Application of Population Pharmacokinetic Modeling to Explore the Impact of Alternative Roflumilast Dosing Regimens on Tolerability

Objective: Roflumilast is the first phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and history of exacerbations. In clinical practice, side effects such as diarrhea appear to be somewhat more frequent in patients than that observed in clinical trials. We hypothesize that if patients could take a reduced dose for the first few weeks of therapy, the incidence of adverse events (AEs) could be reduced.

Methods: We used previously reported population pharmacokinetic/ pharmacodynamic modeling to simulate three dosing scenarios of roflumilast: 500 μ once daily (OD) (approved dose), 250 μ OD and 500 μ every other day (EoD).

Results: These models predicted that the 250 μ and EoD regimens were associated with lower plasma concentrations, lower total PDE4 inhibition, and lower incidence of diarrhea, nausea, and headache, versus the 500 μ OD dose.

Conclusions: Reduction of roflumilast dose in the first few weeks of therapy may be able to reduce the incidence of treatment-related AEs. Clearly, modeling provides only the basis for hypothesis generation, and must be supported with clinical evidence from carefully designed trials.