Pharmacokinetics of total thyroxine in dogs after administration of an oral solution of levothyroxine sodium

Abstract

Oral L-thyroxine (L-T4) supplementation is used to replace thyroid hormone concentrations in dogs with hypothyroidism. The pharmacokinetics of L-T4 following administration of a solution (Leventa) was investigated in healthy dogs. L-T4 was absorbed fairly rapidly (t(max) 3 h). A mean bioavailability of 22% was calculated following a single oral administration of 40 microg L-T4/kg body weight. Repeated oral administration at the same dose for 14 consecutive days did not lead to any accumulation of T4 in serum. After intravenous administration of L-T4, a serum half-life of 11.6 h was calculated. Food intake concomitant with L-T4 oral administration delayed L-T4 absorption and decreased its rate and extent by about 45%. The relative bioavailability of L-T4 following administration of a tablet formulation was about 50% of that of the L-T4 solution. The pharmacokinetic properties of liquid L-T4 after oral administration support the use of a dose rate of 20 microg/kg once daily, as a starting dose for replacement therapy in dogs with hypothyroidism.

Hypothyroidism

“…Maximal and minimal serum T 4 concentrations were higher and lower, respectively with once daily L-T 4 sodium administration, than with twice-daily administration. In dogs the relative bioavailability of a liquid L-T 4 sodium solution was demonstrated to be 50% higher than that of a tablet formulation in euthyroid dogs; however, the dose required for establishment of euthyroidism in hypothyroid dogs (0.02 mg/kg every 24 hours) was similar to that required for an oral tablet formulation (Soloxine, Daniels Pharmaceuticals) (Le Traon et al, 2007;Dixon et al, 2002). The ideal dose and frequency of L-T 4 sodium supplementation varies among dogs because of variability in T 4 absorption and serum half-life between individual dogs.…”

“…As a result, serum T 4 concentrations were above the physiologic range for a number of hours with single L-T 4 sodium administration, whereas concentrations closer to physiologic ranges were achieved by use of divided doses. Administration of L-T 4 sodium with food has been shown to decrease bioavailability of liquid L-T 4 sodium formulations in dogs (Le Traon et al, 2007). A dose of 0.02 mg/kg every 24 hours normalizes TSH concentration in most dogs; higher doses (0.04 mg/kg every 12 hours) are required to consistently normalize T 3 concentration, but there is no evidence that normalization of T 3 is necessary for a good clinical response.…”

Effects of Levothyroxine Administration and Withdrawal on the Hypothalamic‐Pituitary‐Thyroid Axis in Euthyroid Dogs

“…Although once daily dosing results in more fluctuation in serum T 4 concentrations compared to twice daily dosing, the duration of action of T 4 is longer than its plasma half‐life 22, 23, 24, 25, 26. In previous studies of the HPTA, dogs were administered levothyroxine twice daily, making comparisons difficult 6, 14…”

Safety of orally administered,USP‐compliant levothyroxine sodium tablets in dogs

“…Multiple‐dose studies in which levothyroxine sodium was given to euthyroid dogs used either extreme doses of 1 or 2 mg kg −1 day −1 (High, Capen, & Black, ,b; Minaire, Forichon, Freminet, Cagnard, & Dallevet, ) or doses ranging from 1× to 5× (0.02–0.1 mg kg −1 day −1 ) the recommended starting dose for hypothyroid dogs (Heseltine et al., ; Le Traon, Burgaud, & Horspool, ; Li, Chen, Tiller, & Kunkle, ; Panciera, Atkins, Bosu, & MacEwen, ; Panciera, Keene, & Mier, ; Panciera, MacEwen et al., ; Simpson, Devi, & Whittem, ; Tidholm et al., ; Van Vleet, Ferrans, & Badylak, ; Ziglioli et al., ). There was a disparate effect of extreme levothyroxine dosing on body weight, with the dogs that received 1 mg kg −1 day −1 levothyroxine sodium having an 8.6% increase in mean body weight (High et al., ,b) and the dogs that received 2 mg kg −1 day −1 having a mean 12% decrease in body weight (Minaire et al., ).…”

“…In the multiple‐dose studies in which dogs received 1×–5× the starting dose, no behavioral signs (panting, hyperactivity, polyuria/polydypsia) of thyrotoxicosis were reported (Heseltine et al., ; Le Traon et al., ; Li et al., ; Panciera, Atkins et al., ; Panciera, MacEwen et al., ; Panciera et al., ; Simpson et al., ; Tidholm et al., ; Van Vleet et al., ; Ziglioli et al., ). The only overt clinical sign reported in any of these studies was mild weight loss (Heseltine et al., ).…”