15]  Garima Gupta,et al.  Effect of proton pump inhibitors on serum thyroid-stimulating hormone level in euthyroid patients treated with levothyroxine for hypothyroidism. , 2007, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[16]  G. delle Fave,et al.  Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis. , 2006, The New England journal of medicine.

[17]  Johannes W. Dietrich,et al.  Absorption kinetics of levothyroxine is not altered by proton-pump inhibitor therapy. , 2006, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.