Pharmacokinetics of Sustained-release and Extended-release Buprenorphine in Mice after Surgical Catheterization

Saenz, Marissa; Bloom-Saldana, Elizabeth; Synold, Timothy W.; Ermel, Richard W.; Fueger, Patrick T.; Finlay, James

doi:10.30802/aalas-jaalas-22-000025

Cited by 6 publications

(4 citation statements)

References 30 publications

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“…Since this review was prepared, additional studies have been published confirming the utility of LAI buprenorphine analgesics for animal medicine and the relative absence of skin lesions at the injection site with a lipid-based drug carrier. PK studies in Nu/Nu and C57Bl/6J mice [ 70 , 71 , 72 ] and neonatal Sprague Dawley rats [ 73 ] confirmed and extended the evidence supporting LAI buprenorphine products in laboratory animal research.…”

Section: Addendummentioning

confidence: 79%

Long-Acting Opioid Analgesics for Acute Pain: Pharmacokinetic Evidence Reviewed

Tyler

Guarnieri

2023

Veterinary Sciences

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Long-acting injectable (LAI) opioid formulations mitigate the harm profiles and management challenges associated with providing effective analgesia for animals. A single dose of a long-acting opioid analgesic can provide up to 72 h of clinically relevant pain management. Yet, few of these new drugs have been translated to products for veterinary clinics. Regulatory pathways allow accelerated drug approvals for generic and biosimilar drugs. These pathways depend on rigorous evidence for drug safety and pharmacokinetic evidence demonstrating bioequivalence between the new and the legacy drug. This report reviews the animal PK data associated with lipid and polymer-bound buprenorphine LAI formulations. Buprenorphine is a widely used veterinary opioid analgesic. Because of its safety profile and regulatory status, buprenorphine is more accessible than morphine, methadone, and fentanyl. This review of PK studies coupled with the well-established safety profile of buprenorphine suggests that the accelerated approval pathways may be available for this new family of LAI veterinary pharmaceuticals.

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Section: Addendummentioning

confidence: 79%

Long-Acting Opioid Analgesics for Acute Pain: Pharmacokinetic Evidence Reviewed

Tyler

Guarnieri

2023

Veterinary Sciences

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“…XRB (Ethiqa) is currently the only pharmaceutical grade FDA-indexed extended-release buprenorphine formulation that is approved for use in mice and rats. 29,57 In multiple strains of mice and rats, pharmacokinetic studies revealed a single injection of XRB (Ethiqa) provides therapeutic plasma concentrations for 48-72 h. 1,4,21,22,23,26,31,32,40 Additionally, XRB (Ethiqa) has a superior safety profile and long-lasting analgesia effects of up-to 72 h in mice and rats after a single subcutaneous injection. 3,7,16,19,24,40,48 Our results indicate in swine XRB (Ethiqa) provides longer therapeutic buprenorphine concentrations, consistent with what is observed in other non-rodent species and swine breeds.…”

Section: Discussionmentioning

confidence: 99%

“…29,57 In multiple strains of mice and rats, pharmacokinetic studies revealed a single injection of XRB (Ethiqa) provides therapeutic plasma concentrations for 48-72 h. 1,4,21,22,23,26,31,32,40 Additionally, XRB (Ethiqa) has a superior safety profile and long-lasting analgesia effects of up-to 72 h in mice and rats after a single subcutaneous injection. 3,7,16,19,24,40,48 Our results indicate in swine XRB (Ethiqa) provides longer therapeutic buprenorphine concentrations, consistent with what is observed in other non-rodent species and swine breeds. 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.…”

Section: Discussionmentioning

confidence: 99%

“…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. 8,13,17,18,20,30,37,40,45,46,50,55 The long-lasting buprenorphine formulations, formerly sustained-release buprenorphine (SRB; Zoopharm, Fort Collins, CO) and the newly available extended-release buprenorphine (XRB, Ethiqa; Fidelis Pharmaceuticals, North Brunswick, NJ), are superior to the conventional buprenorphine HCl formulations because their long-lasting formulations avoid repeat administrations – an important refinement for minimizing animal distress and pain. However, SRB pharmacokinetics in swine has only been described in two studies with reported dose ranges from 0.12-0.24 mg/kg subcutaneous, once daily and therapeutic plasma concentrations of 0.1 ng/mL or more for at least 96 h. 17,47 To date, no studies have examined the pharmacokinetic profile of XRB in swine.…”

