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

Abstract

BackgroundA novel buprenorphine (BUP) extended‐release formulation (BUP‐XR) produced as a lipid‐encapsulated, low viscosity BUP suspension for subcutaneous (SC) injection to control pain was evaluated for pharmacokinetics and safety in four adult male cynomolgus monkeys.MethodsEach animal was given 0.2 mg/kg reformulated BUP‐XR SC. Clinical observations were made during the course of the study. Blood samples were obtained from each animal before BUP‐XR administration, 6, 24, 48, 72, and 96 h post‐BUP‐XR injection. Plasma levels of buprenorphine were analyzed using HPLC‐MS/MS. The PK values calculated included peak plasma concentration of the BUP analyte, time to peak plasma concentration, plasma half‐life, area under the plasma concentration–time curve, clearance, apparent volume of distribution, and elimination rate constant (Cmax, Tmax, T½, AUC0‐t, CL, Vd, and Ke, respectively).ResultsObservable adverse clinical signs were not detected. BUP concentration peaked from 6 to 48 h, then declined in a linear fashion. Quantifiable plasma BUP was measured in all monkeys at all time points. Results indicate that a single BUP‐XR dose at 0.2 mg/kg can reliably provide plasma levels of BUP reported in the literature to be therapeutically relevant for up to 96 h.ConclusionsBecause of the lack of any clinical observations or adverse effects at the injection site or absence of observable abnormal behaviors, it may be concluded that the use of BUP‐XR is safe and efficacious in this species of non‐human primate at the dose regimen described in this study for up to 96 h post‐administration.

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

“…In the cynomolgus macaque ( Macaca fascicularis ) and the common marmoset ( Callithrix jacchus ), therapeutic buprenorphine plasma levels lasted as long as 96 h after XRB administration. 11,25 Evaluation of another non-FDA approved long-lasting buprenorphine, SRB, in diabetic Yucatan miniature swine revealed therapeutic plasma levels that surpassed 96 h. 17 Furthermore, our study revealed XRB (Ethiqa) injection sites sustained minimal changes including granulomatous inflammation and cholesterol clefts – consistent with what has been reported with injection of XRB (Ethiqa) in other species and likely due to the lipid-bound in a medium chain fatty acid triglyceride (MCT) oil. 11,16,22,23,25 Therefore, XRB (Ethiqa) extra-label use in swine increases our options for long-lasting and safe analgesia in swine.…”

“…56 Studies comparing local injection reactions of SRB and XRB (Ethiqa) in multiple species revealed XRB (Ethiqa) had less inflammatory changes. 11,23,25 These findings encourage further optimization of long-lasting buprenorphine formulation for swine and support the extra-label use of the FDA-indexed XRB (Ethiqa) in this species.…”