Dataset Information

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.

SUBMITTER: Fediuk DJ

PROVIDER: S-EPMC8302239 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Fediuk Daryl J DJ Sweeney Kevin K Sahasrabudhe Vaishali V McRae Thomas T Byon Wonkyung W

CPT: pharmacometrics & systems pharmacology 20210617 7

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 ...[more]

PMID: 34062053

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Project description:IntroductionRisankizumab is an anti-IL23 monoclonal antibody approved for the treatment of moderate to severe plaque psoriasis and active psoriatic arthritis (PsA). This work characterizes the pharmacokinetics of risankizumab in PsA compared with psoriasis and evaluates the efficacy and safety exposure-response relationships in PsA.MethodsThe population pharmacokinetic analyses included data from 1527 participants that originated from one phase 1 healthy participant study, one phase 2 dose-ranging study in patients with PsA with an open-label extension study, and two pivotal phase 3 studies in patients with PsA, where the clinical regimen of risankizumab 150 mg administered subcutaneously (SC) at weeks 0, 4, and every 12 weeks thereafter was compared with placebo. Pharmacokinetics were analyzed using nonlinear mixed-effects modeling. Simulation analyses using the final model were conducted to evaluate the impact of covariates on exposure. Data from 1407 patients with PsA from the phase 3 studies were included in the exposure-response analyses. Graphical analyses were used to evaluate efficacy and safety exposure-response relationships, and logistic regression was conducted for further assessment of efficacy exposure-response relationships.ResultsRisankizumab pharmacokinetics were well described by a two-compartment model with first-order SC absorption and elimination. None of the evaluated covariates showed clinically relevant impact on exposure. On the basis of the final model, systemic clearance, steady-state volume of distribution, and terminal phase elimination half-life were estimated to be ~ 0.31 L/day, 11.1 L, and 26.3 days, respectively, for a typical 90 kg patient with PsA. Absolute SC bioavailability was estimated to be 83.5%. Exposure-response quartile analyses suggested that exposures associated with the clinical regimen maximized efficacy across the endpoints evaluated. No exposure dependency was observed for key safety endpoints.ConclusionsRisankizumab exhibited linear and time-independent pharmacokinetics in patients with PsA and was comparable to patients with plaque psoriasis. Efficacy and safety exposure-response analyses support that the clinical regimen achieved robust efficacy with a favorable safety profile for patients with active PsA.Clinical trialsNCT02596217, NCT02719171, NCT02986373, NCT03671148, and NCT03675308.Clinical trialsNCT02596217, NCT02719171, NCT02986373, NCT03671148, and NCT03675308.

Dataset Information

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

Publications

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

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