Pharmacokinetics and pharmacodynamics of a new reformulated microemulsion and the long‐chain triglyceride emulsion of propofol in beagle dogs

Abstract

Background and purpose: Microemulsion propofol was developed to eliminate lipid solvent-related adverse events of long-chain triglyceride emulsion (LCT) propofol. We compared dose proportionality, pharmacokinetic and pharmacodynamic characteristics of both formulations. Experimental approach: The study was a randomized, two-period and crossover design with 7-day wash-out period. Microemulsion and LCT propofol were administered by zero-order infusion (0.75, 1.00 and 1.25 mg·kg) for 20 min in 30 beagle dogs (male/female = 5/5 for each rate). Arterial samples were collected at preset intervals. The electroencephalographic approximate entropy (ApEn) was used as a measure of propofol effect. Dose proportionality, pharmacokinetic and pharmacodynamic bioequivalence were evaluated by non-compartmental analyses. Population analysis was performed using nonlinear mixed effects modelling. Key results: Both formulations showed dose proportionality at the applied dose range. The ratios of geometric means of AUClast and AUCinf between both formulations were acceptable for bioequivalence, whereas that of Cmax was not. The pharmacodynamic bioequivalence was indicated by the arithmetic means of AAC (areas above the ApEn time curves) and E0 (baseline ApEn)-Emax (maximally decreased ApEn) between both formulations. The pharmacokinetics of both formulations were best described by three compartment models. Body weight was a significant covariate for V1 of both formulations and sex for k21 of microemulsion propofol. The blood-brain equilibration rate constants (ke0, min -1 ) were 0.476 and 0.696 for microemulsion and LCT propofol respectively. Conclusions and implications: Microemulsion propofol was pharmacodynamically bioequivalent to LCT propofol although pharmacokinetic bioequivalence was incomplete, and demonstrated linear pharmacokinetics at the applied dose ranges.

Indução anestésica com nanoemulsão ou emulsão lipídica de propofol durante dias consecutivos em gatas

“…A qualidade de recuperação foi considerada boa ou ótima na maioria dos animais com ambas as formulações, sendo que apenas dois animais do NANO e um do EMU apresentaram-se agitados e reagindo de forma exacerbada aos estímulos externos no primeiro dia. Estas alterações refl etem a não utilização de medicação pré-anestésica e presença de estresse durante a indução anestésica (FANTONI & CORTOPASSI, 2010;TAMANHO, 2010 EBLING, 1998;LEE et al, 2009). A presente nanoemulsão já é patenteada e aprovada para uso em humanos (RODRIGUES et al, 2012), sendo que não se verifi cam diferenças farmacocinéticas e clínicas com a formulação em emulsão lipídica.…”

“…Entretanto, devido às diferentes tecnologias utilizadas na confecção das nanoemulsões, estas podem apresentar efeitos variados na farmacocinética do propofol quando comparada a formulação original (DUTTA & EBLING, 1998;LEE et al, 2009).…”

Intravenous lidocaine pretreatment with venous occlusion for reducing microemulsion propofol induced pain: Comparison of three doses of lidocaine

“…3 This formulation was as effective as lipid emulsion propofol and showed similar pharmacokinetics. 4 The free propofol concentration in the aqueous phase of the reformulated microemulsion propofol is, however, five times greater than that of the original formulation, 21 meaning it has an increased potential to produce frequent and severe pain on injection.…”

“…[1][2][3][4][5][6] Microemulsion propofol has several advantages over lipid emulsion propofol in that it demonstrates higher physicochemical stability and antimicrobial activity, 7 which avoids lipid solvent-related complications such as hyperlipidaemia, pulmonary fat embolism, pancreatitis and propofol-infusion syndrome. 8 It is, however, associated with more intense and frequent pain on injection compared with lipid emulsion propofol.…”

Farmacocinética do propofol em nanoemulsão em gatos

“…Atualmente, sua formulação é composta de óleo de soja, fosfatídeos de ovo purifi cados e glicerol, formando uma emulsão lipídica, que pode acarretar em lipemia, risco de embolismo e até mesmo contaminações bacterianas (BAKER & NAGUIB, 2005). Por isso, novas formulações em nanoemulsões estão sendo propostas com intuito de eliminar os veículos e garantir maior estabilidade e segurança na administração (KIM et al, 2007;LEE et al, 2009;CLEALE et al, 2009;TAMANHO, 2010).…”