Pharmacokinetics and Comparative Bioavailability of a Levothyroxine Sodium Oral Solution and Soft Capsule

These include urticaria, pruritus, skin rash, flushing, angioedema, various GI symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness and wheezing. Studies in women taking levothyroxine sodium during pregnancy have not shown an increased risk of congenital abnormalities. SYNTHROID should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated. Prothrombin time should be closely monitored to permit appropriate and timely dosage adjustments (see Table 2). This two-period, randomized, crossover, blind study was conducted in 80 healthy volunteers, of both sexes, using a single levothyroxine dose of 600μg with a washout period of 42 days. Blood sampling was performed at − 30 min, − 15 min, and 0 h pre-dose and 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, and 48 h post-dose.

Soft Gel Capsules

• Moreover, the administration of levothyroxine oral solution without water did not affect the rate and extent of its absorption with respect to administration with water because 90% geometric CIs of the LSM ratios were also within 90.00% to 111.11% for AUC0‐48 and Cmax (Figure 2).
• Protein-bound thyroid hormones exist in reverse equilibrium with small amounts of free hormone.
• There are several methodological differences between this study and the current one that may explain these findings (e.g., time windows for goal assessment; width of the reference range; composition of cohorts).
• Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism and may result in unpredictable absorption of levothyroxine sodium from the gastrointestinal tract.

Dosing adjustments are based on an assessment of the individual patient’s clinical and laboratory parameters (see PRECAUTIONS – Laboratory Tests). The dose used in the study of 600 μg of levothyroxine allowed one to identify the exogenous supply of this synthetic hormone and to differentiate it from the endogenous production. This high dose of levothyroxine can generate additional intrasubject variability especially in blood samples taken after 12 h by the self-regulatory system of the hypothalamic-pituitary-thyroid axis. Microneedle patch (MNP) is another promising approach for parenteral LT4 delivery.

1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics

• Levothyroxine toxicity is rare; however, it is most likely to occur in the setting of accidental ingestion by children or older adults.
• Liquid formulations (solution and soft-gel capsules) can be used in malabsorption induced by complexing and alkalization.
• The initial dose of levothyroxine varies with age and body weight (see DOSAGE AND ADMINISTRATION – Table 3).
• In a previous study involving 19 patients, the TSH levels were normalized only when patients’ T3 levels were not significantly different from those of controls (159).

The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately 80% of circulating T3 is derived from peripheral T4 by monodeiodination. The liver is the major site of degradation for both T4 and T3, with T4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. Approximately 80% of the daily dose of T4 is deiodinated to yield equal amounts of T3 and reverse T3 (rT3).

An in vitro experiment demonstrated a first-order release profile of 87% of the total contents of 21 µg in an ∼14-day period. This study provided a promising method for cutaneous LT4 delivery, but the load remains to be increased and an animal experiment is needed to evaluate the potential effects of the administration method on the skin. The signs and symptoms of overdosage are those of hyperthyroidism see Warnings and Precautions (5) and Adverse Reactions (6). Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium. Concurrent use of sympathomimetics and SYNTHROID may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.

Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical evaluation. The SYNTHROID dosage is based on the target level of TSH suppression for the stage and clinical status of thyroid cancer. If so, advise them to stop biotin supplementation at least 2 days before assessing TSH and/or T4 levels see Dosage and Administration (2.4) and Drug Interactions (7.10). Larger doses may produce serious or even life-threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects see Adverse Reactions (6), Drug Interactions (7.7), and Overdosage (10). Thyroid hormones, including SYNTHROID, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss.

Michael Grabner and Bal Nepal are employees of HealthCore, Inc., which received funding from AbbVie, Inc., for the conduct of the study. Liya Wang was an employee of HealthCore at the time the study was conducted and is currently an employee of Merck and Co., Inc. Yaozhu J. Chen was an employee of AbbVie, Inc. at the time the study was conducted, and is currently an employee of Takeda Pharmaceuticals USA, Inc. James V. Hennessey is affiliated with Beth Israel Deaconess Medical Center, Boston, MA, and was under contract with AbbVie, Inc., to provide consulting services to the study. In a subpopulation with at least 2 TSH values recorded over 12months follow-up, we found directionally consistent results that were not statistically significant.

The introduction of novel formulations of LT4, with improved drug stability over time, more precise delivery of the active ingredient, and higher levels of bioequivalence compared with existing products promises to simplify accurate titration of LT4 for patients with hypothyroidism. The adequacy of therapy is determined by periodic assessment of appropriate laboratory tests and clinical evaluation. Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of SYNTHROID may be evidence of inadequate absorption, poor compliance, drug interactions, or decreased T4 potency of the drug product. Levothyroxine sodium is a hormone replacement medicine indicated in patients with deficient thyroid hormone production or for TSH suppression due to a history of thyroid cancer 2.

Pediatric Dosage – Congenital or Acquired Hypothyroidism

A physiological gastric pH is essential for tablet dissolution, which removes the sodium ion and increases its solubility. Clinicians, patients and pharmaceutical companies should be aware of the possible interactions. Further well-designed studies are needed to provide more solid evidence on treatment and mechanisms. A systematic review on interfering substances that interact with levothyroxine was performed. Web of Science, Embase, PubMed, the Cochrane library, grey literature from other sources and the lists of references were searched for human studies comparing the levothyroxine efficacy with and without interfering substances. The patient characteristics, drug classes, effects and mechanism were extracted.

• SYNTHROID may be administered to infants and children who cannot swallow intact tablets by crushing the tablet and suspending the freshly crushed tablet in a small amount (5-10 mL or 1-2 teaspoons) of water.
• Similarly, phenytoin and imatinib inactivate LT4 via nondeiodinative hepatic metabolism and decrease the ratio of T3 to T4 (89, 90).
• In the 15 included randomized controlled trials, seven were rated as good quality (Appendix 4 Supplemental Tables 1–6), while the remaining ones were of fair quality.
• Undertreatment may result in poor school performance due to impaired concentration and slowed mentation and in reduced adult height.
• Moreover, Kamali et al designed an injectable SC long-acting LT4 preparation with thermosensitive polymers (278).

In the treatment of benign nodules and nontoxic multinodular goiter, TSH is generally suppressed to a higher target (e.g., 0.1 to either 0.5 or 1.0 mU/L) than that used for the treatment of thyroid cancer. Levothyroxine sodium is contraindicated if the serum TSH is already suppressed due to the risk of precipitating overt thyrotoxicosis (see CONTRAINDICATIONS – WARNINGS and PRECAUTIONS). Caution should be exercised when administering SYNTHROID to patients with underlying cardiovascular disease, to the elderly, and to those with concomitant adrenal insufficiency (see PRECAUTIONS ). Levothyroxine sodium should be reduced in dose or temporarily discontinued if signs or symptoms of overdosage occur. Seizures have been reported rarely with the institution of levothyroxine therapy.

Alomari et al developed a novel approach for mixing T3 and T4 using thermal inkjet elavil synthroid 2D printing (156). The 2 compounds were printed simultaneously and independently onto the same substrate (Fig. 6A). The ratio modification was easily achieved, enabling the formulation of oral tablets for personalized medicine. Notably, the types of substrate potentially influence the degradation rate of drugs (157).