Pharmacokinetics Of Levothyroxine Research Articles

Proton Pump Inhibitors Do Not Affect the Bioavailability of a Novel Liquid Formulation of Levothyroxine

ObjectiveThis study evaluates the impact of a representative proton pump inhibitor (PPI) (omeprazole), administered simultaneously or staggered, on the pharmacokinetics of levothyroxine (LT4) solution (Tirosint-SOL). MethodsThis was a randomized, 3-way crossover, comparative bioavailability study in 36 healthy adults under fasting conditions.Omeprazole 40 mg delayed-release capsule was administered once daily from Day 1 to 6 (mornings, Treatment-A; evenings, Treatment-B; none, Treatment-C) to increase and stabilize gastric pH. In the morning of Day 5, a single dose of LT4 solution 600 mcg was administered. Blood samples were collected 0 to 48 hours post-LT4 administration. Noncompartmental pharmacokinetic parameters were calculated for total serum thyroxine using baseline-corrected data. Maximum concentration (Cmax) and area under the concentration-time curve (AUC0-48) were included in an analysis of variance to obtain geometric mean ratios and 90% confidence intervals. ResultsFor both comparisons (A/C and B/C), geometric mean ratios and 90% confidence intervals for all parameters were within the equivalence boundaries (80%-125%), indicating bioequivalence: for A/C, AUC0-48 98.98% [94%-104%], and Cmax 91.68% [87%-97%]; for B/C, AUC0-48 98.94% [95%-103%], and Cmax 94.90% [90%-100%]. Median Tmax (time associated with Cmax) was similar across treatments. ConclusionThis study demonstrated that Tirosint-SOL bioavailability is unaffected by coadministration of a representative PPI, given simultaneously or staggered by about 12 hours, compared to administration of LT4 solution alone. For hypothyroid patients on PPI therapy, administration of LT4 solution may reduce variations in thyroid stimulating hormone levels related to intermittent use of acid-reducing drugs and consequently the need for dose adjustments.

The Effect of Different Types of Bariatric Surgery on Levothyroxine Requirement in Hypothyroid Bariatric Patients.

BackgroundBariatric surgeries are carried out to improve a patient's quality of life, and to reduce respiratory, cardiac, endocrine, and metabolic complications encountered by those with high body mass index (BMI). A complication associated with high hypothyroidism is weight gain, which may lead to obesity. Here, we explore the effect of different bariatric procedures on thyroid function and levothyroxine dosage. MethodsThis is a retrospective review of 887 patients referred to a tertiary bariatric service between 2008 and 2020 and treated for hypothyroidism at the time of referral.The study identified 57 patients on thyroxine replacement. Of these, 22 underwent restrictive bariatric procedures, 16 underwent restrictive/malabsorptive procedures, and 19 did not undergo operative intervention.Comparisons were made among each group throughout the timeline of interest.ResultsOut of 57 patients, 50 (87.7%) were female. The average age for patients was 47.26+/- 8.89 years. The average BMI at baseline was 48.72+/- 8.68 kg/m2. The mean dose of levothyroxine in controls was 115.8+/- 53.5 mcg while that of surgical patients was 149.8+/- 68.4 mcg.There were no statistically significant differences in levothyroxine doses between surgical and control at T0 (baseline), T1 (one-year post-op in surgical patient, or two-year post referral in control patient), T2 (two-year post-op in surgical patient, or three-year post referral in control patient), and T3 (most recent result available). The surgical group was then categorized further into restrictive and restrictive/malabsorptive. When they were compared with the control group, there were no statistically significant differences in doses.A generalized linear mixed model was applied to assess differences in levothyroxine dose with time as a random variable. This was adjusted for age, sex, BMI, T4 level, and hypothyroid cause. Through this assessment, there were several statistically significant differences in levothyroxine dosage between the groups. Control group required on average 28.06 mcg less levothyroxine than the restrictive/malabsorptive group (p=0.015). Also, the restrictive group required on average 23.57 mcg less levothyroxine than the restrictive/malabsorptive group (p=0.033). There were no statistically significant differences observed between the control group and the restrictive group (p=0.67)ConclusionPatients who have bariatric surgery have changes to their anatomy and physiology which may affect both their thyroid hormone homeostasis and levothyroxine pharmacokinetics. Thus, hypothyroid bariatric patients requiring levothyroxine must have their thyroid function monitored regularly. In this study, it was found that hypothyroid patients who underwent restrictive surgery had an overall statistically significant lower levothyroxine requirement to remain euthyroid as compared to the restrictive/malabsorptive group (p=0.033). Additionally, the control group required statistically significantly less levothyroxine than the restrictive/malabsorptive group (p=0.015). These factors may determine the type of surgery chosen by hypothyroid bariatric patients. However, further studies that are randomized, controlled, and multi-center with a higher population are required.

