Martin H. Plawecki

Intravenous ethanol infusions can mimic the time course of breath alcohol concentrations following oral alcohol administration in healthy volunteers

BACKGROUND Our previous studies have used intravenous (IV) clamping methods to demonstrate that family history positive (FHP) subjects exhibit a greater initial response to alcohol than family history negative (FHN) subjects. These results differ from other studies of family history of alcoholism (FHA) influences, most of which have used an oral alcohol challenge, suggesting that the route of administration may influence both the response to alcohol and FHA-related differences in response. To examine this possibility, one approach would be to directly compare responses following oral and IV alcohol administration in the same subjects. There is, however, a 3- to 4-fold variance, between- and within-subjects, in the breath alcohol concentrations (BrACs) following oral alcohol administration. Thus, our objective was to characterize the between-subject variability in the time course of BrACs following oral alcohol administration in healthy volunteers and to develop an IV infusion method to mimic the BrAC-time course attained following oral alcohol in the same subject. METHODS This was a 2-session study in young adult, healthy, nondependent drinkers. In the first session, subjects ingested an oral dose of alcohol, based on total body water, to achieve a target peak BrAC of 80 mg%. In the second session, subjects received an IV infusion of ethanol designed to achieve the same BrAC time course as that achieved in the first session. The individualized infusion-rate profile was precomputed using a physiologically-based pharmacokinetic (PBPK) model for alcohol with model parameters adjusted to the individuals physiology. The peak BrACs (C(max)), times of peak BrAC (T(max)), and the areas under the BrAC vs. time curve (AUC) were compared between sessions to assess how closely the BrAC exposure during the IV infusion session mimicked the exposure following oral alcohol. RESULTS The time course of BrACs following oral alcohol administration showed a high degree of between-subject variability. Mean C(max), T(max), and AUC did not differ by gender, indicating that calculation of oral doses based on total body water results in comparable BrAC-time courses, on average, for females and males. The IV infusion driven BrAC-time profiles demonstrated good fidelity to the BrAC-time curves resulting from oral alcohol: the mean %difference in C(max) and AUC were both 11%, while the mean %difference for T(max) was 27%. This degree of variability is less than half that seen across individuals following oral alcohol administration, which was substantial [coefficient of variation (%CV) ranging from 22 to 52%]. CONCLUSIONS Despite the use of standardized doses and controlled experimental conditions, there was substantial between-subject variability in the BrAC time course following oral administration of alcohol. The PBPK-model-based infusion method can mimic the BrACs attained with oral alcohol for individual subjects. This method provides a platform to evaluate effects attributable to the route of administration on the response to alcohol, as well as the influence of determinants such as family history of alcoholism on the alcohol response.

Physiologically Based Pharmacokinetic (PBPK) Models for Ethanol

Physiologically based pharmacokinetic models have been used to describe the distribution and elimination of ethanol after intravenous administration. These models have been used to estimate the ethanol infusion profile that is sufficient for achieving a prescribed breath ethanol concentration time course in individuals, providing a useful platform for several pharmacokinetic and pharmacodynamic investigations. Mathematical foundations of these models are examined, including the derivation of an explicit set of governing equations in the form of a system of nonlinear ordinary differential equations. These equations can then be used to formulate and refine parameter identification and control strategies. Finally, a framework in which models related to this model can be constructed and analyzed is described.

Emerging drugs for the treatment of symptoms associated with autism spectrum disorders

Importance of the field: Autism spectrum disorders, or pervasive developmental disorders (PDDs), are neurodevelopmental disorders defined by qualitative impairment in social interaction, impaired communication and stereotyped patterns of behavior. The most common forms of PDD are autistic disorder (autism), Aspergers disorder and PDD not otherwise specified. Recent surveillance studies reveal an increase in the prevalence of autism and related PDDs. The use of pharmacologic agents in the treatment of these disorders can reduce the impact of interfering symptoms, providing relief for affected individuals and their families. Areas covered in this review: This review examines results from neurobiologic research in an attempt to both elucidate the pathophysiology of autism and guide the development of pharmacologic agents for the treatment of associated symptoms. The safety and efficacy data of drugs currently in clinical use for the treatment of these symptoms, as well as pharmaceuticals currently under development, are discussed. What the reader will gain: This comprehensive review will deepen the readers current understanding of the research guiding the pharmacologic treatment of symptoms associated with autism and related PDDs. Areas of focus for future research are also discussed. The need for large-scale investigation of some commonly used pharmacologic agents, in addition to the development of drugs with improved efficacy and safety profiles, is made evident. Take home message: Despite progress in the development of pharmacologic treatments for a number of interfering symptom domains associated with autism and other PDDs, a great deal of work remains.

