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

Li, Qian; Wang, Yiya; Liu, Lingye; Ma, Ping; Ding, Li

doi:10.1007/s13318-016-0343-4

Cited by 4 publications

(10 citation statements)

References 18 publications

(24 reference statements)

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“…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.…”

Section: Resultsmentioning

confidence: 60%

“…The precursor/product ion pairs for quantification were monitored at m/z 403.0 → 186.9 for ROF, m/z 419.0 → 186.9 for RNO and 276.2 → 102.9 for IS. Other iron fragments for identification are listed in Table 1, and have been proved to be correct (Kertys et al, 2018; Li et al, 2017; Thevis, Krug, & Schänzer, 2013). MS parameters of ROF, RNO and IS are also shown in Table 1.…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

et al. 2020

Biomedical Chromatography

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Roflumilast (ROF), a nonsteroidal anti‐inflammatory drug, has successfully been used to treat systemic and pulmonary inflammation associated with chronic obstructive pulmonary disease. To evaluate its pharmacokinetics in monkeys, a sensitive, rapid and reliable liquid chromatography with tandem mass spectrometry (LC–MS/MS) method was developed for the simultaneous determination of ROF and its N‐oxide metabolite (RNO). The mobile phase contained 0.1% formic acid aqueous solution (A) and 0.1% formic acid acetonitrile solution (B). All monkey plasma samples were pretreated using protein precipitation with methanol–acetonitrile (50:50, v/v) in 50 μl plasma samples. Chromatographic separation was performed with mass spectral acquisition performed in positive electrospray ionization, utilizing multiple reaction monitoring. This method was successfully applied to a pharmacokinetic study in cynomolgus monkeys. Following administration of a single oral dose of 1 mg/kg ROF in monkeys, pharmacokinetic data for ROF and RNO was reported for the first time. After oral administration, ROF was rapidly absorbed and metabolized to its metabolite RNO. The mean area under the curve value of RNO was ~13 times larger than that of ROF, suggesting that most ROF was metabolized to RNO in cynomolgus monkeys.

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Section: Resultsmentioning

confidence: 60%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Zhang

et al. 2020

Biomedical Chromatography

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“…However, that study was based on Caucasians. Moreover, the previous literature, 10 which described a parallel-group study conducted in healthy Chinese subjects, did not show considerable dose-proportional pharmacokinetic characteristics because of interindividual variability. This article used a 3×3 Latin square crossover design to investigate single-dose pharmacokinetics while reducing interindividual differences.…”

Section: Discussionmentioning

confidence: 94%

“…However, to our knowledge, there is little literature about the pharmacokinetics of roflumilast and roflumilast N -oxide in healthy Chinese subjects. 10 , 11 As a result, it is important to investigate the pharmacokinetics of these two compounds. This study was designed to evaluate the pharmacokinetics of roflumilast and roflumilast N -oxide in healthy Chinese volunteers.…”

Section: Introductionmentioning

confidence: 99%

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

Huang¹,

Fu²,

Yang³

et al. 2018

DDDT

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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.

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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

Han

Lin

Cui

et al. 2022

Clinical Pharm in Drug Dev

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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.

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

Cited by 4 publications

References 18 publications

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

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

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

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

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