Pharmacokinetics of thalidomide in dogs: can feeding affect it? A preliminary study

Abstract

Background Tumor-associated neoangiogenesis is a crucial target for antitumor therapies. Thalidomide (TAL) is a promising anti-neoangiogenetic drug that has recently been used in the treatment of several malignancies in dogs. Objectives The aim of the study was to assess the pharmacokinetics of TAL after single oral administration in dogs. Additionally, the influence of feeding on the pharmacokinetic profile of TAL in dogs has been preliminarily investigated. Methods Six healthy adult female Labradors were enrolled according to a randomized single-dose, 2-treatment, 2-phase, paired 2 × 2 cross-over study design. The dogs were administered a single 400 mg capsule of TAL in fasted and fed conditions. Blood was collected from 15 min to 48 h after dosing, and TAL quantified in plasma by a validated high-performance liquid chromatography method. The pharmacokinetics of TAL were analyzed using a non-compartmental approach. Results TAL concentration was quantifiable up to 10 h and 24 h after fasted and fed conditions, respectively. C max (fasted, 1.34 ± 0.12 µg/mL; fed, 2.47 ± 0.19 µg/mL) and T max (fasted, 3 h; fed, 10 h) differed substantially between the 2 groups. AUC and t 1/2 λz were significantly higher in fed (42.46 ± 6.64 mg × h/L; 17.14 ± 4.68 h) compared to fasted (12.38 ± 1.13 mg × h/L; 6.55 ± 1.25 h) dogs. The relative oral bioavailability of TAL for the fasted group was low (36.92% ± 3.28%). Conclusions Feeding affects the pharmacokinetics of oral TAL in dogs, showing a delayed, but higher absorption with different rate of elimination. These findings are of importance in clinical veterinary settings, and represent a starting point for further related studies.

Safety and pharmacokinetics of thalidomide in tumor-bearing dogs

“…Adverse events associated with thalidomide have been reported in people and include peripheral neurologic symptoms, such as numbness and tremor [ 7 , 28 , 33 ]. Although there are reports of no peripheral nerve signs in dogs [ 2 , 32 ], tremor, stiff walking, dizziness, and whining have been observed experimentally after a single dose of thalidomide [ 24 ]. However, these signs were transient after administration, and their exact relationship with thalidomide remains unclear.…”

“…In healthy dogs, thalidomide was reported to increase blood levels of thalidomide when administered with food. In this study, thalidomide dosed at 400 mg/head=11.74 ± 0.56 mg/kg with food had an AUC of 42.46 ± 6.64 mg•hr/L, whereas the AUC after overnight fasting was only 12.38 ± 1.13 mg•hr/L, indicating that thalidomide dosed with food was significantly higher than when it was dosed in a fasted state [ 24 ]. In our study, the AUC 0–24 at 10 mg/kg of thalidomide was 22.0 ± 14.7 μg•hr /mL at an intermediate state between a non-fasting and fasting state, as performed in the study by Pierini et al .…”

“…A retrospective study of 15 dogs with hemangiosarcoma also found no adverse events associated with thalidomide other than lethargy [ 2 ]. In contrast, in a study investigating the pharmacokinetics of thalidomide in experimental dogs, tremor and dizziness were observed after thalidomide administration [ 24 ], indicating that dogs can develop peripheral nerve signs similar to those observed in humans.…”

Metronomic chemotherapy: bridging theory to clinical application in canine and feline oncology

“…This drug was considered well-tolerated in canine patients at a daily dose of 10 mg/kg ( 94 ), although, it has typically been used at 2 to 4 mg/kg per day, in combination with cyclophosphamide and piroxicam ( 61 , 69 , 73 , 81 ). Care must be taken with the timing of administration, as food intake seems to affect its bioavailability, delaying but increasing its absorption ( 95 ). Despite this, the accessibility of thalidomide on the global market has been limited due to the severe teratogenic effects reported in humans ( 96 ), which may compromise its routine use in veterinary metronomic protocols in some geographical territories.…”

Veterinary pharmacology: A world almost unexplored with huge potential

“…Differently, companion animals are treated as members of the family and pet owners demand the same level of care, they expect for themselves. This change in attitude has resulted in a push for the development of more effective and innovative veterinary therapies ( Pierini et al., 2020 ).…”