Administration and Pharmacokinetics of Levothyroxine 70 Years of Levothyroxine NCBI Bookshelf

Of note, fetal goiters induced by mutations, which affect the transport and metabolism of T4, may respond more poorly to LT4 supplements (256). In addition to drugs that alter the absorption of LT4, some drugs affect the pharmacodynamics and pharmacokinetics of LT4 after absorption. The induction of cytochrome P450 enzyme activity in the liver by statins or protease inhibitors can accelerate the catabolism of LT4, and hence decrease serum T4 levels (84, 85).

• Serum digitalis glycoside levels may be decreased when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides (see Table 2).
• We hope the article provides novel insights into the drug delivery of levothyroxine.
• Finally, clinicians should refer the patient to an endocrinologist if hypothyroidism is due to central causes.
• While the aim of therapy is to also normalize the serum TSH level, this is not always possible in a small percentage of patients, particularly in the first few months of therapy.
• Preferred provider organization (PPO) health plans were the most common in both cohorts, and approximately 8% had Medicare Advantage plans.
• In cases where suboptimal adherence to LT4 therapy is suspected 32, the LT4 absorption test, where thyroid hormone levels are measured after a supervised dose of LT4, can be useful in distinguishing non-adherence of LT4 from genuine cases of malabsorption of LT4 33.

Levothyroxine: Conventional and Novel Drug Delivery Formulations

Two following articles studied the long-term and short-term effect of PPIs on liquid LT4.28,29 The results suggested that liquid LT4 and soft-gel capsules could eliminate the malabsorption induced by PPIs. Moreover, clinicians can instruct patients to switch to other PPIs or antacids. Mean baseline‐corrected serum levothyroxine concentration‐over‐time profiles for all treatments are shown in Figure 1. 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).

Levothyroxine (LT4) monotherapy is considered the standard of care for the treatment of hypothyroidism 6, with Synthroid® (levothyroxine sodium tablets, AbbVie) and any one of multiple generic levothyroxine (GL) formulations most often prescribed in the US. Levothyroxine has a narrow therapeutic window, and slight variations in dose or differences in bioavailability between products can impact clinical effectiveness 8–10. Previous real-world research using administrative claims data demonstrated differences in outcomes between patients with hypothyroidism treated with Synthroid or GL 9, 10. Compared with patients who received GL, significantly fewer patients in the Synthroid treatment group had TSH levels outside the recommended range (0.3 to 4.12 mIU/L) and a smaller proportion was undertreated 9, 10. Soft gel capsules can also eliminate the impaired bioavailability induced by interfering medications or concomitant disease (195).

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. This was a single‐center comparative bioavailability, open‐label, randomized, single‐dose, 3‐period, 6‐sequence crossover study under fasting conditions.

Years of Levothyroxine Internet.

The rate and extent of absorption of the new levothyroxine solution were also evaluated when administered on dilution in water or directly into the mouth without water. The ideal normalization of TH levels in these patients relies on the elimination of or an improvement in concurrent diseases. Pylori infection, TSH levels usually return to the target range with a normal dose after antiparasitic or antibiotic therapy (12, 23). A lactose-free formulation or gluten-free diet can rid patients with lactose intolerance or celiac disease of impaired absorption, respectively (14, 64). In addition, a switch from LT4 tablets to liquid preparations can restore thyroid function in patients with gastrointestinal dysfunction (Fig. 3) (32, 49, 50, 60, 65, 66). Surprisingly, liquid solutions also alleviate the malabsorption induced by some nongastrointestinal disorders, such as nephrotic syndrome (35, 36) and pregnancy (61).

Subjects and Methods

Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentration. Nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, androgens, and corticosteroids decrease TBG concentration. Consumption of certain foods may affect SYNTHROID absorption thereby necessitating adjustments in dosing see Dosage and Administration (2.1). Soybean flour, cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of SYNTHROID from the gastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability.

Stop biotin and biotin-containing supplements for at least 2 synthroid derived days prior to thyroid testing. The recommended daily dosage of SYNTHROID in pregnant patients is described in Table 3. To minimize the risk of hyperactivity, start at one-fourth the recommended full replacement dosage, and increase on a weekly basis by one-fourth the full recommended replacement dosage until the full recommended replacement dosage is reached.

A total of 153,775 patients (34,828 in the Synthroid cohort and 118,947 in the GL cohort) were initially identified for potential study inclusion (Fig. 1). Of these, roughly half persistently followed index therapy (79,140 total; 18,694 Synthroid; 60,446 GL). After propensity score matching, the Synthroid and GL cohorts each contained 18,382 patients. The statistical analyses were performed using SAS Enterprise Guide 7.1 (SAS Institute Inc., Cary, NC, USA, 2014). Sensitivity analyses of the primary outcome were performed using a narrower TSH range (0.4 mIU/L to 4.0 mIU/L 6) and also among a subset of patients with at least two TSH results at follow-up.

For details about the basic and clinical thyroid effects of tyrosine kinase inhibitors, including enhanced dose of levothyroxine, the reader is referred to a review just released by Makita and Iiri. Finally, some drug interactions with levothyroxine can be explained by an effect on its metabolism, such as the extrathyroidal conversion rate of T4 to T3. Certain drugs, such as propranolol28,29,153,154 and amiodarone,107 reduce this metabolism. Conversely, carbamazepine,133,155–158 phenobarbital,159,160 rifampin107 and phenytoin155,161 induce liver microsomal enzymes and increase this peripheral metabolism.

In each period, according to the randomization scheme, subjects were administered single oral doses of either test, as 4 × 150‐μg unit‐dose ampules, with or without water, or reference, as 4 × 150‐μg capsules in a crossover design. Thirty‐six subjects were randomized and dosed in this study; of these, 31 completed all study periods. When comparing the solution with the capsule (both products administered with water), the 90% confidence intervals for the ratio of log‐transformed values of AUC0‐48 and Cmax were within 90.00% and 111.11%, respectively, for baseline‐corrected levothyroxine. In conclusion, levothyroxine oral solution unit‐dose ampules were bioequivalent to the levothyroxine capsule when administered with or without water. Lifelong treatment with LT4, guided by levels of thyrotropin, is the mainstay of management of hypothyroidism.