Effect of oral semaglutide on the pharmacokinetics of thyroxine after dosing of levothyroxine and the influence of co-administered tablets on the pharmacokinetics of oral semaglutide in healthy subjects: an open-label, one-sequence crossover, single-center, multiple-dose, two-part trial

ABSTRACT Background Oral semaglutide comprises the glucagon-like peptide-1 analog, semaglutide, and sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). Levothyroxine has similar dosing conditions to oral semaglutide. This trial investigated if oral semaglutide co-administered with levothyroxine affects thyroxine (T4) exposure and if multiple placebo tablets co-administered with oral semaglutide affect semaglutide exposure. Research design and methods In this one-sequence crossover trial, 45 healthy subjects received levothyroxine (600 μg single-dose) alone, or with concomitant SNAC 300 mg or concomitant oral semaglutide 14 mg at steady-state. Subjects also received oral semaglutide 14 mg at steady-state alone or with five placebo tablets once-daily for 5 weeks. Results A 33% increase in total T4 exposure was observed with levothyroxine/oral semaglutide vs levothyroxine alone, but baseline-corrected maximum concentration (C max) was unaffected. SNAC alone did not affect total T4 exposure, whereas C max was slightly decreased. A 34% decrease in semaglutide exposure was observed when oral semaglutide was co-administered with placebo tablets, and C max also decreased. Conclusions Levothyroxine pharmacokinetics were influenced by co-administration with oral semaglutide. Monitoring of thyroid parameters should be considered when treating patients with both oral semaglutide and levothyroxine. Oral semaglutide exposure was influenced by co-administration with multiple tablets, which is addressed in the dosing guidance.

Changes in levothyroxine pharmacokinetics following bariatric surgery in obese hypothyroid patients

Aim: Levothyroxine (L-T4) requirements in obese hypothyroid patients receiving L-T4 therapy decrease following bariatric surgery. L-T4 absorption is also thought to decrease after surgery. The purpose of this study was to evaluate L-T4 requirements in hypothyroidism cases before and after weight loss through bariatric surgery. Methods: Seventy-six cases of hypothyroidism receiving L-T4 replacement therapy and with a body mass index over 40 kg/m2 were included in the study. Patients losing at least 10% of basal body weight following bariatric surgery were assessed in terms of thyroid hormone levels and L-T4 requirements over follow-up of at least one year. The L-T4 requirements of patients in whom euthyroidism was achieved were compared in terms of bariatric surgery procedures and hypothyroidism etiology. Results: Seventy-six patients (56 women, 20 men) with a mean age of 38 years (18-51) were included in the study. Mean weight before bariatric surgery was 121.6 ± 6.8 kg, and mean body mass index was 49.5 ± 1.6 kg/m2. Euthyroidism was confirmed at pre- and post-bariatric surgery evaluation. No statistically significant postoperative changes were determined in thyroid-stimulating hormone or free thyroxine-3 and -4 (p > 0.05). A statistically insignificant decrease was observed in L-T4 dosages after surgery in cases of Hashimoto’s thyroiditis (p = 0.064). A statistically significant decrease was determined in L-T4 dosages in cases of non-Hashimoto hypothyroidism (p = 0.001). L-T4 requirements decreased in both surgical procedures (p = 0.001) Conclusion: Postoperative L-T4 requirements decrease with weight loss. In addition, no decrease appeared to occur in L-T4 absorption following the surgical procedures in this study.

