CHF5993 a triple combination therapy for COPD patients: population PK modelling of glycopyrronium bromide (GB) following pMDI inhalation.
Emilie Hénin (1,2), Massimo Cella (3), Koen Jolling (1), Fabrizia Mariotti (3), Christian Laveille (1,2)
(1) SGS Exprimo, Mechelen, Belgium, (2) present affiliation: Calvagone, Lyon, France (3) Chiesi Farmaceutici, Parma, Italy
Objectives: CHF 5993 pMDI is a new extrafine fixed dose combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium bromide (GB), being developed for chronic obstructive pulmonary disease (COPD) and asthma treatment. Data collected in phase II/III studies were used to evaluate the population pharmacokinetics of GB and to investigate the influence of selected covariates on GB pharmacokinetic parameters and their potential clinical impact.
Methods: GB plasma concentrations after oral inhalation in COPD patients were obtained from 2 studies: TRINITY (ph III) and CARSAF (ph II). Both studies were double-blind, randomized, active-controlled. In Triple 6, patients inhaled two puffs twice daily of CHF 5993 pMDI (BDP/FF/GB 100/6/12.5 µg). In CARSAF, patients inhaled two puffs twice daily of Foster® pMDI (BDP/FF 100/6µg) plus either 25 or 50 µg GB pMDI. GB plasma concentrations were modelled with non-linear mixed-effects approaches using NONMEM V7.3.0. The explored covariates were age, smoking status, sex, body weight, body mass index, concomitant medications, study effect, use of spacer, forced expiratory volume in 1 second (FEV1), concomitant diseases and glomerular filtration rate (GFR).
Results: The final population model to describe the PK of GB was a two-compartment disposition model with first-order absorption and first-order elimination, and inter-occasion variability on relative bioavailability. The residual error model was an additive model for the log-transformed data. BQL observations represented 15% of the data and were handled with the M3-method. Bodyweight, study effect and GFR were found to affect GB PK parameters. Simulations were performed in order to visualize the impact of the different covariates on the PK of GB, at steady-state, using a GB dose of 25 or 50 μg BID. For sub-populations with extreme values of body weight and GFR (i.e. low body weight (40 kg) and low GFR (27 mL/min/1.73 m2)), GB exposure increases by a factor around 2.7 compared to the reference patients. This higher exposure is of no clinical concern because, in clinical studies, GB doses of up to 4-fold the one used in CHF5993 formulation didn’t show any safety signal.
Conclusion: The PK model built on data from COPD patients described the GB data well and was able to explain part of the variability in exposure on the basis of some covariates. Based on simulated profiles, no clinical dose adjustments were deemed necessary.