Section: Introductionmentioning

confidence: 99%

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

Stevey-Rindenow,

Saenz,

et al. 2023

Preprint

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Despite the use of swine as a large animal translational surgical model, precise dosing regimens for commonly used analgesics such as buprenorphine, are currently lacking in this species. A newly available extended-release formulation of buprenorphine (XRB, Ethiqa) is FDA-indexed and approved for use in mice and rats; however, no studies have examined the efficacy and pharmacokinetic parameters of XRB in swine. The goal of this study was to determine the pharmacokinetics of the newly available XRB in swine. We hypothesized that after a single subcutaneous administration of XRB in adult swine, buprenorphine plasma concentrations would be at or above the therapeutic threshold of 0.1 ng/mL and that local injection side effects would be minimal. XRB was administered once, subcutaneously to two separate cohorts of adult female Yorkshire swine at low and high doses (0.2 and 0.4 mg/kg, respectively; n = 3 and 2). Blood was collected from an indwelling jugular catheter prior to and after XRB administration (13 total time points). Individual animal data indicated all animals reached therapeutic buprenorphine plasma concentrations by 8 h post administration. Average plasma buprenorphine levels for both the low- and high-dose cohorts reached therapeutic concentrations starting at 1.5 h after XRB administration and were maintained above therapeutic concentrations throughout the 96-h study period. In the low-dose cohort, the average half-life was 212.6 ± 107.1 h, whereas the half-lives in the high-dose cohort was 63.8 and 48.9 h. As expected, histology of XRB subcutaneous sites revealed mild injection site reactions characterized by granulomatous inflammation with intralesional cholesterol cleft formation. These results support our hypothesis and indicate that all animals maintained therapeutic plasma buprenorphine levels beginning at 8 h and maintaining past 96 h. Thus, XRB at either dose provide therapeutic levels of plasma buprenorphine and therefore its use should be further explored in swine.

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Wheel running, but not home cage activity in Digital Ventilated Cages® is impaired in a mouse model of breast cancer-induced bone pain

Hopkins,

Kanneworff,

Kornum

et al. 2024

Preprint

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Introduction: Cancer-induced bone pain (CIBP) due to metastatic breast cancer is common and debilitating. Effective, long-term treatment options have side effects that reduce patients' quality of life. Preclinical models are a valuable tool to test novel analgesics, but new methods that are translationally and clinically relevant are necessary. This study aimed to assess spontaneous pain-like behaviour of home cage activity and wheel running in Digital Ventilated Cages®. Method: Twenty BALB/cAnNHsd mice were housed in Digital Ventilated Cages®from Tecniplast®with GYM500 home cage running wheels. Mice were assessed by limb use analysis and static weight bearing to determine the development of CIBP and this was compared to the dark-phase home cage activity and wheel running in the Digital Ventilated Cages®. Ten mice underwent 4T1-Luc2 mammary gland adenocarcinoma cell inoculation into the right femur to establish CIBP and another ten mice underwent a sham surgical procedure. Results: The 4T1-inoculated mice displayed pain-like behaviour in limb use and weight bearing tests, demonstrating a preference for the contralateral limb. The limb use scores were compared with home cage activity and wheel running. A reduced wheel running distance corresponded to reduced limb use scores, with the shortest wheel running distances corresponding to the lowest limb use scores. However, this behavioural pattern was not observed in home cage activity, which remained consistent over the study period. Discussion: Reduced wheel running corresponded with reduced limb use scores. This suggests that wheel running behaviour is affected by the development of metastatic breast cancer. However, the home cage activity was not influenced by disease development. Digital Ventilated Cage®wheel running may be a useful behavioural assessment of spontaneous pain-like behaviour of CIBP and may be useful to assess analgesic efficacy.

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Pharmacokinetics of Sustained-release and Extended-release Buprenorphine in Mice after Surgical Catheterization

Cited by 6 publications

References 30 publications

Long-Acting Opioid Analgesics for Acute Pain: Pharmacokinetic Evidence Reviewed

Long-Acting Opioid Analgesics for Acute Pain: Pharmacokinetic Evidence Reviewed

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

Wheel running, but not home cage activity in Digital Ventilated Cages® is impaired in a mouse model of breast cancer-induced bone pain

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