SAT-LB85 Use of Weekly Levothyroxine Regimen for Rapid Normalization of Thyroid Hormone Levels: A Case Report

Background: Hypothyroidism affects around 4.6% of the U.S. population1. Non-adherence with thyroid hormone replacement is one of the biggest challenges in treating hypothyroidism1. The half-life of T4 and T3 in hypothyroidism is about 7.5 and 1.4 days respectively2. A large dose once-weekly administration of levothyroxine (Lt4) is possible3, 4. Recent publications suggest that once-weekly Lt4 does not increase the risk of cardiovascular events and is well tolerated by most of patients4. Once weekly Lt4 produces similar results as daily Lt4 as evidenced by thyroid function tests3,4, and potentially improves patient compliance and satisfaction with the treatment4. Clinical Course: A 29-year-old female with a history of Hashimoto’s hypothyroidism, polycystic ovarian syndrome, depression, presented with irregular menses. Her symptoms included depression, fatigue, increased appetite. Her TSH was grossly elevated at 217 uIU/mL (0.27-4.20 uIU/mL). However upon re-visit, after increasing Lt4 to 100 mcg daily her TSH increased to 280 uIU/mL. She admitted to non-adherence with her daily Lt4 prescription. Physical exam was notable for sinus bradycardia and slow mentation, otherwise unremarkable. Blood count, basic metabolic panel and hemoglobin A1C were within normal limits. Liver function tests showed mild transaminitis, ALT 46 U/L (10-45 U/L). Lt4 was started at 875 mcg per week. At five weeks, her TSH was 6.31 uIU/mL and at seven weeks, the patient was euthyroid with a TSH of 2.53 uIU/mL. Her periods have since normalized. Conclusion: The current discourse on weekly dosing mainly focuses on its use for non-adherent patients. This case provides a clear time course also demonstrating rapid normalization of TSH using weekly dosing. Weekly Lt4 dosing as first-line therapy in noncompliant depressed patients with severe hypothyroidism should be considered. 1.Hepp, Z., Wyne, K., Manthena, S., Wang, S. and Gossain, V. (2018). Adherence to thyroid hormone replacement therapy: a retrospective, claims database analysis. Current Medical Research and Opinion, 34(9), pp.1673-1678.2.Colucci, P., Yue, C., Ducharme, M. and Benvenga, S. (2010). A Review of the Pharmacokinetics of Levothyroxine for the Treatment of Hypothyroidism. European Endocrinology, 9(1), p.40.3.Jayakumari, C., Nair, A., Puthiyaveettil Khadar, J., Das, D., Prasad, N., Jessy, S., Gopi, A. and Guruprasad, P. (2019). Efficacy and Safety of Once-Weekly Thyroxine for Thyroxine-Resistant Hypothyroidism. Journal of the Endocrine Society, 3(12), pp.2184-2193.4.Rajput, R. and Pathak, V. (2017). The Effect of Daily versus Weekly Levothyroxine Replacement on Thyroid Function Test in Hypothyroid Patients at a Tertiary Care Centre in Haryana. European Thyroid Journal, 6(5), pp.250-254.

