Pharmacokinetics of single- and multiple-dose roflumilast: an open-label, three-way crossover study in healthy Chinese volunteers

Abstract

PurposeTo determine the pharmacokinetic properties of the common tablet of roflumilast administered in single and multiple oral doses in Chinese subjects.Subjects and methodsBoth the single- and multiple-dose studies included 12 adults (6 males and 6 females). In this single-center, open-label study, single doses of 0.25, 0.375, and 0.5 mg were administered using a randomized, three-way crossover design, and then, the 0.375 mg dose was continued for 11 days once daily. The pharmacokinetic parameters for roflumilast and roflumilast N-oxide were determined and the safety evaluation included adverse events assessed by monitoring, physical examination, vital sign tests, and clinical laboratory tests.ResultsAfter every single dose, the time to the maximum concentration (Cmax) of roflumilast (Tmax) was 0.25–2.0 hours; thereafter, the concentration declined, with a mean half-life (t1/2) of 19.7–20.9 hours over the range of 0.25–0.50 mg. As for roflumilast N-oxide, the mean t1/2 was 23.2–26.2 hours. The area under curve from the beginning to 24 hours (AUC0–24 h), the AUC until infinity (AUCinf), and the Cmax of roflumilast and roflumilast N-oxide increased in a dose-proportional manner. After multiple doses, the accumulation index (Rac) on the 11th day of the steady state was ~1.63 for roflumilast and 3.20 for roflumilast N-oxide. No significant sex differences were observed in the pharmacokinetic parameters of roflumilast and roflumilast N-oxide. In addition, there were no serious adverse events across the trial.ConclusionRoflumilast was safe and well-tolerated in healthy volunteers, and a linear increase in its Cmax and AUC values was observed at doses ranging from 0.25 to 0.50 mg.

Simultaneous quantification and pharmacokinetic evaluation of roflumilast and its N‐oxide in cynomolgus monkey plasma by LC–MS/MS method

“…Compared with Huang and Li's pharmacokinetic results for a single dose to humans (Huang et al, 2018; Li et al, 2017), the values of t max of ROF and RNO between humans and monkeys were close, indicating that the absorption and onset times of ROF in humans and monkeys might be similar. Additionally, the elimination time of RNO in both types of bodies was very long, exceeding 48 h.…”

“…The sensitivity of the present LC-MS/MS detection (LLOQ, 0.10 ng/ml for both ROF and RNO), in combination with the readily available IS (rolipram, a structural analogue of ROF), serves to expand the confidence of previously reported LC-MS/MS methods (Cui et al, 2016;Huang et al, 2018;Kertys et al, 2018;Knebel et al, 2012;Li et al, 2017;Thappali et al, 2012) with regards to the accuracy, precision and application of assessments, by directly providing quality control and assurance data in every sample throughout large sample sets. Additionally, the sample preparation for protein precipitation was much less demanding than the preparations required for liquid-liquid extraction and solid-phase extraction in previously reported LC-MS/MS methods (Cui et al, 2016;Huang et al,…”

“…Notably, several liquid chromatography–tandem mass spectrometry (LC–MS/MS) methods have been developed for the simultaneous quantification of ROF and RNO in biological samples obtained from rats (Thappali, Varanasi, Veeraraghavan, & Vakkalanka, 2012), guinea pigs (Kertys, Urbanova, & Mokry, 2018) and humans (Cui et al, 2016; Huang et al, 2018; Knebel, Herzog, Reutter, & Zech, 2012; Li, Wang, Liu, Ma, & Ding, 2017). These LC–MS/MS methods have been validated for detecting ROF and its active metabolite RNO in different biological samples.…”

A Single‐center, Open‐label, Parallel Control Study Comparing the Pharmacokinetics and Safety of a Single Oral Dose of Roflumilast and Its Active Metabolite Roflumilast N‐oxide in Healthy Chinese and Caucasian Volunteers

“…27,28 After oral administration of 375 μg roflumilast, the peak and systemic exposures to roflumilast and roflumilast N-oxide in Chinese patients were similar to those observed in Caucasians administered 500 μg of roflumilast. 27 On the other hand, no relevant differences in safety or tolerability between such groups were observed in the pooled data of COPD phase II and III studies.…”

“…This study demonstrates that Chinese subjects had higher exposure of roflumilast and roflumilast N-oxide compared to Caucasians, which is consistent with previous research on racial difference and roflumilast metabolism. 5,27,28 We provide new evidence in this area, as our study had a parallel control design and provided uniform criteria for screening between the two racial groups. We also note that the racial differences were observed in subjects both with and without TEAEs, and that body-weight normalization could not eliminate the differences.…”