Population pharmacokinetics and exposure-response analyses of varenicline in adolescent smokers

Abstract

Varenicline is an approved smoking cessation aid in adults. Population pharmacokinetics (popPK) and exposure-response (ER) (continuous abstinence rates [CAR] weeks 9-12 and nausea/vomiting incidence) for varenicline in adolescent smokers were characterized using data from two phase 1 and one phase 4 studies. A one-compartment popPK model with first-order absorption and elimination adequately fitted the observed data. The effect of female sex on apparent clearance was significant. Apparent volume of distribution increased with body weight and decreased by 24%, 15%, and 14% for black race, "other" race, and female sex, respectively. The observed range of exposure in the phase 4 study was consistent with that expected for each dose and body-weight group from the results obtained in adolescent PK studies, supporting that varenicline dose and administration were appropriate in the study. The relationship between CAR9-12 and varenicline area under the concentration-time curve (AUC) from 0 to 24 hours (AUC24 ) was nonsignificant (p = 0.303). Nausea/vomiting incidence increased with AUC24 (p < 0.001) and was higher in females. Varenicline PK and ER for tolerability in adolescent smokers were comparable with adults, while ER for efficacy confirmed the negative results reported in the phase 4 study.

Trial registration: ClinicalTrials.gov NCT00463918 NCT01312909.

Conflict of interest statement

DF, KS, VS, TM and WB are employees of Pfizer and may own shares/stock options in Pfizer.

© 2021 Pfizer Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

FIGURE 1

Visual predictive check. Circles represent observed plasma concentrations. Solid yellow line represents median observed plasma concentrations. Dashed yellow lines represent 2.5% and 97.5% observed percentiles. Solid black line represents simulated median. Dashed black lines represent 2.5% and 97.5% simulated percentiles. Shaded yellow area represents simulation‐based 95% CI for simulated median. Shaded blue areas represent simulation‐based 95% CI for 2.5% and 97.5% percentiles. b.i.d., twice daily; CI, confidence interval; q.d., once daily

FIGURE 2

Covariate effects on AUC24 (95% CI). 95% CI of ratio generated from 1,400 nonparametric bootstrapped sets of population parameter values using final popPK model (50 runs with minimization terminated and 241 runs with estimates near a boundary skipped when calculating bootstrap results). AUC24 was derived from the final apparent clearance estimate. Solid squares represent ratio of typical predicted AUC24 relative to reference subject of white male weighing 70 kg. Thus, a value of 1 (1.0) represents unity or a null covariate effect. Error bars represent 95% CI of ratio. AUC24, area under the concentration–time curve from 0 to 24 hours; CI, confidence interval; popPK, population pharmacokinetics

FIGURE 3

Varenicline ER relationships in adolescent smokers for (a) CAR9–12 and (b) nausea/vomiting incidence. (a) Dotted line represents predicted probability of continuous abstinence at weeks 9‒12. (b) Dotted line represents predicted probability of nausea/vomiting incidence. (a and b) Circles show observed probabilities in each of the six AUCss (0–24) bins. Exposure was set to 0 for placebo group. Box‐and‐whisker plots (lower panels) describe distribution of exposure data. Box indicates difference between first and third quartiles of data, showing spread of data. Solid line represents median value; whiskers indicate range of data or 1.5× interquartile distance, whichever is less. Circles plotted outside whiskers exceed these limits and may be considered outliers. AUCss (0–24), area under the concentration–time curve at steady‐state from 0 to 24 hours; b.i.d., twice daily; CAR, continuous abstinence rate; ER, exposure–response; HBW, high body weight (>55 kg); LBW, low body weight (≤55 kg); q.d., once daily

FIGURE 4

Covariate effects on nausea/vomiting incidence (95% CI). 95% CI of ratio generated from 2,800 nonparametric bootstrapped sets of population parameter values using final nausea/vomiting incidence model (754 runs with minimization terminated skipped when calculating bootstrap results). Solid squares represent point estimate for covariate effect relative to representative subject. Error bars represent 95% CI of ratio. AUC24, area under the concentration–time curve from 0 to 24 hours; CI, confidence interval; cig., cigarette; FSQ1, Fagerström Test for Nicotine Dependence score for question 1