Pharmacokinetics of Buprenorphine and Sustained-release Buprenorphine in Common Marmosets (Callithrix jacchus)

Abstract

Buprenorphine is an essential component of analgesic protocols in common marmosets (Callithrix jacchus). The use of buprenorphine HCl (BUP) and sustained-release buprenorphine (BSR) formulations has become commonplace in this species, but the pharmacokinetics have not been evaluated. Healthy adult (age, 2.4 to 6.8 y; 6 female and 6 male) common marmosets were enrolled in this study to determine the pharmacokinetic parameters, plasma concentration–time curves, and any apparent adverse effects of these compounds. Equal numbers of each sex were randomly assigned to receive BUP (0.02 mg/kg IM) orBSR (0.2 mg/kg SC), resulting in peak plasma concentrations (mean ± 1 SD) of 15.2 ± 8.1 and 2.8 ± 1.2 ng/mL, terminal phase t1/2 of 2.2 ± 1.0 and 32.6 ± 9.6 h, and AUC0-last of 16.1 ± 3.7 and 98.6 ± 42.7 ng×h/mL. The plasma concentrations of buprenorphine exceeded the proposed minimal therapeutic threshold (0.1 ng/mL) at 5 and 15 min after BUP and BSR administration,showing that both compounds are rapid-acting, and remained above that threshold through the final time points of 8 and 72h. Extrapolation of the terminal elimination phase of the mean concentration–time curves was used to develop the clinical dosing frequencies of 6 to 8 h for BUP and 3.0 to 3.5 d for BSR. Some adverse effects were observed after the administration of BUP to common marmosets in this study, thus mandating judicious use in clinical practice. BSR provided a safe, long-acting option for analgesia and therefore can be used to refine analgesic protocols in this species.

A pharmacokinetic study of extended‐release buprenorphine in cynomolgus monkeys (Macaca fasicularis)

“…Compared to the common marmoset, the plasma half-life in cynomolgus monkeys of 42.6 h is longer than that of the common marmoset with either BUP-SR or BUP-XR. 10,12 In the study by Nunamaker, it was reported that there was no statistical difference in the observed half-life for either rhesus or cynomolgus monkeys. 14 This may hold a particular advantage as data from the present study in male cynomolgus monkeys suggests that it may be safe to extrapolate dose regimens for this formulation of XR BUP to rhesus monkeys.…”

“…In this study, no abnormal behaviors or clinical signs, or injection site reactions were observed. By comparison, PK studies in the common marmoset 10,11 using a polymer‐based compounded long‐acting SR‐BUP demonstrated mild localized erythema and swelling of tissues around the injection site, which was reversible over time. This was not observed with Ethiqa XR in marmosets 12 .…”

“…The plasma concentrations of BUP in male cynomolgus monkeys measured over a 96-h period post-injection are similar to those reported in other non-human primate species. 6,8,10,12 These plasma levels have been shown to be efficacious using clinical reports and scoring as well as multiple analgesiometry testing in multiple species such as rodents, non-human primates, and in humans. 13 In the common marmoset, the plasma half-life of a SR BUP formulation resulted in a half-life of 32.6 +/−9.6 h. 10 Data from this study in cynomolgus monkeys support the parallel conclusions that the one-time administration of a SC injection of a commercial formulation of BUP-XR at 0.2 mg/kg can achieve therapeutic plasma levels of BUP (>1 ng/mL) for at least 96 h in an effective and safe manner.…”

Pharmacokinetics of Extended-release Buprenorphine (Ethiqa) in Female Yorkshire Swine (Sus scrofa domestica)

“…10,51,52 Although dose-dependent respiratory depression and sedation are possible, many studies have established buprenorphine to be safe and effective in common laboratory animal species including mice, rats, and non-human primates. 1,4,12,14,16,27,33,38 Despite the plethora of information regarding buprenorphine use in rodents, there is little information on adequate buprenorphine use in swine. The reported dose for buprenorphine HCl in swine is wide and ranges from 0.01-0.1 mg/kg with a dosing frequency of twice or three times daily.…”

“…10,51,52 Although dose-dependent respiratory depression and sedation are possible, many studies have established buprenorphine to be safe and effective in common laboratory animal species including mice, rats, and non-human primates. 1,4,12,14,16,27,33,38…”