Pharmacokinetics, induction of anaesthesia and safety characteristics of Propofol 6% SAZN vs Propofol 1% SAZN and Diprivan^®‐10 after bolus injection

Abstract

Aims In order to avoid the potential for elevated serum lipid levels as a consequence of long term sedation with propofol, a formulation of propofol 6% in LipofundinA MCT/LCT 10% (Propofol 6% SAZN) has been developed. The pharmacokinetics, induction of anaesthesia and safety characteristics of this new formulation were investigated after bolus injection and were compared with the commercially available product ( propofol 1% in IntralipidA 10%, DiprivanA-10) and propofol 1% in LipofundinA MCT/LCT 10% (Propofol 1% SAZN). Methods In a randomised double-blind study, 24 unpremedicated female patients received an induction dose of propofol of 2.5 mg kg −1 over 60 s which was followed by standardized balanced anaesthesia. The patients were randomized to receive propofol as Propofol 6% SAZN, Propofol 1% SAZN or DiprivanA-10. Results For all formulations the pharmacokinetics were adequately described by a tri-exponential equation, as the propofol concentrations collected early after the injection suggested an additional initial more rapid phase. The average values for clearance (CL), volume of distribution at steady-state ( V d,ss ), elimination half-life (t 1/2,z ) and distribution half-life (t 1/2,l2 ) observed in the three groups were 32±1.5 ml kg −1 min −1 , 2.0±0.18 l kg −1 , 95±5.6 min and 3.4±0.20 min, respectively (mean±s.e.mean, n=24) and no significant differences were noted between the three formulations ( P >0.05). The half-life of the additional initial distribution phase (t 1/2,l1 ) in all subjects ranged from 0.1 to 0.6 min. Anaesthesia was induced successfully and uneventfully in all cases, and the quality of induction was adequate in all 24 patients. The induction time did not vary between the three formulations and the average induction time observed in the three groups was 51±1.3 s which corresponded to an induction dose of propofol of 2.1±0.06 mg kg −1 (mean±s.e.mean, n=24). The percentage of patients reporting any pain on injection did not vary between the formulations and was 17% for the three groups. No postoperative phlebitis or other venous sequelae of the vein used for injection occurred in any of the patients at recovery of anaesthesia nor after 24 h. Conclusions From the above results, we conclude that the alteration of the type of emulsion and the higher concentration of propofol in the new parenteral formulation of propofol does not affect the pharmacokinetics and induction characteristics of propofol, compared with the currently available product. Propofol 6% SAZN can be administered safely and has the advantage of a reduction of the load of fat and emulsifier which may be preferable when long term administration of propofol is required.

The allometric exponent for scaling clearance varies with age: a study on seven propofol datasets ranging from preterm neonates to adults

“…An overview of the data of the seven propofol PK studies [17][18][19][20][21][22][23], which were merged into six study populations for the type I models and into five paediatric FDA age groups for the type II models, are summarized in Table 1 and Table 2, respectively. Table 3 provides an overview of of the results of all 19 models (15 type I models and four type II models) indexed by the model number with their estimated allometric exponent, including the relative standard error (RSE%) and corresponding 95% confidence interval (95% CI), for propofol clearance.…”

“…A total of 174 subjects from seven previously published studies on propofol PK were included in the current study, including neonates (1-25 days) [17], infants (3.8-17.3 months) [18], toddlers (12-31 months) [19], children (3-11 years) [20], adolescents (9.8-20.1 years) [21], adults I (33-57 years) [22] and adults II (26-81 years) [23]. Detailed information on the studies is summarized below.…”

“…neonates [17], infants [18], toddlers [19], children [20], adolescents [21] and adults [22,23], were identified from the data of the seven original studies by merging datasets Adults I [22] and Adults II [23] into one adult population. In a systematic manner, two out of these six study populations were selected resulting 15 combined datasets.…”

“…Type II models: For the type II models, the data of the seven propofol studies [17][18][19][20][21][22][23] were regrouped into five age groups as defined by the FDA Guidance for industry of 1998 [16]:…”

Nanoemulsões como sistemas de liberação parenteral de fármacos

“…114,120,122 Além disso, permitiu a redução da proporção de TCL, responsável pela elevação dos triglicerídeos plasmáticos, principalmente quando administrados por infusão contínua, por longos períodos de tempo, ou concomitantemente com a nutrição parenteral total. 121,123 As formulações alternativas têm sido desenvolvidas como, por exemplo, a incorporação de maior concentração de propofol (6%) na nanoemulsão, [123][124][125] …”