IMPROVED TRANSFORMATION OF MORPHOMETRIC MEASUREMENTS FOR A PRIORI PARAMETER ESTIMATION IN A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL OF ETHANOL.

Prescription of the brains time course of exposure to experimentally administered ethanol can be achieved with intravenous infusion profiles computed from a physiologically-based pharmacokinetic (PBPK) model of alcohol distribution and elimination. Previous parameter estimation employed transformations of an individuals age, height, weight and gender inferred from the literature, with modeling errors overcome with real-time, intermittent feedback. Current research applications, such as ethanol exposures administered during fMRI scanning, require open-loop infusions, thus improved transformation of morphometric measurements.Records of human breath alcohol concentration (BrAC) clamp experiments were analyzed. Optimal, unique PBPK parameters of a model of the distribution and elimination of ethanol were determined for each record and found to be in concordance with parameter values published by other investigators. A linear transformation between the readily measurable physical characteristics or morphometrics, including gender, age, height, weight, and TBW estimates, and the model parameters were then determined in a least squares sense according to the formula theta=F(x)=F(m)x where x=(age height weight TBW)(T)inR(4) and theta =(R(C) V(P) V(B) m(max)k(AT))(T)inR(5).The transformation was then evaluated with several parameter prediction performance measures. A substantial improvement in all error statistics, in relation to an earlier affine transformation that used only body weight as the relevant morphometric was obtained. Deviation from the measured response was reduced from 27 to 20%. Error in parameter estimation was reduced from 109 to 38%. Percent alcohol provided in error was reduced from 46 to 28%. Error in infusion profile estimation was reduced from 55 to 33%.The algorithm described, which optimizes individual pharmacokinetic parameter values and then subsequent extension to a priori prediction, while not unique, can be readily be adapted to other molecules and pharmacokinetic models. This includes those used for distinct purposes, such as automated control of anesthetic agents.

Subjective Perceptions Associated with the Ascending and Descending Slopes of Breath Alcohol Exposure Vary with Recent Drinking History

BACKGROUND The differentiator model predicts that individuals with a positive family history of alcoholism (FHA) or heavy alcohol consumers will feel more sensitive to the effects of alcohol on the ascending phase of the blood alcohol content while feeling less sedated on the descending phase. This study tested whether subjective perceptions are sensitive to the slope of breath alcohol concentration (BrAC) and whether that sensitivity is associated with an FHA and/or recent drinking history (RDH). METHODS Family-history-positive (FHP, n = 27) and family-history-negative (FHN, n = 27) young adult nondependent drinkers were infused intravenously with alcohol in 2 sessions separated by 1 week. After 20 minutes, one session had an ascending BrAC (+3.0 mg%/min), while the other session had a descending BrAC (-1 mg%/min). The BrAC for both sessions at this point was approximately 60 mg%, referred to as the crossover point. Subjective perceptions of intoxication, high, stimulated, and sedation were sampled frequently and then interpolated to the crossover point. Within-subject differences between ascending and descending responses were examined for associations with FHA and/or RDH. RESULTS Recent moderate drinkers reported increased perceptions of feeling intoxicated (p < 0.023) and high (p < 0.023) on the ascending slope compared with the descending slope. In contrast, recent light drinkers felt more intoxicated and high on the descending slope. CONCLUSIONS Subjective perceptions in young adult social drinkers depend on the slope of the BrAC when examined in association with RDH. These results support the differentiator model hypothesis concerning the ascending slope and suggest that moderate alcohol consumers could be at risk for increased alcohol consumption because they feel more intoxicated and high on the ascending slope. Subjects did not feel less sedated on the descending slope, contrary to the differentiator model but replicating several previous studies.

Alcohol Exposure Rate Control through Physiologically-Based Pharmacokinetic Modeling

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 subjects 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 individuals 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.

Exposure-Response Relationships during Free-Access Intravenous Alcohol Self-Administration in Nondependent Drinkers: Influence of Alcohol Expectancies and Impulsivity.

