DrugRes/2015-04-0999/23.6.2015/MPS Original Article Persiani S et al. Isoflavones Effect on Levothyroxine PK … Drug Res received 20.04.2015 accepted 11.06.2015 Bibliography DOI http://dx.doi.org/ 10.1055/s-0035-1555784 Published online: 2015 Drug Res © Georg Thieme Verlag KG Stuttgart · New York ISSN 2194-9379 Correspondence S. Persiani, PhD, Director Translational Sciences and Pharmacokinetics Rottapharm Biotech S.r.l Via Valosa di Sopra 9 20900 Monza Italy Tel.: + 39/039/7390 396 Fax: + 39/039/7390 627 stefano.persiani@rottapharm- biotech.com Key words ● ▶ interactions ● ▶ food supplement ● ▶ pharmacokinetics ● ▶ clinical study ● ▶ climacteric syndrome Evaluation of Levothyroxine Bioavailability after Oral Administration of a Fixed Combination of Soy Isoflavones in Post-menopausal Female Volunteers Authors S. Persiani 1 , F. Sala 1 , C. Manzotti 1 , M. Colovic 1 , M. Zangarini 1 , Y. Donazzolo 2 , B. Barbetta 1 , C. Vitalini 1 , G. Giacovelli 1 , C. Benvenuti 3 , L. C. Rovati 1 Affiliations 1 Rottapharm Biotech S.r.l., Monza, Italy 2 Eurofins|OPTIMED Clinical Research, Gieres, France 3 Rottapharm S.p.A., Monza, Italy Introduction ▼ Menopause is associated with estrogen defi- ciency and its related metabolic effects such as accelerated bone loss and atherosclerosis. Estro- gen replacement therapy has been used for nearly 60 years to treat menopause-related con- ditions [1]. However, following the publication of the Women’s Health Initiative findings suggest- ing that the overall risks outweigh the benefits, the interest in alternative therapies for meno- pause and related symptoms was increased [2]. Soy-derived products with comparable benefits to estrogens but fewer side effects have been pro- posed [3, 4]. Their properties are due to the phy- toestrogen components and include protection against coronary heart disease, breast cancer, osteoporosis and alleviation of hot flushes [5]. The most common forms of phytoestrogens are the soy isoflavones genistein and daidzein that have both estrogenic and antiestrogenic effects, depending on the target tissue [6]. Based on their pharmacological profile, soy isoflavones appear as a possible alternative to ameliorate some cli- macteric symptoms (e. g., hot flashes) and to improve lipoprotein levels [7, 8], although clinical trials provided controversial results [9]. Since it has estimated that as many as 10 % of postmenopausal women in the United States may suffer from hypothyroidism [10] and that worldwide prevalence of subclinical hypothy- roidism ranging from 1 to 10 % with the highest age- and sex-specific rates in women older than 60 years, approaching 20 % in some reports [5], it is possible that post-menopausal women under treatment with levothyroxine, take concomi- tantly dietary supplements containing soy isofla- vones to treat their post-menopausal symptoms. It has been shown that food supplements con- taining soy might reduce the oral absorption of Abstract ▼ Background: Post-menopausal women under treatment with levothyroxine for their medical conditions may take concomitantly dietary sup- plements containing soy isoflavones in combina- tion to treat their post-menopausal symptoms. The aim of this study was to investigate the effect of a fixed combination of soy isoflavones on the oral bioavailability of levothyroxine in post- menopausal female volunteers. Methods: 12 healthy post-menopausal female, who were on stable oral levothyroxine as replacement/supplementation therapy for hypo- thyroidism, received a single recommended oral dose of a food supplement containing 60 mg of soy isoflavones ( > 19 % genistin and daidzin) con- comitantly with (test) and 6 h later (reference) the administration of levothyroxine in a rand- omized, open label, crossover fashion. Plasma concentrations of levothyroxine and soy iso- flavones (daidzin, daidzein, genistin, genistein, S-equol) were determined by LC-MS/MS. Phar- macokinetic (PK) parameters were determined by non-compartmental analysis. No effect of soy isoflavones was assumed if the 90 % confidence intervals (CIs) for the estimated ratio test/refer- ence was included in the acceptance limits 0.80– 1.25 for PK parameters C max and AUC t . Results: The test/reference ratios C max and AUC t of levothyroxine were very close to unity (1.02 and 0.99, respectively) and the corresponding 90 % CIs (0.99–1.04 and 0.88–1.12, respectively) fell entirely within the acceptance bioequiva- lence limits. Conclusion: The combination of soy isoflavones used in the present investigation does not affect the rate and extent of levothyroxine absorption when administered concomitantly in post-men- opausal women. Downloaded by: IP-Proxy Rottapharm, Rottapharm Madaus. Copyrighted material.