CHF5993 a triple combination therapy for COPD patients: population PK modelling of formoterol following pMDI inhalation
Christian Laveille (1,2), Massimo Cella (3), Koen Jolling (1), Fabrizia Mariotti (3), Erno van Schaick (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 FF and to investigate the influence of selected covariates on FF pharmacokinetic parameters and their potential clinical impact.
Methods: FF 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 TRINITY, 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 100/6 µg) plus either 25 or 50 µg GB pMDI. FF 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 (WT), 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 FF was a two-compartment disposition model with a combined first-order and zero-order absorption process, with inter-occasion variability on relative bioavailability. The residual error model was an additive model for the log-transformed data. BQL concentrations (13% of the data) were handled with the M3-method. WT, study effect, use of spacer and GFR were found to affect FF PK parameters. Simulations were performed to visualize the impact of these covariates on the PK of FF, at steady-state, using a FF dose of 12 μg BID. For sub-populations with extreme values of WT and GFR (i.e. low WT (40 kg) and low GFR (27 mL/min/1.73 m2)), FF exposure increases by a factor ≈2.5 compared to the reference patients. This higher exposure is of no clinical concern because individual therapeutic doses of up to 2-fold the FF doses used in CHF5993 formulation are currently available on the market and thus this doubling in exposure can be considered safe.
Conclusions: The PK model built on data from COPD patients described the FF exposure well and was able to explain part of the variability in exposure on the basis of some covariates. Based on simulated profiles, no dose adjustments were deemed necessary.
