Population pharmacokinetic analysis of carboxyhaemoglobin concentrations in adult cigarette smokers

AIMS

To develop a population-based model to describe and predict the pharmacokinetics of carboxyhaemoglobin (COHb) in adult smokers.

METHODS

Data from smokers of different conventional cigarettes (CC) in three open-label, randomized studies were analysed using NONMEM (version V, Level 1.1). COHb concentrations were determined at baseline for two cigarettes [Federal Trade Commission (FTC) tar 11 mg; CC1, or FTC tar 6 mg; CC2]. On day 1, subjects were randomized to continue smoking their original cigarettes, switch to a different cigarette (FTC tar 1 mg; CC3), or stop smoking. COHb concentrations were measured at baseline and on days 3 and 8 after randomization. Each cigarette was treated as a unit dose assuming a linear relationship between the number of cigarettes smoked and measured COHb percent saturation. Model building used standard methods. Model performance was evaluated using nonparametric bootstrapping and predictive checks.

RESULTS

The data were described by a two-compartment model with zero-order input and first-order elimination with endogenous COHb. Model parameters included elimination rate constant (k₁₀), central volume of distribution (Vc/F), rate constants between central and peripheral compartments (k₁₂ and k₂₁), baseline COHb concentrations (c0), and relative fraction of carbon monoxide absorbed (F1). The median (range) COHb half-lives were 1.6 h (0.680–2.76) and 30.9 h (7.13–367) (α and β phases, respectively). F1 increased with increasing cigarette tar content and age, whereas k₁₂ increased with ideal body weight.

CONCLUSION

A robust model was developed to predict COHb concentrations in adult smokers and to determine optimum COHb sampling times in future studies.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The pharmacokinetics of carboxyhaemoglobin have been reported previously, primarily with regard to poisoning and toxicity.
• Most of these reports have involved noncompartmental analysis of data obtained where the actual dose of carbon monoxide was not known.

WHAT THIS STUDY ADDS

• This study presents a comprehensive population pharmacokinetic model for carboxyhaemoglobin in adult cigarette smokers.
• Since carboxyhaemoglobin is a marker of cigarette smoke exposure, model-based evaluations can be used for simulation and other evaluations of the kinetics of this agent.