Pharmacokinetics of Single-Dose Intramuscular and Subcutaneous Injections of Buprenorphine in Common Marmosets (Callithrix jacchus)

Although buprenorphine is the most frequently used opioid analgesic in common marmosets (Callithrix jacchus), there is limited information in the literature supporting current dosing regimens used for this species. The purpose of this study was to determine the pharmacokinetic profiles of single-dose buprenorphine HCl administered intramuscularly (IM) at 0.01 mg/kg in 6 adult marmosets (1.8 to 12.8 y old; 2 males, 4 females) and subcutaneously (SQ) at 0.01 mg/kg in 6 adult marmosets (2.3-4.4 y old; 3 males, 3 females) by mass spectrometry. Blood was collected at multiple time points from 0.25 to 24 h from unsedated animals following a hybrid sparse-serial sampling design. The maximal observed plasma concentration of buprenorphine (C_max) administered IM (2.57 ± 0.95 ng/mL) was significantly higher than administered SQ (1.47 ± 0.61 ng/mL). However, the time to C_max (T_max) was not statistically different between routes (17.4 ± 6 min for IM and 19.8 ± 7.8 min for SQ). The time of the last quantifiable concentration of buprenorphine was 5 ± 1.67 h for IM compared with 6.33 ± 1.51 h for SQ, which was not statistically different. The mean buprenorphine plasma concentration-time curves were used to propose a dosing frequency of 4 to 6 h for buprenorphine at 0.01 mg/kg IM or SQ based on a theoretical therapeutic plasma concentration threshold of 0.1 ng/mL. Based on the mean pharmacokinetic parameters and plasma-concentration time curves_, both IM and SQ routes of buprenorphine at this dose provide a rapid increase in the plasma concentration of buprenorphine above the therapeutic threshold, and may be more effective for acute rather than long-lasting analgesia. Further studies are needed to examine repeated dosing regimens and the efficacy of buprenorphine in common marmosets.

The common marmoset (Callithrix jacchus), a New World (platyrrhine) monkey belonging to the Callitrichidae family, is an important experimental model used in diverse areas of study, including neuroscience, behavior, drug metabolism and toxicology, infectious diseases, and in the development of genetically modified NHP models for biomedical research.^11,28,32,33 Marmosets often undergo minor and major survival surgical procedures as part of experimental protocols, including implantations, laparotomies, and obstetric procedures. However, biomedical research and veterinary procedures performed on marmosets have the potential to cause pain and distress, requiring effective analgesic regimens.⁵ The provision of appropriate analgesia to counteract painful stimuli is a humane necessity fundamental to multiple animal research regulatory policies.^3,14,24Buprenorphine, a Schedule III opioid analgesic, is a partial μ-agonist, δ- and κ-antagonist, and nociceptin receptor agonist.^2,8,48 This drug is the most commonly used opioid analgesic in NHPs, including laboratory marmosets.^{7,18,31,33,35} Dosages recommended for marmosets range from 0.005 to 0.02 mg/kg, either alone for mild to moderate pain or as part of a multimodal analgesic plan for moderate-to-severe pain.^6,18,30,33 These dosage recommendations have been primarily based on anecdotal information and limited evidence related to use and efficacy present in the literature. However, a recent study by Fitz and colleagues evaluated the pharmacokinetics of single-dose intramuscular (IM) buprenorphine at 0.02 mg/kg and subcutaneous (SQ) sustained-release buprenorphine (Bup SR) at 0.2 mg/kg in marmosets. Based on a therapeutic plasma concentration threshold of 0.1 ng/mL, the authors recommended dosing frequencies of 6 to 8 h for buprenorphine and 3.0 to 3.5 d for Bup SR.¹⁸New World monkey species are more sensitive to opioid-induced adverse side effects such as profound respiratory depression at doses considered safe in other NHPs, rodents, and other laboratory animal species.^{6,10,18,27,35,46} For example, in one study, buprenorphine, administered to C. jacchus at 0.02 mg/kg IM as a premedication before alfaxalone induction, resulted in apnea in 8 out of 9 study animals.⁶ In unsedated marmosets, administration of buprenorphine at 0.02 mg/kg IM has resulted in mild to moderate ataxia and moderate sedation.¹⁸At the Massachusetts Institute of Technology (MIT, Cambridge, MA), buprenorphine HCl is administered to marmosets at 0.005–0.01 mg/kg IM and SQ, and rarely elicits adverse effects. However, analgesic efficacy at these doses is unknown and redosing schedules have been empirically based. In addition, absorption of SQ buprenorphine in some species such as cats can be highly variable and unreliable.⁴³ Although IM and SQ routes are commonly used in marmosets, how the route of administration affects buprenorphine absorption and plasma clearance is unknown. These issues underscore the importance of experimentally determining PK data and developing optimal dosing strategies for the use of this drug in marmosets.We performed a study using healthy adult marmosets to evaluate and compare the IM and SQ pharmacokinetics of single-dose buprenorphine HCl, administered at a clinically relevant dosage of 0.01 mg/kg. Liquid chromatography–electrospray ionization–tandem mass spectrometry was used to demonstrate that buprenorphine reached quantifiable plasma concentrations after administration, and to determine the interval for which buprenorphine was quantifiable in the plasma. We hypothesized that a single-dose of buprenorphine administered SQ would have slower absorption (longer T_max) and longer duration (longer T_last), when compared with IM administration.