Fentanyl's Analgesic, Respiratory, and Cardiovascular Actions in Relation to Dose and Plasma Concentration in Unanesthetized Dogs

dose selection of a novel, long-acting transdermal fentanyl solution in healthy laboratory Beagles. J. vet. Pharmacol. Therap. 35 (Suppl. 2), 21-26.A novel, transdermal fentanyl solution (TFS) was developed that delivers sustained concentrations of fentanyl for days following a single application. The pharmacokinetics following a single topical dose was examined. Eighteen adult Beagle dogs were divided into three groups of six dogs (3M, 3F). Each group was administered a single dose of 1.3 (25), 2.6 (50), or 5.2 mg ⁄ kg (100 lL ⁄ kg) of TFS. The dose was applied to the clipped, ventral abdominal skin using a 1-mL tuberculin syringe. Immediately following dosing, collars were placed on each dog through 72 h to prevent direct licking of the application site. Serial jugular venous blood samples were collected at 0 (predosing), 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 240, 336, 408, and 504 h after dosing and assayed for plasma fentanyl concentration. Fentanyl was rapidly detected following application with a mean absorption lag time (t lag ) of 0.333 h in the 1.3 mg ⁄ kg group and 0 in the other two groups. The mean C max increased with dose and were 2.28, 2.67, and 4.71 ng ⁄ mL in the 1.3, 2.6 and 5.2 mg ⁄ kg dose groups, respectively. Mean terminal half-lives were 53.7, 69.6, and 103 h in the 1.3, 2.6, and 5.2 mg ⁄ kg dose groups, respectively. The mean AUC 0-LLOQ from lowest to highest dose groups were 157, 268, and 645 ngAEh ⁄ mL and were dose proportional with a R 2 value of 0.9818. Adverse reactions were limited to the highest dose group and included sedation (four of six dogs) and decreased food and water intake (one dog). A dose of 2.6 mg ⁄ kg (50 lL ⁄ kg) is proposed for further development studies based on the lack of adverse events that were observed compared to the 5.2 mg ⁄ kg group and a more rapid onset of action and longer duration of action compared to the 1.3 mg ⁄ kg group.

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and dose selection of a novel, long‐acting transdermal fentanyl solution in healthy laboratory Beagles

Freise¹,

Savides²,

Riggs

et al. 2012

“…pharmacokinetics of fentanyl has also been described. Adverse reactions to fentanyl include an increase in locomotor activity in horses (Kamerling, DeQuick, Weckman, & Tobin, ), and respiratory depression when too high systemic concentrations are reached (30 ng/ml) in dogs (Arndt, Mikat, & Parasher, ). Pharmacokinetics of fentanyl metabolites, while readily available in human medical studies, is limited in veterinary medicine.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of fentanyl citrate and norfentanyl in Holstein calves and effect of analytical performances on fentanyl parameter estimation

Smith

Coetzee

Fisher

et al. 2018

This study describes the pharmacokinetics of intravenously administered (i.v.) fentanyl citrate, and its primary metabolite norfentanyl in Holstein calves. Eight calves (58.6 ± 2.2 kg), aged 3-4 weeks, were administered fentanyl citrate at a single dose of 5.0 μg/kg i.v. Blood samples were collected from 0 to 24 hr. Plasma (nor)fentanyl concentrations were determined using liquid chromatography with mass spectrometry and a lower limit of quantification (LLOQ) of 0.03 ng/ml. To explore the effect of analytical performance on fentanyl parameter estimation, the noncompartmental pharmacokinetic analysis was then repeated with a hypothetical LLOQ value of 0.05 ng/ml. Terminal elimination half-life was estimated at 12.7 and 3.6 hr for fentanyl and norfentanyl, respectively. For fentanyl, systemic clearance was estimated at 2.0 L hr kg , volume of distribution at steady-state was 24.8 L/kg and extraction ratio was 0.42. At a hypothetical LLOQ of 0.05 ng/ml fentanyl half-life, volume of distribution at steady-state and clearance were, respectively, of 3.0 hr, 8.8 L/kg and 3.4 L kg hr . Fentanyl citrate administered i.v. at 5.0 μg/kg can reach levels associated with analgesia in other species. Pharmacokinetic parameters should be interpreted with respect to LLOQ, as lower limits can influence estimated parameters, such as elimination half-life or systemic clearance and have significant impact on dosage regimen selection in clinical practice.

“…, 2000). Arndt et al. (1984) suggested that the analgesic effect of fentanyl occurs at plasma concentrations greater than 2 ng/mL in conscious dogs.…”

Section: Introductionmentioning

confidence: 99%

Relationship between plasma concentrations and analgesia after intravenous fentanyl and disposition after other routes of administration in cats¹

Robertson

Taylor

Sear

et al. 2005

Data allowing rational use of analgesics in cats are limited. Pharmacokinetics and pharmacodynamics of fentanyl were studied in cats. Plasma fentanyl concentrations were measured using radioimmunoassay in a crossover study in six cats after 10 microg/kg (i.v.) or by application of fentanyl in pluronic lecithin organogel (PLO) to the inner ear pinna. On a separate occasion thermal thresholds were measured after i.v. fentanyl (10 microg/kg) or saline. Plasma fentanyl concentrations reached 4.7-8.31 ng/mL 2 min after i.v. administration and were undetectable after 95 min. Fentanyl was not detected in plasma at any time after PLO use. Thermal thresholds did not change following saline administration but were increased above baseline from 5 to 110 min after i.v. fentanyl. In this model a plasma concentration of >1.07 ng/mL was required to provide analgesia. Plasma concentrations were measured in additional cats after intranasal or oral dosing (2 microg/kg) and after 30 microg/kg in PLO gel. After oral and nasal dosing, Cmax values were 0.96 and 1.48 ng/mL at 5 and 2 min, respectively. Plasma fentanyl was not detected after application of the higher dose of fentanyl in PLO.