Dose‐Proportional Intraindividual Single‐ and Repeated‐Dose Pharmacokinetics of Roflumilast, an Oral, Once‐Daily Phosphodiesterase 4 Inhibitor

Bethke, Thomas D.; Böhmer, Gabriele M.; Hermann, Róbert; Hametner, Bernhard; Fux, Richard; Mörike, Klaus; David, Michael D.; Knoerzer, Dietrich; Wurst, W.; Gleiter, Christoph H.

doi:10.1177/0091270006294529

Cited by 78 publications

(133 citation statements)

References 18 publications

(28 reference statements)

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…A recent human study with roflumilast addressed the question of efficacy in type 2 diabetes (E.F.M Wouters, Maastricht University Medical Center, Maastricht, the Netherlands, unpublished results). In humans, roflumilast is metabolised to the active metabolite roflumilast-N-oxide, which exhibits a nearly 10-fold higher exposure compared Data are presented as geometric means (68% range) tPDE4i values were calculated using f u and IC 50 values of 3.7% and 0.282 μg/l for roflumilast and 12.7% and 0.629 μg/l for roflumilast-N-oxide, respectively (N. Kaessner, unpublished data) tPDE4i rof and tPDE4i rofNO correspond to the separate tPDE4 inhibition of roflumilast and roflumilast-N-oxide in the circulation, whereas the combined value considers the contribution of both compounds and was calculated from the individual combinations of tPDE4i rof and tPDE4i rofNO Animals received roflumilast (0.3, 1 or 3 mg kg −1 day −1 ) or roflumilast-N-oxide (3 mg kg −1 day −1 ) once daily for 28 days with its parent compound and acts as the principal contributor to the roflumilast drug effect [14]. As roflumilast metabolism in db/db mice was unknown, we included one treatment arm with roflumilast-N-oxide to assure efficacious plasma concentrations.…”

Section: Discussionmentioning

confidence: 99%

The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice

Vollert

Kaessner²,

Heuser

et al. 2012

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis The cAMP-degrading phosphodiesterase 4 (PDE4) enzyme has recently been implicated in the regulation of glucagon-like peptide-1 (GLP-1), an incretin hormone with glucose-lowering properties. We investigated whether the PDE4 inhibitor roflumilast elevates GLP-1 levels in diabetic db/db mice and whether this elevation is accompanied by glucose-lowering effects. Methods Plasma GLP-1 was determined in db/db mice after single oral administration of roflumilast or its active metabolite roflumilast-N-oxide. Diabetes-relevant variables including HbA 1c , blood glucose, serum insulin, body weight, food and water intake, and pancreas morphology were determined in db/db mice treated daily for 28 days with roflumilast or roflumilast-N-oxide. Pharmacokinetic/pharmacodynamic analysis clarified the contribution of roflumilast vs its metabolite. In addition, the effect of roflumilast-N-oxide on insulin release was investigated in primary mouse islets.Results Single treatment of db/db mice with 10 mg/kg roflumilast or roflumilast-N-oxide enhanced plasma GLP-1 2.5-and fourfold, respectively. Chronic treatment of db/db mice with roflumilast or roflumilast-N-oxide at 3 mg/kg showed prevention of disease progression. Roflumilast-N-oxide abolished the increase in blood glucose, reduced the increment in HbA 1c by 50% and doubled fasted serum insulin compared with vehicle, concomitant with preservation of pancreatic islet morphology. Furthermore, roflumilast-N-oxide amplified forskolininduced insulin release in primary islets. Roflumilast-N-oxide showed stronger glucose-lowering effects than its parent compound, consistent with its greater effect on GLP-1 secretion and explainable by pharmacokinetic/pharmacodynamic modelling. Conclusions/interpretation Our results suggest that roflumilast and roflumilast-N-oxide delay the progression of diabetes in db/db mice through protection of pancreatic islet physiology potentially involving GLP-1 and insulin activities.

show abstract

Section: Discussionmentioning

confidence: 99%

The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice

Vollert

Kaessner²,

Heuser

et al. 2012

Diabetologia

View full text Add to dashboard Cite

show abstract

“…In this study, the doses of roflumilast were selected in order to imitate the plasma concentration in the clinical setting. The plasma concentration of roflumilast and N-oxide roflumilast after oral administration of 500 μg of roflumilast, the recommended clinical dose, in human subjects has been reported to be approximately 5 and 9 ng/ml at peak concentration, respectively [23]. As shown in Table 2, the doses up to 200 μg/kg of rofulmilast covered the range of the plasma concentration in the clinical settings.…”

