Search Results
You are looking at 1 - 2 of 2 items for
- Author or Editor: Charles W. Locuson x
- Refine by Access: All Content x
Abstract
OBJECTIVE
To determine the effects of coadministration of naltrexone, a human opioid abuse deterrent, on the pharmacokinetics and pharmacodynamics of a methadone-fluconazole combination administered orally to dogs.
ANIMALS
12 healthy Beagles.
PROCEDURES
Dogs (body weight, 10.7 to 13.9 kg) were randomly allocated to 2 groups in a parallel design study. All dogs received fluconazole (100 mg [7.19 to 9.35 mg/kg], PO). Twelve hours later (time 0), dogs were administered methadone (10 mg [0.72 to 0.93 mg/kg]) plus fluconazole (50 mg [3.62 to 4.22 mg/kg]; methadone-fluconazole) or methadone (10 mg [0.72 to 0.93 mg/kg]) plus fluconazole (50 mg [3.60 to 4.67 mg/kg]) and naltrexone (2.5 mg [0.18 to 0.23 mg/kg]; methadone-fluconazole-naltrexone), PO, in a gelatin capsule. Blood samples were collected for pharmacokinetic analysis, and rectal temperature and sedation were assessed to evaluate opioid effects at predetermined times up to 24 hours after treatment.
RESULTS
Most dogs had slight sedation during the 12 hours after drug administration; 1 dog/group had moderate sedation at 1 time point. Mean rectal temperatures decreased significantly from baseline (immediate pretreatment) values from 2 to ≥ 12 hours and 2 to ≥ 8 hours after methadone-fluconazole and methadone-fluconazole-naltrexone treatment, respectively. Geometric mean maximum observed concentration of methadone in plasma was 35.1 and 33.5 ng/mL and geometric mean terminal half-life was 7.92 and 7.09 hours after methadone-fluconazole and methadone-fluconazole-naltrexone treatment, respectively. Naltrexone was sporadically detected in 1 dog. The active naltrexone metabolite, β-naltrexol, was not detected. The inactive metabolite, naltrexone glucuronide, was detected in all dogs administered methadone-fluconazole-naltrexone.
CONCLUSIONS AND CLINICAL RELEVANCE
Opioid effects were detected after oral administration of methadone-fluconazole or methadone-fluconazole-naltrexone. Further studies assessing additional opioid effects, including antinociception, are needed.
Abstract
OBJECTIVE
To assess the pharmacokinetics and opioid effects of methadone after administration of multiple doses by means of 2 dosing regimens of methadone-fluconazole-naltrexone.
ANIMALS
12 healthy Beagles.
PROCEDURES
Dogs were randomly allocated (6 dogs/group) to receive 1 of 2 oral dosing regimens of methadone-fluconazole-naltrexone. Treatment 1 doses were administered at 0 (methadone-to-fluconazole-to-naltrexone ratio of 1:5:0.25 mg/kg), 14 (1:5:0.25), 24 (0.5:2.5:0.125), and 38 (0.5:2.5:0.125) hours. Treatment 2 doses were administered at 0 (1:5:0.25), 4 (0.5:2.5:0.125), 10 (0.5:2.5:0.125), and 24 (0.5:2.5:0.125) hours. Blood samples, rectal temperatures, and von Frey antinociceptive measurements were obtained at designated times.
RESULTS
Compared with baseline, temperatures significantly decreased for treatment 1 group dogs at 2 to ≥ 4 hours and from 16 to ≥ 50 hours (12 hours after last dose) and for treatment 2 group dogs at 2 to ≥ 36 hours (12 hours after last dose), when trough methadone concentrations were ≥ 21.3 ng/mL. Antinociception occurred after the first dose but was not maintained throughout the study. Lesions were noted in some dogs at the application site of the von Frey device. Naltrexone and β-naltrexol were sporadically detected in plasma, and naltrexone glucuronide was consistently detected.
CONCLUSIONS AND CLINICAL RELEVANCE
Opioid effects were noted after oral administration of the first dose, and data suggested that administering a second dose 6 hours later and every 12 hours thereafter was necessary to maintain opioid effects. Antinociception may have been lost because dogs became averse or hyperalgesic to the von Frey device, such that the antinociception model used here may not be robust for repeated measurements in dogs.