SAT-114 Problems In Postoperative Hypothyroidism And Hypoparathyrosis Treatment Because Of Bariatric Surgery

Background: Bariatric surgery remains the most effective method of weight loss and can result in partial or complete resolution of multiple obesity-related comorbidities. Bariatric surgery should be performed in conjunction with a comprehensive preoperative assessment and a follow-up plan consisting of nutritional, behavioral, and medical programs. The bariatric surgical procedures are associated with significant long-term complications, primarily malnutrition. Clinical case: A 56-year-old woman was presented with complaints about tingling in her fingertips, painful muscle cramps, and difficulties with finger extension. It was found out from medical history that total thyroidectomy with parathyroidectomy because of papillary thyroid cancer was performed in 2007 and oral levothyroxine was prescribed. Bariatric surgery SADI-S (sleeve gastrectomy, duodeno-ileal anastomosis) was performed because of morbid obesity in September 2018. On physical examination Chvostek and Trousseau signs were noted. BMI was 39 kg/m2. Laboratory examination was carried out. Increased level of TSH and decreased value of calcium and 25-OH vitamin D were revealed. Laboratory results demonstrated postoperative hypothyroidism decompensation due to abnormal gastric acid secretion because of sleeve gastrectomy and postoperative hypoparathyrosis decompensation due to reduced calcium absorption because of duodeno-ileal anastomosis. So, the dosage of calcium, vitamin D and levothyroxine was increased. Also 10% calcium gluconate was prescribed. But compensation of postoperative hypothyroidism and hypoparathyrosis was not achieved. Thus, reconstructive operation was recommended due to ineffective medical treatment of hypothyroidism and hypoparathyrosis. Conclusion: This clinical case demonstrates that lack of comprehensive preoperative assessment indications to bariatric surgery leads to complication in compensation of comorbid states, such as postoperative hypothyroidism and hypoparathyrosis. Reference: (1) Nancy Puzziferri, MD, MS, Thomas B. Roshek III, MD, Helen G. Mayo, BS, MLS, Ryan Gallagher, BA, Steven H. Belle, PhD, MScHyg, and Edward H. Livingston, MD Long-term Follow-up After Bariatric Surgery: A Systematic Review. JAMA. 2014 September 3; 312(9): 934-942. (2) Improved levothyroxine pharmacokinetics after bariatric surgery. Thyroid 2013; 3; 23: 414-9.

Attitudes and perceptions of health professionals towards management of hypothyroidism in general practice: a qualitative interview study

ObjectiveTo explore the attitudes and perceptions of health professionals towards management of hypothyroidism that contributes to the suboptimal treatment of hypothyroidism in general practice.DesignA qualitative interview study using semistructured interviews.ParticipantsSixteen...

Stable Isotope Pharmacokinetic Studies Provide Insight into Effects of Age, Sex, and Weight on Levothyroxine Metabolism.

This study sought to determine whether levothyroxine pharmacokinetics (PKs) are affected by age, weight, and sex. A PK study was performed after administration of a tracer dose of carbon-13-labeled LT4 (13C-LT4). The study was conducted at an academic medical center. Adults of any age being treated with levothyroxine for hypothyroidism were enrolled in the study. A single dose of 13C-LT4 was administered. Eighteen serial plasma samples were collected. One sample was obtained before the 13C-LT4 dose, and the majority of the remaining samples were collected over the 120-hour period post dosing. 13C-LT4 concentration was quantified using liquid chromatography tandem mass spectrometry. PK analysis was conducted using a linear log trapezoidal non-compartmental analysis using Phoenix 6.4. Eight males and 33 females with a median age of 50 years (range 22-78 years) and median weight of 65.9 kg (range 50-150 kg) were enrolled in the study. The median 13C-LT4 dose administered was 100 μg (range 70-300 μg). The median oral clearance rate (CL/F), apparent volume of distribution (V/F), time to peak concentration (Tmax), and dose-normalized peak concentration (Cmax) of 13C-LT4 were estimated to be 0.712 L/h, 164.9 L, 4 h, and 7.5 ng/L/μg, respectively. The dose-normalized area under the concentration-time curve from time 0 to 120 hours and half-life of the terminal distribution phase were 0.931 ng.h/mL/μg and 172.2 h, respectively. There was no significant difference in any 13C-LT4 PK parameter between patients aged >60 years (n = 10) and patients aged ≤60 years (n = 31), nor was there a relationship between age as a continuous variable and 13C-LT4 PK parameters. Sex only affected CL/F, V/F, and dose-normalized Cmax in univariate analyses. However, after adjusting for weight, sex was no longer a significant covariate. Weight was a significant predictor for CL/F, V/F and dose-normalized Cmax of 13C-LT4 in multivariate analyses. Prior studies suggest that patient age affects levothyroxine dose requirement. This study did not identify an effect of age and suggests that age-related changes in levothyroxine pharmacokinetics may be mediated by age-related weight differences. Physicians should consider a patient's weight, rather than age, for estimating levothyroxine dosage requirement.

