Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease

Arthur Lo, Marie T Borin, David L Bourdet, Arthur Lo, Marie T Borin, David L Bourdet

Abstract

Background and objectives: Revefenacin is a lung-selective, long-acting muscarinic antagonist indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease. The objectives of this analysis were to evaluate the pharmacokinetics of revefenacin and its major metabolite (THRX-195518) in patients with chronic obstructive pulmonary disease, and identify significant covariates affecting revefenacin disposition using a population pharmacokinetic approach based on plasma concentration-time data obtained after single- and repeated-dose once-daily administration in three phase II and two phase III studies.

Methods: Plasma concentrations of revefenacin and THRX-195518 following once-daily administration via nebulization at a dose levels ranging from 22-700 μg in 935 patients (488 men, 447 women; age 41-88 years) were analyzed using nonlinear mixed-effects modeling.

Results: Plasma revefenacin pharmacokinetics was best described by a two-compartment model with first-order absorption and elimination. Pharmacokinetic parameters for THRX-195518 were estimated using a sequential approach, where the concentration-time profiles were fit to a combined model. The formation of the metabolite in each subject was estimated to be a fixed fraction of the individually estimated (post-hoc) clearance rate of revefenacin. Four statistically significant covariates were identified: for revefenacin, age on apparent clearance and body weight on apparent intercompartment clearance, for THRX-195518, age on apparent clearance and body weight on the fraction of revefenacin apparent clearance that was metabolized to THRX-195518.

Conclusions: None of the identified statistically significant covariates were associated with a clinically meaningful effect on revefenacin or THRX-195518 exposure in patients with chronic obstructive pulmonary disease.

Registration: ClinicalTrials.gov identifier number NCT03064113, NCT01704404, NCT02040792, NCT02459080, and NCT02512510.

Conflict of interest statement

Arthur Lo and David L. Bourdet are employees of Theravance Biopharma US, Inc. Marie T. Borin is a consultant for Theravance Biopharma US, Inc.

Figures

Fig. 1
Fig. 1
Schematic of the revefenacin and THRX-195518 combined pharmacokinetic (PK) model. CLmet/F apparent THRX-195518 clearance, Fmet fraction of revefenacin clearance that is metabolized to THRX-195518, Ka first-order absorption, Q/F apparent revefenacin intercompartmental clearance, Qmet/F apparent THRX-195518 intercompartmental clearance, V1/F apparent revefenacin volume of the central compartment, V2/F apparent revefenacin volume of the peripheral compartment, V3/F apparent THRX-195518 volume of the central compartment, V4/F apparent THRX-195518 volume of the peripheral compartment
Fig. 2
Fig. 2
Effect of age and weight on a individually predicted steady-state revefenacin plasma pharmacokinetic (PK) profiles [95% prediction interval (PI)] after a 175-µg dose and b exposures in patients from phase III studies. AUC0–24 steady-state exposure
Fig. 3
Fig. 3
Effect of age, sex, smoking status, and weight on the steady-state plasma a revefenacin and b THRX-195518 exposure. AUC area under the curve, Cmax maximum exposure, PK pharmacokinetic
Fig. 4
Fig. 4
Observed vs post-hoc predicted plasma concentrations for final revefenacin (a) and THRX-195518 (b) models. Cp plasma concentration

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