Steady-State Pharmacokinetics of Roflumilast and Roflumilast N-Oxide in Patients with Mild and Moderate Liver Cirrhosis

Abstract

Mild and moderate liver cirrhosis resulted in distinct alterations of exposure to roflumilast but only in modest alterations of exposure to roflumilast N-oxide. The integrated exposure-weighted assessment of the observed pharmacokinetic changes of roflumilast and roflumilast N-oxide (tPDE4i) indicates modest average exposure increases to the sum of both compounds. These findings and the favourable tolerability profile suggest that roflumilast can be safely used in patients with mild and moderate liver cirrhosis without special precautions or dose adjustment.

Treatment of Chronic Obstructive Pulmonary Disease with Roflumilast, a New Phosphodiesterase 4 Inhibitor

“…Although the metabolism of roflumilast is significantly arrested in patients with mild and moderate hepatic insufficiency leading to increased systemic exposure (AUC 0-24 = 51% and 92% higher in patients meeting Child-Pugh A and Child-Pugh B criteria, respectively, when compared to healthy subjects), changes to the pharmacokinetics of roflumilast N-oxide are relatively modest (62). Since the primary metabolite is believed to account for approximately 90% of the pharmacodynamic impact of roflumilast, the small pharmacokinetic changes reported are not believed to be clinically relevant.…”

“…Since the primary metabolite is believed to account for approximately 90% of the pharmacodynamic impact of roflumilast, the small pharmacokinetic changes reported are not believed to be clinically relevant. Thus, no dose adjustments are predicted to be required in patients with mild and moderate liver compromise (62).…”

“…Correspondingly, agents that are metabolized by the same system could compete with roflumilast and delay its inactivation, in effect raising its level. A number of studies have been performed to evaluate such drug-drug interactions and their potential for adverse reactions (59)(60)(61)(62)(63)(64)(65)(66)(67). The results published so far indicate that there is not a substantial effect of a range of potential agents and conditions on roflumilast levels.…”

Pharmacokinetic Behaviors of Orally Administered Drugs

“…In patients with mild liver cirrhosis (Child-Pugh A), the apparent oral clearance (CL/F) and total exposure (AUC 0-24h ) of parent roflumilast was 37% lower and 51% higher, respectively, compared to that in healthy control subjects, whereas no differences were observed in C max between both groups. In patients with moderate liver cirrhosis (Child-Pugh B), the apparent oral clearance (CL/F), total exposure (AUC 0-24h ), and C max of the metabolite roflumilast N -oxide were 44% lower, 92% higher, and 27% higher, respectively, compared to that in healthy control subjects (Hermann et al, 2007).…”

Pharmacokinetics of Roflumilast and Its Active Metabolite Roflumilast N-Oxide in Healthy Chinese Subjects After Single and Multiple Oral Doses

“…The N-oxide metabolite accounts for about 90 % of roflumilast's total PDE4 inhibitory activity [5,8]. The pharmacokinetics of roflumilast and roflumilast N-oxide have been well described in the white population, including healthy subjects, patients with severe renal impairment and patients with mild/moderate hepatic impairment [8][9][10].…”