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A Recirculatory Model for Pharmacokinetics and the Effects on Bispectral Index After Intravenous Infusion of the Sedative and Anesthetic AZD3043 in Healthy Volunteers
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (farmakometri)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (farmakometri)
2015 (English)In: Anesthesia and Analgesia, ISSN 0003-2999, E-ISSN 1526-7598, Vol. 121, no 4, 904-913 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: AZD3043 is a positive allosteric modulator of the γ-aminobutyric acid type A receptor, with sedative and anesthetic properties. We describe a population pharmacokinetic (PK) model of arterial and venous concentrations of AZD3043 and the pharmacodynamic effects on bispectral index (BIS) in healthy volunteers.

METHODS: Arterial and venous plasma concentrations of AZD3043 and BIS were measured in 2 clinical studies in 125 healthy volunteers, where AZD3043 was given as a 1-minute bolus (1-6 mg/kg), a 30-minute infusion (1-81 mg/kg/h), or 0.8 + 10, 1 + 15, 3 + 30, and 4 + 40 (mg/kg bolus + mg/kg/h infusion for 30 minutes). Population PK/pharmacodynamic analysis was performed with NONMEM.

RESULTS: A recirculatory model, comprising a series of 5 compartments for the transit of drug between venous and arterial plasma, 2 peripheral distribution compartments, and 1 compartment for the nondistributive transit of drug from arterial to venous plasma, described the PK of AZD3043. Systemic clearance was high (2.2 L/min; 95% confidence interval, 2.12-2.25), and apparent volumes of distribution were low, leading to a short elimination half-life. The apparent volumes of distribution of the arterial and peripheral compartments increased with increasing administered dose, giving a total apparent volume of distribution of 15 L after the lowest dose and 37 L after the greatest dose. A sigmoid maximum effect (Emax) model with an EC50 of 15.6 µg/mL and a γ of 1.7 described the relationship between AZD3043 effect-site concentrations and BIS. The between-subject variability in EC50 was 37%. An effect compartment model, with a half-life of the equilibration rate constant ke0 of 1.1 min, described the delay in effect in relation to the arterial plasma concentrations.

CONCLUSIONS: AZD3043 had a high clearance and a low apparent volume of distribution, leading to a short half-life. However, the apparent volume of distribution was dose dependent (P < 0.001), leading to an increased half-life with increasing dose. The distribution to the effect site was fast and together with the short plasma half-life led to a fast onset and offset of effects.

Place, publisher, year, edition, pages
2015. Vol. 121, no 4, 904-913 p.
National Category
Anesthesiology and Intensive Care
URN: urn:nbn:se:uu:diva-273520DOI: 10.1213/ANE.0000000000000814ISI: 000369601500013PubMedID: 26097984OAI: oai:DiVA.org:uu-273520DiVA: diva2:894733
Available from: 2016-01-15 Created: 2016-01-15 Last updated: 2016-04-01Bibliographically approved

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Simonsson, Ulrika S H
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