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

Background: This study sought to determine whether levothyroxine pharmacokinetics (PKs) are affected by age, weight, and sex. Methods: A PK study was performed after administration of a tracer dose of carbon-13-labeled LT4 ( 13 C-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 13 C-LT4 was administered. Eighteen serial plasma samples were collected. One sample was obtained before the 13 C-LT4 dose, and the majority of the remaining samples were collected over the 120-hour period post dosing. 13 C-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. Results: 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 13 C-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 (T max ), and dose-normalized peak concentration (C max ) of 13 C-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 13 C-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 13 C-LT4 PK parameters. Sex only affected CL/F, V/F, and dose-normalized C max 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 C max of 13 C-LT4 in multivariate analyses. Conclusion: 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.