Levothyroxine Pharmacokinetics and Dosing
Absorption and Administration
Levothyroxine must be administered on an empty stomach, one-half to one hour before breakfast, to ensure optimal absorption 1. The medication should be taken at least 4 hours before or after drugs that interfere with absorption, including iron, calcium supplements, and antacids 1. Foods that decrease absorption, particularly soybean-based products, should be avoided around dosing time 1.
Dosing Strategy
Initial Dosing in Adults
The full replacement dose is approximately 1.6 mcg/kg/day for patients under 70 years without cardiac disease 2, 3, 1. This represents the standard starting approach for most adults with primary hypothyroidism 2.
For patients over 70 years or with cardiac disease, start with 25-50 mcg/day and titrate gradually 2, 3, 1. This conservative approach prevents cardiac complications, as rapid normalization can unmask or worsen cardiac ischemia 2, 4. Elderly patients and those with coronary artery disease face increased risk of cardiac decompensation even with therapeutic doses 2.
Dose Titration
Adjust levothyroxine by 12.5-25 mcg increments every 4-6 weeks based on TSH levels 2, 1. The peak therapeutic effect may not be attained for 4-6 weeks, requiring patience during titration 1. Larger adjustments risk iatrogenic hyperthyroidism and should be avoided, especially in elderly or cardiac patients 2.
Use smaller increments (12.5 mcg) for patients over 70 years or with cardiac disease 2. More aggressive titration with 25 mcg increments may be appropriate for younger patients without cardiac disease 2.
Monitoring Timeline
Check TSH every 6-8 weeks during dose titration until target range is achieved 2, 3, 5. This interval is critical because levothyroxine requires this time to reach steady state 2. Adjusting doses more frequently before steady state leads to inappropriate dose changes 2.
Once stable, monitor TSH annually or sooner if symptoms change 2, 3. Free T4 can help interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize 2.
Target TSH Levels
For primary hypothyroidism, target TSH within the reference range of 0.5-4.5 mIU/L with normal free T4 2, 5. This represents the goal for most patients without thyroid cancer 2.
For thyroid cancer patients, TSH targets vary by risk stratification:
- Low-risk patients with excellent response: 0.5-2 mIU/L 2
- Intermediate-to-high risk patients: 0.1-0.5 mIU/L 2
- Structural incomplete response: <0.1 mIU/L 2
Critical Safety Considerations
Approximately 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH, increasing risks for atrial fibrillation, osteoporosis, fractures, abnormal cardiac output, and ventricular hypertrophy 2, 3, 5. This represents a major pitfall in long-term management requiring vigilant monitoring 2.
Overtreatment with TSH suppression (<0.1 mIU/L) increases atrial fibrillation risk 3-5 fold, particularly in patients over 60 years 2. Prolonged suppression also increases cardiovascular mortality and accelerates bone loss in postmenopausal women 2.
In patients with suspected central hypothyroidism or concurrent adrenal insufficiency, always start corticosteroids before levothyroxine to prevent life-threatening adrenal crisis 2. This represents an absolute contraindication to starting thyroid hormone first 2.
Special Populations
Pregnant women require 25-50% dose increase immediately upon pregnancy confirmation 2. Levothyroxine requirements increase during early pregnancy, necessitating proactive dose adjustments for proper fetal neurologic development 2. Monitor TSH every 4 weeks until stable, then at minimum once per trimester, targeting TSH <2.5 mIU/L in the first trimester 2.
Patients on immune checkpoint inhibitors should have TSH monitored every 4-6 weeks for the first 3 months, then every second cycle thereafter 2. Thyroid dysfunction occurs in 6-9% with anti-PD-1/PD-L1 therapy and 16% with combination immunotherapy 2.
Drug Interactions
Levothyroxine absorption is reduced by iron, calcium supplements, proton pump inhibitors, and soybean-based products 1. Maintain at least 4 hours separation between levothyroxine and these agents 1. Enzyme inducers reduce levothyroxine efficacy and may require dose adjustments 6.