Primary Congenital Hypothyroidism: Pharmacokinetics of Levothyroxine for the Treatment of Hypothyroidism

Primary Congenital Hypothyroidism: Pharmacokinetics of Levothyroxine for the Treatment of Hypothyroidism

Levothyroxine Dosing Following Bariatric Surgery.

Based on the mechanisms of drug absorption, increased levothyroxine requirements are expected after bariatric surgery. However, there are conflicting data on this topic. This review evaluates the effects of bariatric surgery on levothyroxine dosing. Data were obtained from PubMed, Scopus, and review of published bibliographies. Six of 10 studies demonstrated decreased postoperative requirements. Most demonstrated correlations between weight loss and dose. Only 3 case reports and 1 case series demonstrated increased levothyroxine requirements, attributed to malabsorption. The loss of both fat and lean body mass may counteract malabsorptive effects from surgery, resulting in decreased postoperative levothyroxine requirements. In addition, the reversal of impaired levothyroxine pharmacokinetics and an altered set point of thyroid hormone homeostasis may also contribute to postoperative levothyroxine reductions.

Thyroxine replacement: a clinical endocrinologist’s viewpoint

Hypothyroidism affects 2-5% of the general population. Patients with uncorrected disease suffer significant morbidity and have an increased risk of cardiovascular disease and neurocognitive impairment. Levothyroxine, the treatment of choice, is inexpensive, easy to administer and in most cases restores well-being while normalizing thyroid function. However, 30-50% of individuals on levothyroxine are either over-treated or under-treated and others remain dissatisfied with treatment despite achieving thyroid hormone concentrations within the laboratory reference interval. This review is based on a systematic search of the literature for controlled trials, systematic reviews, guideline papers and cohort studies addressing best practice in thyroid hormone replacement. Recent decades have seen improvements in patient management strategies driven by a better appreciation of levothyroxine pharmacokinetics. However, aspects of therapy such as the optimal timing of medication, strategies to overcome treatment non-adherence and target thyroid stimulating hormone concentrations in pregnancy and in patients with differentiated thyroid cancer remain challenging. Furthermore, there is now a substantial body of literature on common genetic variations in the deiodinases and thyroid hormone transporters and their role in the local regulation of thyroid hormone delivery. The benefits of combination therapy with liothyronine and levothyroxine are uncertain, and while it is theoretically probable that subsets of genetically predisposed individuals will benefit from combination therapy the existing evidence is as yet limited. Despite the availability of thyroid hormone replacement for more than a century, there are still substantial challenges in practice and opportunities to improve treatment outcomes.

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.

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. 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. 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. 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.

Clinical Efficacy and Pharmacokinetics of Levothyroxine Suppository in Patients with Hypothyroidism

