Pharmacokinetics of Methadone in Cynomolgus Macaques

Introduction: Methadone, a synthetic opioid has gained popularity as an analgesic for surgical procedures as it provides a longer effective duration compared to common opioids for moderate to severe pain. Pharmacokinetic (PK) data in dogs and humans demonstrate therapeutic duration for 12-14 hours. This study investigates the pharmacokinetics of methadone at 2 dose levels in Cynomolgus Macaques for use as extended duration opioid for surgical procedures involving moderate to severe pain post-operatively.
Methods: 8 Mauritius origin Cynomolgus Macaques were administered 0.2mg/kg and 0.5 mg/kg methadone hydrochloride intramuscularly (IM) and plasma and urine collected at predetermined time points and analyzed. Average mean total plasma concentration at 15 minutes post-administration: 37.7ng/mL Average mean total plasma concentration at 8 hours: 4.48ng/mL
Results: After IM administration, 0.2 mg/kg dose terminal half-life was 3.61 hrs and in therapeutic range for 8 hours; 0.5 mg/kg dose terminal half-life was 21.3 hrs and in therapeutic range for a minimum of 12 hours. Time points between 12-16 hours should be considered to determine when levels begin to decrease (plan to investigate in future study)
Conclusion: Established dosing ranges and duration for Methadone in NHPs to effectively address moderate-severe pain. Half-life increases significantly at higher dose Based on clinical application, 0.5mg/kg Methadone can be effectively dosed in NHPs at 12 hour intervals for moderate-severe pain Doses may need to be adjusted for chronic administration due to cumulative effect