PK/PD assessment of tapentadol in yellow-bellied slider turtles (Trachemys scripta scripta).

In reptiles, administration of opioid drugs has yielded unexpected results with respect to analgesia. Tapentadol (TAP) is a novel atypical opioid drug labelled for human use. The aim of this study was to evaluate the pharmacokinetics (PK) and the pharmacodynamics (PD) of this drug in yellow-bellied slider turtles, after a single IM injection of 5 mg/kg of TAP. The Animal Welfare Committee of the University of Pisa approved the study protocol (n° 37070/2013). Turtles (n = 9) were randomly assigned to two treatment groups, according to an open, single-dose, singletreatment, unpaired, two-period crossover design. Group A (n = 5) received a single IM dose of TAP (5 mg/mL) at 5 mg/kg and Group B (n = 4) a single IM injection of saline. The wash out period was 1 month. Blood samples (1 mL) were collected from the dorsal cervical at assigned times. TAP plasma concentrations were evaluated according to a HPLC method (Giorgi et al., 2012) while an infrared thermal stimuli was applied to the plantar surface of the turtles' hind limbs to evaluate the thermal withdrawal latency (TWL). The PK calculations were carried out with WinNonLin v 5.3 (Pharsight) using standard non-compartmental equations. The antinociceptive effect was expressed as percentage of Maximum Possible Response (% MPR) and calculated as: % MPR=(Ttest-Tcon)/(Tcut-Tcon)×100 where Ttest is TWL value after injection of TAP, Tcon is TWL value after injection of saline (control) and Tcut is the cut-off time. PK: The plasma concentrations of TAP were in the range (37-1619 ng/mL) and detectable up to 24 h, except in three subjects. Cmax of 1641±749 ng/mL was observed at 1.22±0.44 h after injection. TAP was eliminated slowly with a long terminal half-life of 4.04±2.10 h and a large volume of distribution of 4.30±1.79 L/kg. PD: Differences in TWL in controls (n = 9) were not statistically significant at any point tested. The T0 was 5.660.92 s. Animals given TAP showed a drastic increase in TWL 1 h after drug administration (13.326.40 s). Subsequently, TWL decreased in proportion to time with significant differences from the controls still apparent up to 10 h and it was still greater than baseline, but not statistically significant, at 24 h. Mean MPR started at 1.69±1.80 % (T0), increased to a maximum of 46.68±12.30 % at 1 h and decreased to a minimum of 1.62±2.77 % at 24 h. The MPR difference between TAP and controls was still significant at 10 h. PK/PD evaluation: The mean TAP plasma concentration and % MPR vs time curves were very similar. Average plasma concentration associated with maximum % MPR of 46.68±12.30 % was 1619±242 ng/mL. A linear relationship (r2 = 0.99) between TAP plasma concentration and % MPR was found. TAP appears to be an attractive option for antinociception in turtles, due to its rapid onset and acceptable duration of effect. However, systemic pharmacokinetics and biophase distribution should be considered along with a sound assessment of drug safety before its use in reptile clinical practice.In reptiles, administration of opioid drugs has yielded unexpected results with respect to analgesia. Tapentadol (TAP) is a novel atypical opioid drug labelled for human use. The aim of this study was to evaluate the pharmacokinetics (PK) and the pharmacodynamics (PD) of this drug in yellow-bellied slider turtles, after a single IM injection of 5 mg/kg of TAP. The Animal Welfare Committee of the University of Pisa approved the study protocol (n° 37070/2013). Turtles (n = 9) were randomly assigned to two treatment groups, according to an open, single-dose, singletreatment, unpaired, two-period crossover design. Group A (n = 5) received a single IM dose of TAP (5 mg/mL) at 5 mg/kg and Group B (n = 4) a single IM injection of saline. The wash out period was 1 month. Blood samples (1 mL) were collected from the dorsal cervical at assigned times. TAP plasma concentrations were evaluated according to a HPLC method (Giorgi et al., 2012) while an infrared thermal stimuli was applied to the plantar surface of the turtles' hind limbs to evaluate the thermal withdrawal latency (TWL). The PK calculations were carried out with WinNonLin v 5.3 (Pharsight) using standard non-compartmental equations. The antinociceptive effect was expressed as percentage of Maximum Possible Response (% MPR) and calculated as: % MPR=(Ttest-Tcon)/(Tcut-Tcon)×100 where Ttest is TWL value after injection of TAP, Tcon is TWL value after injection of saline (control) and Tcut is the cut-off time. PK: The plasma concentrations of TAP were in the range (37-1619 ng/mL) and detectable up to 24 h, except in three subjects. Cmax of 1641±749 ng/mL was observed at 1.22±0.44 h after injection. TAP was eliminated slowly with a long terminal half-life of 4.04±2.10 h and a large volume of distribution of 4.30±1.79 L/kg. PD: Differences in TWL in controls (n = 9) were not statistically significant at any point tested. The T0 was 5.660.92 s. Animals given TAP showed a drastic increase in TWL 1 h after drug administration (13.326.40 s). Subsequently, TWL decreased in proportion to time with significant differences from the controls still apparent up to 10 h and it was still greater than baseline, but not statistically significant, at 24 h. Mean MPR started at 1.69±1.80 % (T0), increased to a maximum of 46.68±12.30 % at 1 h and decreased to a minimum of 1.62±2.77 % at 24 h. The MPR difference between TAP and controls was still significant at 10 h. PK/PD evaluation: The mean TAP plasma concentration and % MPR vs time curves were very similar. Average plasma concentration associated with maximum % MPR of 46.68±12.30 % was 1619±242 ng/mL. A linear relationship (r2 = 0.99) between TAP plasma concentration and % MPR was found. TAP appears to be an attractive option for antinociception in turtles, due to its rapid onset and acceptable duration of effect. However, systemic pharmacokinetics and biophase distribution should be considered along with a sound assessment of drug safety before its use in reptile clinical practice.