This study aimed to elucidate the clinical efficacy and pharmacokinetics of levothyroxine (LT4) suppository, thus, we examined the pharmacokinetics of thyroxine (T4) after the administration of the suppository in thyroidectomized rats and examined dose and the levels of free T4 (FT4) in patients with hypothyroidism receiving suppositories. Thyroidectomized rats were administered with LT4 solution and LT4 suppository (30 µg/kg), and plasma T4 concentrations were measured using LC/MS. The AUC0-168 of T4 after rectal administration of the LT4 suppository was 64% lower than these values after oral administration. To evaluate clinical effect of LT4 suppository, we enrolled 6 Japanese patients with hypothyroidism (2 men and 4 women; age, 68.2±13.5 years) who were administered LT4 suppository at Kameda Medical Center from 2007 to 2013 in this case series. The FT4 level during the administration of suppositories was significantly lower than that during the administration of tablets (0.657±0.183 ng/dL vs. 1.25±0.51 ng/dL, p=0.034). The FT4/dose ratio for the suppository was significantly 44% lower than that for the tablet (p=0.020). In conclusion, although the bioavailability of LT4 is lower after administration of the suppository than after the oral formulation, it was suggested that T4 levels can be maintained in patients with hypothyroidism by administering LT4 suppositories at a dose 1.8 times higher than that of the tablet. Thus, the administration of LT4 suppository can be an alternative for treatment with oral medication in clinical practice.

Impaired Pharmacokinetics of Levothyroxine in Severely Obese Volunteers

Suppressive or replacement doses of levothyroxine (LT4) are affected by the rate and extent of the active ingredient absorbed, as well as by the lean body mass. Obesity has reached epidemic proportions worldwide and is related with many comorbidities. The aim of this study was to determine the pharmacokinetic parameters of LT4 in severely obese individuals and compared them with similar data in lean control subjects. We studied 62 euthyroid subjects who had negative tests for anti-thyroid peroxidise antibodies (Ab-TPO). Thirty eight of these subjects were severely obese but otherwise healthy (severe obese subjects [SOS] group). Twenty-four were healthy control subjects (control group), with a body mass index of 23.3 ± 1.7 kg/m(2). Subjects received 600 μg oral sodium LT4 after an overnight fast. Serum triiodothyronine (T3), T4, and thyroid-stimulating hormone were measured at baseline. Serum T4 and T3 was measured 0.5, 1, 1.5, 2, 2.5, 3, and 4 hours after LT4 administration. Baseline serum T4 and thyroid-stimulating hormone concentrations were higher in the SOS group than in the control group; serum T3 was similar in the two groups. The corrected area under the curve and the maximum T4 concentration after LT4 administration were lower, whereas the time to maximum concentration from the baseline was higher in SOS than in the control group. The estimated plasma volume was higher in the SOS than in the control group. Mean serum T3 levels increased gradually during the four hours after LT4 administration in the control group. In contrast, they decreased gradually in the SOS group. Severely obese individuals may need higher LT4 suppressive or replacement doses than normal-weight individuals due, among other factors, to impaired LT4 pharmacokinetic parameters. The latter could be attributed to their higher plasma volume and/or to delayed gastrointestinal LT4 absorption. T4 conversion to T3 might be defective in severe obesity.

Longitudinal Comparison of Thyroxine Pharmacokinetics Between Pregnant and Nonpregnant Women: A Stable Isotope Study

The treatment of maternal hypothyroidism presents clinicians with a unique challenge, because dosing regimens previously developed and validated for nonpregnant women cannot be easily extrapolated to dosing in pregnancy. Thyroid hormone requirement increases by 20% to 40% early during pregnancy, persisting throughout gestation. Accordingly, women with treated hypothyroidism need to increase their levothyroxine dose to prevent maternal hypothyroidism and the associated impaired cognitive development and increased fetal mortality. We investigated the pharmacokinetic properties of levothyroxine during pregnancy through the use of a novel, traceable form of levothyroxine. The objective was to conduct a longitudinal study to determine whether levothyroxine pharmacokinetics differ in the pregnant versus nonpregnant state. We used a unique C-levothyroxine-tracer method to distinguish between endogenous and exogenous levothyroxine and studied the pharmacokinetics of a single oral dose of levothyroxine using tandem mass spectrometry. Moreover, we were able to detect single dose amounts of the drug, in picogram/mL concentrations. The area under the curve was 23.0 ng*h/mL in pregnancy and 14.8 ng*h/mL in nonpregnant women (P < 0.03) with median serum half-lives of 32.1 hours and 24.1 hours, respectively (P < 0.04). Further research involves the measurement of free thyroxine on these samples using tandem mass spectrometry. Future work should focus on the mechanisms responsible for the gestational differences in pharmacokinetics and whether these should necessitate dose schedule changes in pregnancy.

