Fentanyl Pharmacokinetics in Pregnant Sheep after Intravenous and Transdermal Administration to the Ewe

Abstract

Fentanyl is used for pain treatment during pregnancy in human beings and animals. However, fentanyl pharmacokinetics during pregnancy has not been fully established. The aim of this study was to characterize fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal dosing during surgical procedure performed to ewe and foetus. Pharmacokinetic parameters reported for non-pregnant sheep and nominal transdermal dose rate were utilized for a priori calculation to achieve analgesic fentanyl concentration (0.5-2 ng/ml) in maternal plasma. A total of 20 Aland landrace ewes at 118-127 gestational days were used. In the first protocol, 1 week before surgery, 10 animals received 2 lg/kg fentanyl intravenous bolus, and on the operation day, transdermal fentanyl patches at nominal dose rate of 2 lg/kg/hr were applied to antebrachium, and ewes were then given a 2 lg/kg intravenous bolus followed by an intra-operative 2.5 lg/kg/hr infusion. In the second protocol, 10 animals received fentanyl only as transdermal patches on the operation day and oxycodone for rescue analgesia. The data were analysed with population pharmacokinetic modelling. Intra-and post-operative fentanyl concentrations were similar and slightly lower than the a priori predictions, and elimination and distribution clearances appeared slower during than before or after the surgery. Transdermal patches provided sustained fentanyl absorption for up to 5 days, but the absorption rate was slower than the nominal dose rate and showed a high interindividual variability. Further research is warranted to evaluate the clinical relevance of the observations made in sheep.Opioids are commonly used to treat pain during labour and caesarean section, and also for pregnant women for surgical procedures and other severe pain conditions. Fentanyl, a synthetic opiate derivative, has a rapid onset and short half-life [1]. It is metabolized to inactive metabolites. These properties make fentanyl a feasible compound for labour analgesia. During labour, fentanyl is commonly administered spinally, epidurally, intravenously or intramuscularly. Transdermal delivery of fentanyl has been studied in other populations, but the pharmacokinetics of transdermal fentanyl in pregnant women is not known. Furthermore, possible impact of labouror caesarean section-induced transient changes in physiology on pharmacokinetics of fentanyl is not established.In animal studies, intravenous and transdermal fentanyl pharmacokinetics has been studied in several species, including llamas, non-pregnant sheep and horses [2][3][4][5]. Pharmacokinetics of intravenously administered fentanyl in pregnant sheep has been studied by Craft et al. [6] with radioimmunoassay. However, the results may be confounded by cross-reaction of radioimmunoassay with fentanyl metabolites in plasma as shown in horses [7]. Furthermore, the fentanyl concentrations were monitored only up to 120 min. after administration during which the fentanyl kinetics are mainly governed by distribution processes, t...

Pharmacokinetics of intranasal fentanyl in parturient

“…The fentanyl concentration in plasma was measured with an ultra-performance liquid chromatographic system. 2 Ten out of 15 subjects took 250 µg [range 100-250] cumulative dose. It seems that physiological changes, oedema during pregnancy, affect the pharmacokinetics fentanyl mucosal absorption in labouring women.…”

Foetal Fentanyl Exposure and Ion Trapping after Intravenous and Transdermal Administration to the Ewe

“…During exposure study, transdermal fentanyl matrix patches 25–100 μg (Durogesic; Janssen Pharmaceutica N. V., Beerse, Belgium) were used to obtain a total dose of 2.0 μg/kg/h (range: 1.87–2.13 μg/kg/h). The skin of patch application site was prepared and adhesive tape was used to hold the patches in place as described earlier . Before surgery, a standardized endotracheal anaesthesia was induced with IV propofol and maintained with isoflurane end‐tidal concentration of 1–2.5% in an oxygen/air mixture.…”

“…Plasma was analysed with ultra‐performance liquid chromatography–mass spectrometry system (Waters Acquity UPLC liquid chromatograph; Waters corp, Milford, MA, USA) as described earlier .…”

Predicting transdermal fentanyl delivery using mechanistic simulations for tailored therapy

“…The dermis could also play a role in drug transport and drug retention during transdermal delivery [50]. Previous works modeled the dermis (1) as an additional depot in which drugs can be stored [51]; (2) as an additional layer in which only diffusion and no drug removal by the blood flow was modeled [52]; (3) by adding a sink condition to the system [53]; (4) by modeling simplified capillary loops in the dermis [54]. An even more realistic model of dermis would require modeling the patient's blood flow since capillaries and vessels are present in the papillary and reticular dermis, respectively.…”