Population pharmacokinetic analysis of carboxyhaemoglobin concentrations in adult cigarette smokers

Abstract

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 (k(10)), central volume of distribution (Vc/F), rate constants between central and peripheral compartments (k(12) and k(21)), 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) (alpha and beta phases, respectively). F1 increased with increasing cigarette tar content and age, whereas k(12) 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.

Figure 1

Relationship between ideal body weight and interindividual variability (IIV or η) for k₁₂, Federal Trade Commission (FTC) tar content and IIV for relative fraction of carbon monoxide absorbed (F1), and age and IIV for F1 from the final carboxyhaemoglobin model. The circles are observed data and the solid line is a loess smooth added to facilitate visualization of the trend in the data

Figure 2

Diagnostic plots for a representative individual from the Federal Trade Commission 6 group. The filled circles are observed data, the dashed line is the population (typical) predicted curve and the solid line is the individual predicted curve. (Individual Predicted, (—) Population Predicted, (- - -) Observed, (•))

Figure 3

Mean typical predicted and observed carboxyhaemoglobin (COHb) percentage saturation based on the final COHb model. The symbols represent the observed mean (SD) COHb percentage saturation and the solid line depicts the population (typical) predicted COHb percentage saturation from the final model. (CC1, (•); CC2, (); CC3, (); Non-smoking, () Individual Predicted, (—))

Figure 4

Diagnostic plots for the final carboxyhaemoglobin (COHb) pharmacokinetic model. (A) Population (typical) predicted vs. observed COHb percentage saturation. (Data, (○); (B) Weighted residuals vs. observed COHb percentage saturation. Line of Unity, (—); Linear Regression, (- - -))

Figure 5

Visual predictive checks. Observed carboxyhaemoglobin (COHb) concentrations overlaid on the 95% prediction intervals for Federal Trade Commission (FTC) 0 (nonsmoking) group, the FTC1 group, the FTC6 group and the FTC11 group. The area containing the hashed lines represents the 95% prediction intervals, the solid line the median of the prediction interval, and the triangles the observed COHb percentage saturation data