Section: Discussionmentioning

confidence: 93%

“…Roflumilast is metabolized principally via the liver into N-oxide roflumilast, which is pharmacologically active with a lower potency but longer half-life than the parent compound [23,24]. Roflumiast was reported to have no PDE4 subtype selectivity apart from PDE4C while N-oxide rofulmilast has no selectivity for PDE4 subtypes [25].…”

Section: Discussionmentioning

confidence: 99%

A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram

Takano

Garcia‐Segovia

et al. 2018

Mol Imaging Biol

View full text Add to dashboard Cite

Purpose: Phosphodiesterase 4 (PDE4) inhibition in the brain has been reported to improve cognitive function in animal models. Therefore, PDE4 inhibitors are one of key targets potential for drug development. Investigation of brain PDE4 occupancy would help to understand the effects of PDE4 inhibition to cognitive functions. Roflumilast is a selective phosphodiesterase type 4 (PDE4) inhibitor used clinically for severe chronic obstructive pulmonary disease, but the effects to the brain have not been well investigated. In this study, we aimed to investigate whether roflumilast entered the brain and occupied PDE4 in nonhuman primates. Procedures: Positron emission tomography (PET) measurements with (R)-[11 C]rolipram were performed at baseline and after intravenous (i.v.) administration of roflumilast (3.6 to 200 μg/kg) in three female rhesus monkeys. Arterial blood samples were taken to obtain the input function. Protein binding was measured to obtain the free fraction (fp) of the radioligand. Total distribution volume (V T ) and V T /fp were calculated as outcome measures from two tissue compartment model. Lassen plot approach was taken to estimate the target occupancy.Results: The brain uptake of (R)-[ 11 C]rolipram decreased after roflumilast administration. PDE 4 occupancy by roflumilast showed dose-and plasma concentration-dependent increase, although PDE4 occupancy did not reach 50 % even after the administration of up to 200 μg/ kg of roflumilast, regardless of outcome measures, V T or V T /fp. Conclusions: This PET study showed that the brain PDE4 binding was blocked to a certain extent after i.v. administration of clinical relevant doses of roflumilast in nonhuman primates.Further clinical PET evaluation is needed to understand the relationship between PDE4 inhibition and potential improvement of cognitive function in human subjects.

show abstract

“…Karaciğer sitokrom P450 enzimleri tarafından aktif metaboliti olan roflumilast N-okside metobolize olur (28). N-okside roflumilastın etkinliği, roflumilasttan 2-3 kat daha düşük olup, %97'si plazma proteinlerine bağlanır (29). İnaktif metabolitlerin yaklaşık %70'i idrarla atılır (30).…”

Section: Farmakoki̇neti̇k Profi̇lunclassified

A new alternative treatment in COPD: phosphodiesterase-4 inhibitors

Sezgı

Şenyiğit²

2011

Tuberk Toraks

View full text Add to dashboard Cite

ÖZET KOAH'da yeni tedavi seçeneği: Fosfodiesteraz-4 inhibitörleri Kronik obstrüktif akciğer hastalığı (KOAH) ilerleyici hava akımı kısıtlanması ile karakterize, zararlı gaz ve tozlara karşı abartılı inflamatuvar yanıtla ortaya çıkan bir hastalıktır. İnflamatuvar hücrelerin aktivasyonunu engelleyen oral fosfodiesteraz-4 (FDE-4) inhibitörleri son yıllarda KOAH tedavisinde yeni bir yaklaşım olarak denenmektedir. Çalışmalar FDE-4 inhibitörlerinin orta-ağır KOAH hastalarının semptomlarını, solunum fonksiyonlarını ve yaşam kalitesini düzelttiğini, akut atak sayısını azalttığını, bronşlardaki inflamasyonu baskıladığını göstermiştir. Ancak bu ilaçlar bulantı, ishal ve baş ağrısı gibi istenmeyen yan etkilere neden olmaktadır. Bu derlemede özellikle "Food and Drug Administration (FDA)" onayı almış, yeni "The Global Initiative for Chronic Obstructive Lung Disease (GOLD)" rehberinde ağır KOAH tedavisine dahil edilmiş selektif bir fosfodiesteraz inhibitörü olan roflumilast tartışılmıştır.

show abstract

Dose‐Proportional Intraindividual Single‐ and Repeated‐Dose Pharmacokinetics of Roflumilast, an Oral, Once‐Daily Phosphodiesterase 4 Inhibitor

Cited by 78 publications

References 18 publications

The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice

The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice

A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram

A new alternative treatment in COPD: phosphodiesterase-4 inhibitors

Contact Info

Product

Resources

About