What are the pharmacokinetic considerations for dosing Synthroid (levothyroxine) in hypothyroidism?

Pharmacokinetics of Synthroid (Levothyroxine)

Absorption

Levothyroxine must be administered as a single daily dose on an empty stomach, one-half to one hour before breakfast, to optimize absorption. 1

• Absorption occurs primarily in the small intestine, with approximately 40-80% bioavailability depending on individual factors 2
• Peak therapeutic effect of a given dose may not be attained for 4 to 6 weeks, reflecting the time needed to reach steady-state concentrations 1
• Any condition affecting the gastrointestinal epithelium reduces and/or slows absorption, including ulcerative colitis, celiac disease, bariatric surgery, Helicobacter pylori infection, food intolerance, gastritis, and various medications 2

Critical Absorption Interactions

• Administer levothyroxine at least 4 hours before or after drugs known to interfere with absorption, including iron supplements, calcium supplements, and antacids 1
• Mineral supplements, dietary fiber, resins, and various drugs can significantly impair levothyroxine absorption 2
• Foods that decrease absorption (such as soybean-based formulas) should be avoided within one hour of dosing 1

Distribution

Once absorbed, levothyroxine is almost fully bound to plasma proteins (primarily thyroxine-binding globulin, transthyretin, and albumin), with only a small fraction remaining as free T4 2

• Free T4 and liothyronine concentrations are extensively buffered by protein binding 2
• Drug- or disorder-induced changes in plasma protein levels can potentially modify free hormone levels, though free hormone concentrations are generally well-maintained 2

Metabolism

Levothyroxine undergoes peripheral deiodination to the active hormone triiodothyronine (T3) in target tissues 2

• The clinical significance of genetic variants in deiodinase genes remains contradictory, and wide-scale genotyping of hypothyroid patients is not currently justified 2
• Enzyme-inducing medications can reduce levothyroxine efficacy by increasing its metabolism 3

Elimination

The long half-life of levothyroxine (approximately 7 days) necessitates waiting 6-8 weeks between dose adjustments to reach a new steady state 4, 1, 3

• This extended half-life explains why dose adjustments should only be considered after 6 to 12 weeks of therapy 3
• TSH monitoring should be performed 6 to 8 weeks after initiating treatment or changing the dose, as this represents the time needed to achieve steady-state conditions 1, 5

Dosing Implications Based on Pharmacokinetics

Initial Dosing

For adults without cardiac disease or advanced age, the full replacement dose is approximately 1.6 mcg/kg/day (typically 75-100 mcg/day for women and 100-150 mcg/day for men) 4, 6

For elderly patients or those with cardiac disease, start with a lower dose of 25-50 mcg/day to avoid cardiac complications, as the pharmacodynamic effects can unmask coronary ischemia 4, 3

Dose Titration

• Titrate dosage by 12.5 to 25 mcg increments every 4 to 6 weeks based on TSH levels until the patient is euthyroid 1
• Smaller increments (12.5 mcg) should be used for elderly patients or those with cardiac disease 4
• Once adequately treated, repeat TSH testing every 6-12 months to ensure appropriate dosing 4

Common Pitfalls Related to Pharmacokinetics

Approximately 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH, increasing risks for atrial fibrillation, osteoporosis, and cardiac complications 4

• Adjusting doses too frequently before reaching steady state (waiting less than 6-8 weeks between adjustments) leads to inappropriate dose changes 4
• Failure to maintain the 4-hour separation from interfering medications results in suboptimal absorption and apparent treatment resistance 1, 2
• An inadequate response to daily dosages greater than 300 mcg/day is rare and may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors 1