Roflumilast N-oxide

Roflumilast is a phosphodiesterase‐4 inhibitor which treats chronic obstructive pulmonary disease (COPD). Roflumilast N‐oxide is the major metabolite of roflumilast with a similar mechanism of action to roflumilast. Although racial differences in roflumilast drug disposition have been observed, the necessity of dose adjustment is subject to debate. This study compares the pharmacokinetics of a single 500 μg dose of roflumilast in healthy Chinese and Caucasian subjects under uniform conditions. Chinese subjects were found to have longer t1/2 and higher AUC0‐t and Cmax than Caucasian subjects. The point estimates on the geometric mean of AUC0‐t in Chinese subjects were 22% higher for roflumilast and 46% higher for roflumilast N‐oxide. Point estimates on the geometric mean of Cmax were 9% and 24% higher for roflumilast and roflumilast N‐oxide, respectively. Total phosphodiesterase‐4 (PDE4) inhibitory (tPDE4i) activity, a theoretical parameter that describes the combined contribution to PDE4 inhibitory activity of roflumilast and roflumilast N‐oxide, was 44% higher in Chinese subjects than in Caucasian subjects. With about a 10‐fold higher plasma AUC compared to the parent roflumilast and a much longer observed half‐life, roflumilast N‐oxide has been estimated to contribute about 90% of tPDE4i, with 10% attributed to the parent compound roflumilast. Following body weight normalization, these figures were lower but remained significant. Safety analysis showed signs of reduced tolerance or different pharmacodynamic response to roflumilast in Chinese recipients than in Caucasians. Our results suggest that Chinese patients should receive a dose of roflumilast lower than 500 μg daily during future clinical trials.

Roflumilast is an oral, add‐on option for treating patients with severe COPD and frequent exacerbations despite optimal therapy with inhaled drugs. The present study focused on whether this phosphodiesterase 4 inhibitor and its active metabolite roflumilast N‐oxide affect the tone of human bronchial rings. We also investigated the interactions between roflumilast, roflumilast N‐oxide and the long‐acting β2‐agonist formoterol with regard to the relaxation of isolated human bronchial rings at basal tone or pre‐contracted with histamine. Our results demonstrated for the first time that at a clinically relevant concentration (1 nm), roflumilast N‐oxide and roflumilast induce a weak relaxation of the isolated human bronchus either at resting tone (22% and 16%, respectively) or even weaker on pre‐contracted bronchus with histamine (7% and 5%, respectively). In addition, the combination of formoterol with roflumilast or roflumilast N‐oxide is more potent than each component alone for relaxing pre‐contracted isolated bronchi ‐ the apparent pD2 of formoterol was significantly reduced for the threshold concentration of 1 nm of the phosphodiesterase 4 inhibitors by a factor of 2.4 for roflumilast N‐oxide and 1.9 for roflumilast. The full inhibition of phosphodiesterase 4 activity is achieved at 100 nm but this high concentration only caused partial relaxations of the human bronchi. At a clinically relevant concentration, these oral phosphodiesterase 4 inhibitors are not effective direct bronchodilators but could enhance the efficacy of inhaled long‐acting β2‐agonists.