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

摘要

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.