Marcus A. Björnsson (1,2), Åke Norberg (3), Sigridur Kalman (3), Ulrika S.H. Simonsson (2)
(1) Clinical Pharmacology Science, AstraZeneca R&D, Södertälje, Sweden; (2) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (3) Karolinska Institutet at Department of Anesthesiology and Intensive Care, Karolinska University Hospital, Huddinge, Sweden
Objectives: The objective of the analysis was to describe the population pharmacokinetics (PK) of the sedative and anesthetic compound AZD3043 and its pharmacological effect assessed by the bispectral index (BIS) in healthy volunteers.
Methods: In two clinical studies, in a total of 125 healthy volunteers, AZD3043 was given either as a 1-min infusion (1 to 6 mg/kg/min), as a 30-min infusion (1 to 81 mg/kg/h) or as a 1-min infusion (0.8 to 4 mg/kg/min) immediately followed by a 30-min infusion (10 to 40 mg/kg/h). Arterial plasma concentrations of AZD3043 were measured up to 150 minutes after the start of infusion, and BIS were recorded until the subject was regarded as awake after sedation or anesthesia. A population pharmacokinetic/pharmacodynamic analysis was performed using NONMEM 7 (ICON, Hanover, MD, USA) [1] and PsN [2]. Goodness of fit was assessed using objective function values, standard errors, graphics and visual predictive checks.
Results: A 3-compartment model, with a lag-time for the drug to appear at the site of sampling, described the PK of AZD3043. The clearance (CL) and volume of distribution (V) parameters were allometrically scaled with body weight. CL was high, 2.1 L/min, suggesting elimination occured not only in the liver as the CL was higher than liver blood flow. Plasma esterase activity did not, however, influence CL. Peripheral V's were low, but increased with increasing dose. Vss (sum of all V's) ranged from 12 L in the lowest dose group to 35 L in the highest dose group. A sigmoid Emax model was used to describe the relationship between arterial concentrations and BIS. EC50 was estimated to 54 µmol/L. Between-subject variability in EC50 was 35%, suggesting that individual titration to the desired effect may be needed. An effect compartment model, with a half-life of ke0 estimated to 1 min, was used to describe the delay in effects in relation to the concentrations. A two-compartment effect-site model [3] did not improve the fit, suggesting rapid and/or limited distribution within the brain.
Conclusions: AZD3043 was rapidly metabolized and distributed. The extent of distribution was low but dose dependent. The short half-life and rapid equilibration with the effect site was reflected in a fast onset and offset of effects on BIS.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ, eds. NONMEM users guides. Ellicott City, MD: ICON Development Solutions, 1989-2006
[2] Lindbom L, Pihlgren P, Jonsson EN. PsN-Toolkit–a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed (2005); 79:241-257
[3] Björnsson MA, Norberg Å, Kalman S, Karlsson MO, Simonsson USH. A two-compartment effect site model describes the bispectral index after different rates of propofol infusion. J Pharmacokinet Pharmacodyn (2010); 37:243-255
Reference: PAGE 21 (2012) Abstr 2408 [www.page-meeting.org/?abstract=2408]
Poster: CNS