Pharmacokinetics and Potential Advantages of a New Oral Solution of Levothyroxine vs. other Available Dosage Forms
received 10 June 2012
accepted 15 October 2012
15 November 2012 (eFirst)
To better understand the pharmacokinetics and potential advantages of a levothyroxine oral solution vs. tablets and soft gel capsules.
4 randomized, 2-treatment, single-dose (600 mcg levothyroxine), 2-way crossover bioequivalence studies in 84 healthy subjects were analyzed. Samples were collected before dosing and until 48–72 h post-dose to calculate noncompartmental baseline-adjusted pharmacokinetic parameters: maximum concentration, time to maximum concentration, and area-under-the-concentration-time-curve from 0 to 48 h and from 0 to 2 h.
Mean pharmacokinetic parameters (±standard deviation) for tablets, capsules and solution, respectively, were: area-under-the-concentration-time-curve from 0 to 2 h (ng*h/mL)=68.4±32.8, 64.4±24.4, 99.1±22.7; area-under-the-concentration-time-curve from 0 to 48 h (ng*h/mL)=1 632±424, 1 752±445, 1 862±439; maximum concentration (ng/mL)=67.6±20.9, 68.0±15.9, 71.4±16.0; time of maximum concentration (hours)=2.25±0.99, 2.38±1.58, 1.96±1.07. Overall rate and extent of exposure were not statistically different between formulations, but a faster onset of absorption for the solution was suggested (greater area-under-the-concentration-time-curve from 0 to 2 h and faster time to maximum concentration by an average of 30 min).
Levothyroxine rate and extent of exposure are similar between tested formulations. The solution appears however to reach systemic circulation quicker as dissolution is not needed before absorption starts. The solution’s greater early exposure and a faster time to maximal concentration of around 30 min may be of benefit to minimize drug-food interactions and deserves further investigations.
- 1 Wartofsky L. Levothyroxine: therapeutic use and regulatory issues related to bioequivalence. Expert Opinion on Pharmacotherapy 2002; 3 (06) 727-732
- 2 AHFS Drug Information® . Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2011
- 3 Brent GA, Keonig RJ. Thyroid and Anti-Thyroid Drugs. 12th ed McGraw-Hill Companies; 2011
- 4 Woeber KA. Treatment of Hypothyroidism. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005
- 5 Liwanpo L, Hershman JM. Conditions and drugs interfering with thyroxine absorption. Best Practice & Research Clinical Endocrinology & Metabolism 2009; 23: 781-792
- 6 Bianco AC, Larsen PR. Intracellular Pathways of Iodothyronine Metabolism. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005
- 7 Yannovits N, Zintzaras E, Pouli A et al. A bioequivalence study of levothyroxine tablets versus an oral levothyroxine solution in healthy volunteers. European Journal of Drug Metabolism and Pharmacokinetics 2006; 31 (02) 73-78
- 8 Colucci P, D’Angelo P, Mautone G 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. Therapeutic Drug Monitoring 2011; 33 (03) 355-361
- 9 Dunn OJ. Multiple comparisons using rank sums. Technometrics 1964; 6: 241-252
- 10 Gibaldi M. Bioequivalence of thyroid preparations: the final word? The AAPS Journal 2005; 7 (01) E59-E60
- 11 Colucci P, Turgeon J, Ducharme MP. How critical is the duration of the sampling scheme for the determination of half-life, characterization of exposure and assessment of bioequivalence?. Journal of Pharmacy & Pharmaceutical Sciences: a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 2011; 14 (02) 217-226
- 12 Lilja JJ, Laitinen K, Neuvonen PJ. Effects of grapefruit juice on the absorption of levothyroxine. British Journal of Clinical Pharmacology 2005; 60 (03) 337-341
- 13 Siraj ES, Gupta MK, Reddy SS. Raloxifene causing malabsorption of levothyroxine. Archives of Internal Medicine 2003; 163 (11) 1367-1370
- 14 Singh N, Singh PN, Hershman JM. Effect of calcium carbonate on the absorption of levothyroxine. JAMA: the Journal of the American Medical Association 2000; 283 (21) 2822-2825
- 15 Campbell NR, Hasinoff BB, Stalts H et al. Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism. Annals of Internal Medicine 1992; 117 (12) 1010-1013
- 16 Sherman SI, Tielens ET, Ladenson PW. Sucralfate causes malabsorption of L-thyroxine. The American Journal of Medicine 1994; 96 (06) 531-535
- 17 Havrankova J, Lahaie R. Levothyroxine binding by sucralfate. Annals of Internal Medicine 1992; 117 (05) 445-446
- 18 Sperber AD, Liel Y. Evidence for Interference With the Intestinal Absorption of Levothyroxine Sodium by Aluminum Hydroxide. Archives of Internal Medicine 1992; 152 (01) 183-184
- 19 Northcutt RC, Stiel JN, Hollifield JW et al. The influence of cholestyramine on thyroxine absorption. JAMA: the Journal of the American Medical Association 1969; 208 (10) 1857-1861
- 20 Liel Y, Sperber AD, Shany S. Nonspecific intestinal adsorption of levothyroxine by aluminum hydroxide. The American Journal of Medicine 1994; 97 (04) 363-365
- 21 Liel Y, Harman-Boehm I, Shany S. Evidence for a clinically important adverse effect of fiber-enriched diet on the bioavailability of levothyroxine in adult hypothyroid patients. The Journal of Clinical Endocrinology and Metabolism 1996; 81 (02) 857-859