pharmacokinetics and pharmacodynamics of a 4-week up-titration regimen of roflumilast in the optimize study

Background:

Roflumilast (ROF) has been shown to reduce exacerbations in patients with severe COPD with chronic bronchitis and a history of exacerbations. However, early treatment discontinuations due to gastrointestinal adverse events (AEs) are common. In the OPTIMIZE study (NCT02165826) an initial 4-week up-titration regimen of ROF 250 µg once-daily (OD) followed by the approved 500 µg OD maintenance dose reduced discontinuations and improved tolerability. Here we report PK/PD modelling data from OPTIMIZE.

Methods:

Patients with COPD associated with chronic bronchitis and a history of exacerbations were randomised to 4-weeks' ROF 250 µg OD, 500 µg every other day, or 500 µg OD, each followed by ROF 500 µg OD for 8 weeks. A non-linear mixed-effect population PK (popPK) model using combined datasets from OPTIMIZE and REACT (NCT01329029) studies was developed and used to predict individual ROF exposure and total PDE4 inhibitory (tPDE4i) activities, and assess if patients unable to tolerate ROF 500 µg OD have drug exposure with 250 µg similar to patients on 500 µg OD.

Results:

1238 of the 1321 patients treated in OPTIMIZE had quantifiable PK samples for analysis of tPDE4i and ROF and ROF N-oxide average concentrations. The model could adequately describe average PK concentrations and inter-individual variability across study treatment phases and dosing schemes. A PK/PD time-to-event analysis predicted that patients receiving the 250 µg up-titration regimen had significantly lower discontinuation rates and later time to discontinuation vs. the other regimens.

Patients unable to tolerate ROF 500 µg OD had a slightly higher median tPDE4i (< 10%) than those able to tolerate this dose; however, reducing the dose to 250 µg OD in these patients reduced tPDE4i to well below that typically observed in patients able to tolerate 500 µg OD. Treatment-emergent AEs (TEAEs) of interest increased with predicted tPDE4i exposure.

Conclusions:

Consistent with the main study findings, these PK/PD analyses suggest that a 4-week up-titration regimen with ROF 250 µg OD reduces discontinuations and improves tolerability. However, use of this lower dose as long-term maintenance therapy may not induce sufficient PDE4 inhibition to exert clinical efficacy, supporting earlier findings and approval of 500 µg as maintenance dose.