Alcohol Exposure Rate Control Through Physiologically Based Pharmacokinetic Modeling

• Published in: Alcoholism, clinical and experimental research Vol. 36; no. 6; pp. 1042 - 1049
• Main Authors: Plawecki, Martin H., Zimmermann, Ulrich S., Vitvitskiy, Victor, Doerschuk, Peter C., Crabb, David, O'Connor, Sean
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Blackwell Publishing Ltd 01.06.2012; Wiley
• Subjects: Acute Tolerance; Adult; Alcohol; Alcoholism and acute alcohol poisoning; Biological and medical sciences; Biphasic Effects; Brain - drug effects; Brain Exposure; Breath Tests - methods; Central Nervous System Depressants - pharmacokinetics; Ethanol - pharmacokinetics; Female; Humans; Infusions, Intravenous - methods; Male; Medical sciences; Models, Theoretical; Physiologically Based Pharmacokinetic Models; Rate of Change; Time Factors; Toxicology; Biphasic Effects; Ethanol; Acute; Rate of Change; Central nervous system; Tolerance; Alcohol; Exposure; Modeling; Encephalon; Alcoholic beverage; Physiologically Based Pharmacokinetic Models; Physiologically based pharmacokinetic model; Acute Tolerance; Brain Exposure
• ISSN: 0145-6008; 1530-0277; 1530-0277
• DOI: 10.1111/j.1530-0277.2011.01706.x

Background The instantaneous rate of change of alcohol exposure (slope) may contribute to changes in measures of brain function following administration of alcohol that are usually attributed to breath alcohol concentration (BrAC) acting alone. To test this proposition, a 2‐session experiment was designed in which carefully prescribed, constant‐slope trajectories of BrAC intersected at the same exposure level and time since the exposure began. This paper presents the methods and limitations of the experimental design. Methods Individualized intravenous infusion rate profiles of 6% ethanol (EtOH) that achieved the constant‐slope trajectories for an individual were precomputed using a physiologically based pharmacokinetic model. Adjusting the parameters of the model allowed each infusion profile to account for the subject's EtOH distribution and elimination kinetics. Sessions were conducted in randomized order and made no use of feedback of BrAC measurements obtained during the session to modify the precalculated infusion profiles. In one session, an individual's time course of exposure, BrAC(t), was prescribed to rise at a constant rate of 6.0 mg% per minute until it reached 68 mg% and then descend at −1.0 mg% per minute; in the other, to rise at a rate of 3.0 mg% per minute. The 2 exposure trajectories were designed to intersect at a BrAC (t = 20 minutes) = 60 mg% at an experimental time of 20 minutes. Results Intersection points for 54 of 61 subjects were within prescribed deviations (range of ±3 mg% and ±4 minutes from the nominal intersection point). Conclusions Results confirmed the feasibility of applying the novel methods for achieving the intended time courses of the BrAC, with technical problems limiting success to 90% of the individuals tested.