A comparative study of two methods for attaining constant alcohol levels

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • In determining the effects of alcohol or assessing alcohol–drug interactions, it is helpful if the alcohol plasma concentration can be maintained at reasonably stable levels. • To achieve pseudo‐steady state alcohol concentrations various methods are used. • In this study two different methods were optimized and compared in the search for an accurate method to maintain constant alcohol levels for a prolonged period of time. WHAT THIS STUDY ADDS • Although it seems clear that alcohol clamping improves the stability of alcohol levels, it has not yet been established how this compares with other procedures, such as two‐step prekinetic methods. • The adapted clamping paradigm was superior to the prekinetic method in this study. • The novel clamping procedure is an accurate, user‐friendly method, with low variability, able to maintain constant alcohol levels for hours. • Moreover, the procedure gave an opportunity to perform intensive pharmacodynamic or functional assessments during the execution of the clamp, which could be of great value for future studies of alcohol. AIMS Alcohol effects or drug–alcohol interactions are preferably studied at constant blood levels. To achieve pseudo‐steady state levels, various methods are used, which usually produce adequate averages but variable individual concentration profiles. The aim was to compare two modes of alcohol administration: a ‘two‐step prekinetic procedure’ and a ‘clamping method’. METHODS The two‐step prekinetic procedure started with determination of individual pharmacokinetic (PK) parameters, during a prestudy occasion. Individual infusion regimens were calculated afterwards, based on a pseudo‐steady state breath alcohol concentration (BrAC) of 0.65 g l−1 and applied on a separate occasion. For the clamping procedure, a spreadsheet‐based paradigm was developed using BrAC‐guided adjustments of infusion rates, to maintain stable BrAC levels of 0.6 g l−1. RESULTS The mean BrAC during clamping [0.61 g l−1, 95% confidence interval (CI) 0.58, 0.63] did not differ from its intended level of 0.6 g l−1 (1.0% on average). In contrast, the mean BrAC during the prekinetic procedure was significantly lower than the 0.65 g l−1 set‐point (0.59 g l−1, 95% CI 0.54, 0.63) and deviated from this target by 9.7% on average. The clamping method also showed less variation between subjects [coefficient of variation (CV) 6.2%] compared with the prekinetic procedure (CV 14.6%). CONCLUSIONS Although the two methods differ considerably in their approach, clamping of BrAC resulted in more accurate alcohol levels than infusion based on PK modelling and does not require an extra prestudy occasion. The novel alcohol clamping paradigm can be of value in future studies of alcohol interactions or the pharmacodynamics of acute alcohol administration.