Evaluation of the predictive performance of a pharmacokinetic model for propofol in Japanese macaques (Macaca fuscata fuscata)

Abstract

Propofol is a short-acting intravenous anesthetic used for induction/maintenance anesthesia. The objective of this study was to assess a population pharmacokinetic (PPK) model for Japanese macaques during a step-down infusion of propofol. Five male Japanese macaques were immobilized with ketamine (10 mg/kg) and atropine (0.02 mg/kg). A bolus dose of propofol (5 mg/kg) was administrated intravenously (360 mg/kg/h) followed by step-down infusion at 40 mg/kg/h for 10 min, 20 mg/kg/h for 10 min, and then 15 mg/kg/h for 100 min. Venous blood samples were repeatedly collected following the administration. The plasma concentration of propofol (Cp) was measured by high-speed LC-FL. PPK analyses were performed using NONMEM VII. Median absolute prediction error and median prediction error (MDPE), the indices of prediction inaccuracy and bias, respectively, were calculated, and PE - individual MDPE vs. time was depicted to show the variability of prediction errors. In addition, we developed another population pharmacokinetic model using previous and current datasets. The previous PK model achieved stable prediction of propofol Cp throughout the study period, although it underestimates Cp. The step-down infusion regimen described in this study would be feasible in macaques during noninvasive procedures.

Propofol infusions using a human target controlled infusion (TCI) pump in chimpanzees (Pan troglodytes)

“…The difference between measured and predicted Cps deviated more in the early phase compared to later phases. This observation is consistent with previous reports that the measured propofol Cps can differ greatly from predicted Cps during the first few minutes of administration in humans 22 and also in Japanese macaques 23,24 and common marmosets 25 . This is probably because these models make the incorrect assumption of immediate mixing of administered drugs within the central compartment.…”

Pharmacokinetics and effects on clinical and physiological parameters following a single bolus dose of propofol in common marmosets (Callithrix jacchus)

“…The final model was better than the model established with all Cp data because MDPE and MDAPE were better due to large variations of Cps at 2 min after administration. It was reported that Cps of propofol within a few min after starting administration varied greatly in human medicine and Japanese macaque studies (Masui et al, 2009; Miyabe‐Nishiwaki et al 2010, 2013). It might cause the variation of Cps due to reduction of flow back from the caudal circulation to systemic circulation in marmosets as well.…”

Validation of Individual Non-Linear Predictive Pharmacokinetic Parameters in a Rabbit Phenytoin Model

“…For example, the pharmacokinetic model achieved stable prediction of propofol plasma concentrations in Japanese macaques [22].…”

“…To check kinetic nonlinearity, the first experiments were performed on 10 rabbits, which received 3 different single doses of phenytoin (11,22, 44 mg/kg). The period between administration of doses was 10 days.…”