Bruno Bieth (1), Aurelie Gautier (1), Michael Looby (1), Gordon Graham (1), Romain Sechaud (2)
(1) Modeling and Simulation, Novartis, Basel, Switzerland. (2) DMPK, Novartis, Basel, Switzerland
Objectives: QVA149 is an inhaled, once-daily, first fixed-dose combination of indacaterol maleate (long-acting β2-agonist) and glycopyrronium bromide (long acting muscarinic antagonist) for the treatment of COPD [1,2]. The objective of the population pharmacokinetics analysis was the assessment of the pharmacokinetic of the fixed dose combination and the comparison of the its dose exposure to the monotherapies (providing an additional level of complexity) .
Methods: A phase III 26-weeks treatment multi-center, randomized, double-blind, parallel-group study was performed on 190 patients. All subjects received either the fixed dose combination (110ug/50ug) or the monotherapy (indacaterol 150ug / glycopyrronium 50ug). Blood samples were collected at pre-dose and over 4 hours after dosing with a total of 10 samples at two different days at steady state. Population PK modeling was performed using NONMEM (version 6 and 7).
Results: The final population models for indacaterol and glycopyrronium bromide given as a fixed dose combination were both a two-compartment disposition model with first-order absorption and first-order elimination. A visual predictive check (VPC) and normalized prediction distribution errors (NPDE) displayed no serious model misspecification. A covariate search found lean body weight as a significant covariate on the relative bioavailability. In addition, the correlation in exposure of the combined drugs observed on the data was fully assessed by a combination model successfully implemented in NONMEM 7.
Conclusions: A population pharmacokinetic model incorporating day and between occasion effects was developed for the monotherapy and combination therapy arms that adequately described the study data. Lean body weight was found as a covariate on the relative bioavailability. The observed correlation in exposure between the therapies was further confirmed by an innovative nonlinear mixed-effects combination model.
References:
[1] Bateman E et al. Benefits of dual bronchodilation with QVA149 once daily versus placebo, indacaterol, NVA237 and tiotropium in patients with COPD: the SHINE study. [ERS abstract 700179; Session 306; Monday September 3, 2012; 14:45:-16:45].
[2] Vogelmeier C et al. Once-daily QVA149 significantly improves lung function and symptoms compared to twice-daily fluticasone/salmeterol in COPD patients: The ILLUMINATE study. [ERS abstract 70045; Session 52; Sunday September 2, 2012; 08:30-10:30].
Reference: PAGE 22 (2013) Abstr 2800 [www.page-meeting.org/?abstract=2800]
Poster: Model evaluation