Therapeutic Drug Monitoring During Pregnancy and Lactation: Thyroid Function Assessment in Pregnancy—Challenges and Solutions

The diagnosis and monitoring of thyroid disease necessitates the knowledge of thyroid pathophysiology and of the technical limitations of current thyroid-related biochemical tests. Thyroid disease diagnosis and monitoring are further complicated during pregnancy and lactation, due to pregnancy-related changes in thyroid hormone metabolism. Dramatic changes that occur in thyroxine and triiodothyronine ranges during pregnancy pose challenges for hypothyroid gravidas. Very early in pregnancy, levothyroxine replacement needs to be increased. Moreover, increases in thyroid hormone replacement need to be conducted individually and on a timely basis. For reasons that are still not entirely clear, although dependent in part on changes in thyroxine binding, free thyroxine (FT4) levels decrease as pregnancy progresses necessitating the use of trimester-specific reference intervals for appropriate replacement. Thyroxine binding protein levels vary by hormonal status, inheritance, and disease states and are higher in pregnancy; hence, FT4 assays became popular because they measure the unbound hormone. However, current FT4 immunoassays are estimate tests that do not reliably measure FT4 and are known to be sensitive to alterations in binding proteins and therefore are method-specific. The need to reliably identify hypothyroxinemic pregnant patients, especially in the first trimester, is of prime importance for early fetal brain development before the fetal thyroid functions. This article addresses 1) the current limitations of laboratory-free thyroxine immunoassay methodologies and especially during pregnancy; 2) trimester-specific reference intervals for thyroid function tests; and 3) the study of levothyroxine pharmacokinetics in pregnant and nonpregnant women.

A Review of the Pharmacokinetics of Levothyroxine for the Treatment of Hypothyroidism.

Thyroxine hormone has been recognised since the early part of the nineteenth century and levothyroxine has been available since the mid-nineteenth century as a replacement for deficient thyroid hormones. While levothyroxine remains the staple treatment for hypothyroidism even to this day, its optimal use can be challenging. As is often the case with older drugs, the pharmacokinetics of levothyroxine is often under-appreciated or misunderstood and many factors influence the optimal dosing of levothyroxine. This article will review the pharmacokinetics of levothyroxine in the treatment of hypothyroidism and highlight major concepts that should aid both clinicians and researchers.

Nonspecific intestinal adsorption of levothyroxine by aluminum hydroxide

purpose: To evaluate the adverse effect of aluminum hydroxide on levothyroxine pharmacokinetics in hypothyroid patients and study the mechanism of this effect. design: An in vivo open study supplemented by in vitro experiments. setting: A university hospital-based outpatient service. intervention: Administration for 2 to 4 weeks of an aluminum hydroxide-containing preparation to patients balanced on replacement thyroxine therapy. measurements: Serum thyrotropin (TSH). results: A significant increase in serum TSH was observed during seven periods of aluminum hydroxide administration (7.19 ± 1.3 versus 2.62 ± 0.8 mU/L; P = 0.012). In vitro studies indicated a considerable nonspecific adsorptive capacity of aluminum hydroxide for thyroxine. conclusions: The results indicate an adverse effect of aluminum hydroxide on levothyroxine bioavailability through a mechanism involving nonspecific adsorption, or complexing, of levothyroxine to aluminum hydroxide. We recommend close monitoring of serum TSH levels in patients receiving oral thyroid hormone replacement therapy who concurrently take aluminum hydroxide-containing medications. Adjustment of the levothyroxine dose, or cessation of the antacid, may be necessary.