Pharmacokinetic and Pharmacodynamic Modelling to Characterize the Tolerability of Alternative Up-Titration Regimens of Roflumilast in Patients with Chronic Obstructive Pulmonary Disease

Clin Pharmacokinet. 2018 Aug;57(8):1029-1038. doi: 10.1007/s40262-018-0671-4.


Background: In the OPTIMIZE study, 4 weeks of roflumilast 250 µg once daily before escalation to the approved 500 µg once daily maintenance dose reduced treatment discontinuations and improved tolerability to roflumilast among patients with chronic obstructive pulmonary disease (COPD). In this study, we present the pharmacokinetic (PK) results and PK/pharmacodynamic (PD) modelling data from OPTIMIZE.

Methods: OPTIMIZE was a multicentre, double-blind, phase III study in which patients with severe COPD were randomized 1:1:1 to receive oral roflumilast 250 μg once daily, 500 μg every other day, or 500 μg once daily for 4 weeks, followed by 500 μg once daily for 8 weeks. A population PK (popPK) model characterized roflumilast exposure levels (total phosphodiesterase-4 inhibition [tPDE4i]). Furthermore, models characterized the percentage of patients with adverse events (AEs) of interest (PK/AE model), and time to discontinuation due to such AEs (PK/time-to-event model).

Results: The popPK model adequately described average plasma concentrations and variability from 1238 patients. The percentage of patients with AEs of interest increased with predicted tPDE4i exposure (logit scale slope 0.484; confidence interval 0.262-0.706; p = 2 × 10-5). PK/time-to-event model analysis predicted that patients receiving the 250 μg up-titration regimen had significantly lower discontinuation rates and longer time to discontinuation compared with roflumilast 500 μg every other day or 500 μg once daily (p = 0.0014).

Conclusions: In this PK/PD model, a 4-week up-titration regimen with roflumilast 250 µg once daily was found to reduce discontinuations and improve tolerability, confirming the main clinical findings of the OPTIMIZE study. However, use of this lower dose as long-term maintenance therapy may not induce sufficient phosphodiesterase-4 inhibition to exert clinical efficacy, supporting the approval of 500 µg as maintenance dose.

Trial registration: OPTIMIZE: NCT02165826; REACT: NCT01329029.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / administration & dosage*
  • Aminopyridines / pharmacokinetics*
  • Aminopyridines / therapeutic use
  • Benzamides / administration & dosage*
  • Benzamides / pharmacokinetics*
  • Benzamides / therapeutic use
  • Cyclopropanes / administration & dosage
  • Cyclopropanes / pharmacokinetics
  • Cyclopropanes / therapeutic use
  • Double-Blind Method
  • Drug Monitoring
  • Drug Tolerance*
  • Humans
  • Models, Biological*
  • Phosphodiesterase 4 Inhibitors / administration & dosage*
  • Phosphodiesterase 4 Inhibitors / pharmacokinetics*
  • Phosphodiesterase 4 Inhibitors / therapeutic use
  • Pulmonary Disease, Chronic Obstructive / drug therapy*


  • Aminopyridines
  • Benzamides
  • Cyclopropanes
  • Phosphodiesterase 4 Inhibitors
  • Roflumilast

Associated data