Thyroxine hormone has been recognised since the early part of the nineteenth century and levothyroxine has been available since the mid-nineteenth century as a replacement for deficient thyroid hormones. 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.

To better understand the pharmacokinetics and potential advantages of a levothyroxine oral solution vs. tablets and soft gel capsules.4 randomized, 2-treatment, single-dose (600 mcg levothyroxine), 2-way crossover bioequivalence studies in 84 healthy subjects were analyzed. Samples were collected before dosing and until 48-72 h post-dose to calculate noncompartmental baseline-adjusted pharmacokinetic parameters: maximum concentration, time to maximum concentration, and area-under-the-concentration-time-curve from 0 to 48 h and from 0 to 2 h.Mean pharmacokinetic parameters (±standard deviation) for tablets, capsules and solution, respectively, were: area-under-the-concentration-time-curve from 0 to 2 h (ng*h/mL)=68.4±32.8, 64.4±24.4, 99.1±22.7; area-under-the-concentration-time-curve from 0 to 48 h (ng*h/mL)=1 632±424, 1 752±445, 1 862±439; maximum concentration (ng/mL)=67.6±20.9, 68.0±15.9, 71.4±16.0; time of maximum concentration (hours)=2.25±0.99, 2.38±1.58, 1.96±1.07. Overall rate and extent of exposure were not statistically different between formulations, but a faster onset of absorption for the solution was suggested (greater area-under-the-concentration-time-curve from 0 to 2 h and faster time to maximum concentration by an average of 30 min).Levothyroxine rate and extent of exposure are similar between tested formulations. The solution appears however to reach systemic circulation quicker as dissolution is not needed before absorption starts. The solution's greater early exposure and a faster time to maximal concentration of around 30 min may be of benefit to minimize drug-food interactions and deserves further investigations.

-Purpose:Clinical studies have suggested that proton pump inhibitors may decrease levothyroxine absorption and an in vitro study suggested that the effect of pH on dissolution may differ with formulation. To determine the impact of formulation on the pharmacokinetics of levothyroxine in altered gastric pH conditions, this study compared the pharmacokinetics of levothyroxine capsules and tablets, two formulations deemed bioequivalent in healthy volunteers under fasting conditions, when taken with or without esomeprazole. Methods: Two clinical studies were conducted in healthy volunteers given single dose levothyroxine (600 g) with a 45-day washout period. In Study 1 (parallel-design/two-way crossover), 16 subjects received either levothyroxine capsules or tablets, each group with or without prior administration of intravenous esomeprazole (maximum dose of 80 mg). In Study 2 (two-way crossover), 16 subjects received both capsules or tablets after intravenous esomeprazole. Blood samples were collected pre-dose and up to 24 hours post-dose. Baselineadjusted pharmacokinetic parameters were calculated: C max (maximal concentration), T max (time to C max ), AUC 0-t (area under the concentration-time curve from 0 to the last detectable concentration), AUC 0-6 and AUC 0-12 (areas under the curve from 0 to 6 and 12 hours, respectively). Analyses of variance were conducted to compare lntransformed C max and AUC. Non-parametric T max analyses were done. Results: In Study 1, esomeprazole caused a greater decrease in overall levothyroxine exposure of tablets vs. capsules (13% vs 6% for C max , 18% vs. 14% for AUC 0-6 , 17% vs. 5% for AUC 0-12 and 10% vs. 8% for AUC 0-t ). In Study 2 esomeprazole administration resulted in a 16% smaller levothyroxine exposure with tablets vs. capsules. No statistically significant differences in T max were found. Conclusions: Although both formulations are considered "bioequivalent" in healthy volunteers, they may not necessarily be bioequivalent in patients with impaired gastric pH conditions. Levothyroxine capsules may therefore be more appropriate for patients with decreased gastric acidity.

Pegloticase is designed to convert urate into the easily excretable allantoin to treat hyperuricemia in gout. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of pegloticase in 40 gout patients. Pegloticase was administered as intravenous infusions every 2 weeks at 4- and 8-mg doses or every 4 weeks at 8- or 12-mg doses for 12 weeks. Serum pegloticase concentrations, plasma urate, and serum antibody response were determined. Population pharmacokinetics and pharmacodynamics analyses were performed. Data were modeled simultaneously, and covariates were investigated (age, gender, race, body weight, ideal body weight, and antibody response). The dosing regimens to maintain uric acid levels below the therapeutic target of 6 mg/dL were then predicted by the model. The pharmacokinetics were best described by a 1-compartment linear model, while the pharmacodynamics model was fitted as a direct effect of pegloticase on uric acid concentrations with a suppressive maximum effect attributed to drug (E(max)) function. Pegloticase suppressed uric acid levels up to 83%. Weight only affected clearance and volume of distribution. No covariates affected pharmacodynamics. Simulation suggests pegloticase administered at 8 mg every 2 or 4 weeks as 2-hour intravenous infusions will maintain uric acid levels well under 6 mg/dL.

This study shows that SPS reduced Li T(1/2) and suggests that SPS is capable of promoting Li elimination in chronic intoxications. These results warrant a prospective trial looking at the use of SPS in the treatment of Li overdose as an adjunct to supportive measures and hemodialysis.