Abstract Background: Self-administration is a hallmark of all addictive drugs, including alcohol. Human laboratory models of alcohol self-administration have characterized alcohol-seeking behavior and served as surrogate measures of the effectiveness of pharmacotherapies for alcohol use disorders. Intravenous alcohol self-administration is a novel method that assesses alcohol exposure driven primarily by the pharmacological response to alcohol and may have utility in characterizing unique behavioral and personality correlates of alcohol-seeking and consumption. Methods: This study examined exposure-response relationships for i.v. alcohol self-administration, and the influence of impulsivity and alcohol expectancy, in healthy, nondependent drinkers (n=112). Participants underwent a 2.5-hour free-access i.v. alcohol self-administration session using the Computerized Alcohol Infusion System. Serial subjective response measures included the Drug Effects Questionnaire and Alcohol Urge Questionnaire. To characterize the motivational aspects of alcohol consumption prior to potential acute adaptation, the number of self-infusions in the first 30 minutes of the free-access session was used to classify participants as low- and high-responders. Results: High-responders showed greater subjective responses during i.v. alcohol self-administration compared with low responders, reflecting robust exposure-driven hedonic responses to alcohol. High-responders also reported heavier drinking patterns and lower scores for negative alcohol expectancies on the Alcohol Effects Questionnaire. High-responders also showed higher measures of impulsivity on a delayed discounting task, supporting previous work associating impulsivity with greater alcohol use and problems. Conclusions: These findings indicate that early-phase measures of free-access i.v. alcohol self-administration are particularly sensitive to the rewarding and motivational properties of alcohol and may provide a unique phenotypic marker of alcohol-seeking behavior.

Estimation of ethanol infusion profile to produce specified BrAC time course using physiologically-based pharmacokinetic (PBPK) models

A procedure for estimating the alcohol infusion profile required to produce a specific breath alcohol concentration (BrAC) time course using a PBPK model is described. Model parameter values are predicted from linear relationships to readily measurable physical characteristics or morphometrics. An algorithm to optimize this transformation, based upon recorded clinical experimental data, is provided. A substantial improvement in all error statistics, in relation to the original transform was obtained.

Adolescent women induce lower blood alcohol levels than men in a laboratory alcohol self-administration experiment

BACKGROUND Adolescence is a critical period for the development of alcohol use disorders; drinking habits are rather unstable and genetic influences, such as male sex and a positive family history of alcoholism (FH), are often masked by environmental factors such as peer pressure. METHODS We investigated how sex and FH modulate alcohol use in a sample of 18- to 19-year-olds from the Dresden Longitudinal Study on Alcohol use in Young Adults. Adolescents reported their real-life drinking in a TimeLine Follow-Back interview. They subsequently completed a training and an experimental session of free-access intravenous alcohol self-administration (i.v. ASA) using the computer-assisted alcohol infusion system to control for environmental cues as well as for biological differences in alcohol pharmacokinetics. During i.v. ASA, we assessed subjective alcohol effects at 8 time points. RESULTS Women reported significantly less real-life drinking than men and achieved significantly lower mean arterial blood alcohol concentrations (aBACs) in the laboratory. At the same time, women reported greater sedation relative to men and rated negative effects as high as did men. A positive FH was associated with lower real-life drinking in men but not in women. In the laboratory, FH was not linked to i.v. ASA. Greater real-life drinking was significantly positively associated with higher mean aBACs in the laboratory, and all i.v. ASA indices were highly correlated across the 2 sessions. CONCLUSIONS We conclude that adolescent women chose lower aBACs because they experienced adverse alcohol effects, namely sedation and negative effects, at lower aBACs than men. A positive FH was not apparent as risk factor for drinking in our young sample. The i.v. ASA method demonstrated good external validity as well as test-retest reliability, the latter indicating that a separate training session is not required when employing the i.v. ASA paradigm.

Ordinary differential equation models for ethanol pharmacokinetic based on anatomy and physiology

Physiologically-based pharmacokinetic (PBPK) models have been used to describe the distribution and elimination characteristics of intravenous ethanol administration. Further, these models have been used to estimate the ethanol infusion profile required to prescribe a specific breath ethanol concentration time course in a specific human being, providing a platform upon which other pharmacokinetic and pharmacodynamic investigations are based. In these PBPK models, the equivalence of two different peripheral tissue models are shown and issues concerning the mass flow into the liver in comparison with ethanol metabolism in the liver are explained