A Physiologically‐Based Pharmacokinetic (PBPK) Model for Alcohol Facilitates Rapid BrAC Clamping

Alcohol clamping is a technique that maintains a constant breath alcohol concentration (BrAC) for prolonged intervals, thereby reducing experimental variance in the time course of organ exposure to alcohol, when compared with oral alcohol administration paradigms. The technique employs an intravenous (iv) infusion of an ethanol solution at a rate that is intermittently adjusted based on real‐time BrAC measurements. In earlier studies, when the clamped state was induced with an oral ethanol loading dose, the vagaries of gastric emptying and absorption were associated with a 45 min delay (RST: reliable start time) before collection of dependent measurements could be planned with confidence. The objective of the present study was to develop an induction method that provides an earlier RST, and to compare the performance of the two methods. The “quick‐clamping” method replaced the oral loading dose with a preprogrammed infusion rate profile. A three‐compartment physiologically‐based pharmacokinetic (PBPK) model for ethanol was constructed, then tailored to each subject using individualized estimates of model parameters. The model was used to compute the infusion‐rate profile that would produce the desired time course of BrAC when infused in the corresponding subject. The two clamping methods were compared in a two‐session crossover study in 20 healthy young subjects (10 males, 10 females). Compared with the oral/iv method, quick clamping produced a comparable precision in the control of BrACs during the clamped interval, and provided a much earlier RST (mean ± SE for quick‐clamp: 17 ± 4 min; for oral/iv clamp: 45 ± 7 min). The quick‐clamping method enables, for the first time, the examination of the early‐phase neuroadaptive responses to alcohol in human subjects.