Short-acting and Long-acting Buprenorphine Therapeutic Drug Levels Following Single Subcutaneous Administration in Diabetic Yucatan Miniswine
Hanks, B.C., Schlink, S., Brown, L.D., Luna, M., Liu, J., Stricker-Krongrad, A., Bouchard, G.F.
Sustained and controlled analgesia for animals involved in potentially painful procedures, such as surgery, is required for animal welfare and ethical considerations. Many analgesics are available to Laboratory Animal Veterinarians but the pharmacokinetic and pharmacodynamicdata are not always available for every species. This is the situation for miniswineand porcine models. Standard short-acting buprenorphine HCl(BUP), an opioid, is routinely used in swine models on a BID basis (dose range 0.005-0.02 mg/kg im, scor iv) while BUP SR (Sustained Release) is dosed at approx. 10-fold levels in large animals. The published data supporting this porcine BUP regimen or the use of Sustained Release (SR) buprenorphine (BUP SR) in swine is quite limited, thereby forcing investigators to favor on the side of caution which can be expensive. Therefore, we designed a study to assess the PK for buprenorphine analgesics in Yucatan miniswine. The diabetic Yucatan was selected because we chemically induce, place VAPS, and maintain a large herd of these animal models. Four castrated male alloxandiabetic animals weighing approximately 30 kg were used in a complete cross-over design. For standard buprenorphine HClanimals were dosed subcutaneously (left flank fold) with either 0.01 mg/kg (low-dose) or 0.02 mg/kg (high-dose), while for sustained release buprenorphine the dose was either 0.12 mg/kg (low-dose) or 0.24 mg/kg (high-dose) s.c.in left flank-fold. Washout was set at 9d before animals were redosedwith another formulation. For the shorter acting buprenorphine, blood samples were collected at pre-dose, 0, 15, 30, 60, 120, 240 and 480 minutes (8 timepointstargeted). For the sustained formulation, samples were collected at pre-dose, 0, 30, 60, 90, 240 and 480 minutes, and 12h, 24h, 48h, 72h, and 96h (12 timepointstargeted). Buprenorphine was analyzed in K2EDTA plasma samples by liquid-liquid extraction and LC-MS/MS (quantitation range 50 to 5000 pg/mL). Results were reported in picograms/mL of plasma. All data were quality controlled and outliers removed before summary statistics were calculated and plotted. Results for buprenorphine high-& low-dose plasma drug profile curves showed that BUP peaked at 2192 pg/ml for the high-dose and 842 pg/mL for the low dose. Following single s.c.administration, short-acting BUP drug was onboard in plasma for 240-480 min (above 0.1 ng/mL efficacious threshold for 480 min or 8 hrs). Results for buprenorphine SR high-& low-dose plasma drug profile curves showed that BUP SR peaked at 1795.5 pg/ml at 240 min (high-dose) and peaked at 1531.8 pg/mL (low dose) at 30 min. Sustained release drug was present in plasma for 96 hrsfor both high-& low-dose (above 0.1 ng/mL). In conclusion, these data suggest that these dose levels provide sufficient plasma levels of drug for analgesia (>0.1 ng/mL) for at least 8 hr(short-acting BUP) or for at least 96 hr(long-acting BUP SR). Standard pharmacokinetic parameters were calculated.