CHF5993 a triple combination therapy for COPD patients: population pharmacokinetic modelling of beclometasone-17-monopropionate (B17MP) following pMDI inhalation.
Koen Jolling (1), Massimo Cella (2), Fabrizia Mariotti (2), Christian Laveille (1,3)
(1) SGS Exprimo, Mechelen, Belgium, (2) Chiesi Farmaceutici, Parma, Italy, (3) present affiliation: Calvagone, Lyon, France
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 from phase II/III studies were used to evaluate the population pharmacokinetics of B17MP (main BDP metabolite) and to investigate the influence of selected covariates on B17MP PK parameters and their potential clinical impact.
Methods: B17MP 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. B17MP 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 model describing B17MP PK was a three-compartment disposition model with first-order formation process and first-order elimination with inter-occasion variability on relative bioavailability. The residual error model was a combination of a proportional and an additive component for the log transformed data. GFR, WT, smoking, study effect and repeated administrations were found to affect B17MP PK parameters. Simulations were performed to visualize the impact of the different covariates on the PK of B17MP, at steady-state, using a BDP dose of 200 μg BID. For a sub-population with extreme values of WT and GFR (i.e. low WT (40 kg) and low GFR (27 mL/min/1.73 m2)), B17MP exposure increases by a factor of 1.8 compared to reference patients. This higher exposure is of no clinical concern because BDP therapeutic doses up to 2-fold the doses used in the CHF5993 formulation are currently available on the market and this doubling in exposure can thus be considered safe.
Conclusions: The PK model built on data from COPD patients described the B17MP 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.
