Magnesium Hydroxide/Aluminium Hydroxide‐Containing Antacid Does Not Affect the Pharmacokinetics of the Targeted Phosphodiesterase 4 Inhibitor Roflumilast

Nassr, Nassr; Lahu, Gëzim; Hünnemeyer, Andreas; Richter, Oliver von; Knoerzer, Dietrich; Reutter, Felix; Zech, K.; Hermann, Róbert

doi:10.1177/0091270006297920

Cited by 17 publications

(20 citation statements)

References 26 publications

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“…The median (range) age was 25 (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39) years, median (range) body weight was 69 (53-110) kg, median (range) height was 174 (163-202) cm, and median (range) body mass index was 23 (20-28) kg/m 2 .…”

Section: Participant Demographic and Baseline Characteristicsmentioning

confidence: 99%

No Dose Adjustment on Coadministration of the PDE4 Inhibitor Roflumilast With a Weak CYP3A, CYP1A2, and CYP2C19 Inhibitor: An Investigation Using Cimetidine

Böhmer

Gleiter

Mörike

et al. 2011

The Journal of Clinical Pharmacology

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This nonrandomized, fixed-sequence, 2-period crossover study investigated potential pharmacokinetic interactions between the phosphodiesterase 4 inhibitor roflumilast, currently in clinical development for the treatment of chronic obstructive pulmonary disease, and the histamine 2 agonist cimetidine. Participants received roflumilast, 500 µg once daily, on days 1 and 13. Cimetidine, 400 mg twice daily, was administered from days 6 to 16. Pharmacokinetic analysis of roflumilast and its active metabolite roflumilast N-oxide was performed, and the ratio of geometric means for roflumilast alone and concomitantly with steady-state cimetidine was calculated. The effect of cimetidine on the total PDE4 inhibitory activity (tPDE4i; total exposure to roflumilast and roflumilast N-oxide) was also calculated. Coadministration of steady-state cimetidine increased mean tPDE4i of roflumilast and roflumilast N-oxide by about 47%. The maximum plasma concentration (C(max)) of roflumilast increased by about 46%, with no effect on C(max) of roflumilast N-oxide. The increase in tPDE4i of roflumilast and roflumilast N-oxide following coadministration with cimetidine was mainly due to the inhibitory effect of cimetidine on cytochrome P450 (CYP) isoenzymes CYP1A2, CYP3A, and CYP2C19. These moderate changes indicate that dose adjustment of roflumilast is not required when coadministered with a weak inhibitor of CYP1A2, CYP3A, and CYP2C19, such as cimetidine.

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Section: Participant Demographic and Baseline Characteristicsmentioning

confidence: 99%

No Dose Adjustment on Coadministration of the PDE4 Inhibitor Roflumilast With a Weak CYP3A, CYP1A2, and CYP2C19 Inhibitor: An Investigation Using Cimetidine

Böhmer

Gleiter

Mörike

et al. 2011

The Journal of Clinical Pharmacology

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“…The pharmacokinetics of roflumilast N-oxide generally are distinct from the parent compound. Thus, the T max is between 4 hr and 12 hr and the maximum observed plasma concentration (C max ) is typically one-to two-fold higher (54,57,(59)(60)(61). Steady-state plasma levels of roflumilast N-oxide are usually achieved within 6 days of once-daily oral administration and the elimination t 1/2 is approximately 27 hr, which is significantly prolonged relative to the parent compound.…”

Section: Pharmacokinetics Of Roflumilast and Roflumilast N-oxidementioning

confidence: 99%

“…Neither roflumilast nor roflumilast N-oxide by themselves inhibit CYP3A4 or CYP1A2 (40). Other data suggest a low potential for roflumilast to interact adversely with other drugs including montelukast, erythromycin, ketoconazole, budesonide, albuterol, midazolam (40), and antacids containing magnesium hydroxide or aluminium hydroxide (59)(60)(61)(63)(64)(65)(66)(67). This is important to determine because inducers of CYP3A4 and CYP1A2 have the potential to increase the CL of roflumilast thereby lowering its efficacy.…”

Section: Contraindications Effect Of Food and Drug-drug Interactionsmentioning

confidence: 99%

“…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.…”

Section: Safety Outcomesmentioning

confidence: 99%

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

Gross

Giembycz

Rennard

2010

COPD: Journal of Chronic Obstructive Pulmonary Disease

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Recent advances in chronic obstructive pulmonary disease (COPD) treatment offer symptom relief, but disease modification remains an unmet goal of pharmacotherapy. Reducing the frequency and severity of COPD exacerbations may help slow disease progression and reduce the morbidity, mortality, and costs associated with these major events. Other desirable characteristics for a COPD treatment include a once-daily dosing schedule, an oral formulation, and a low frequency of systemic side effects. Phosphodiesterase 4 inhibitors have been in clinical development for some years and roflumilast is currently the most advanced of these agents. In this review, the preclinical evidence, clinical safety, and efficacy of roflumilast available in published reports are considered. The data reviewed here suggest that the clinical efficacy of roflumilast occurs through a mechanism unrelated to bronchodilation and may be due to the suppression of lung inflammation. Lung function improved with roflumilast treatment and in some studies, the reduction in exacerbations was substantial and statistically significant. Notably, this effect appeared to be greatest in the subgroup of patients with more severe disease and more severe exacerbations. The evaluation of roflumilast safety largely centers on gastrointestinal adverse events, with diarrhea, nausea, and weight loss occurring more frequently with the drug than placebo. If approved for general use, we expect roflumilast to find its role initially as a substitute for inhaled corticosteroids in the maintenance treatment of severe and very severe disease, particularly in patients who have frequent acute exacerbations, and perhaps as a supplementary drug when symptoms are not adequately controlled by current conventional COPD therapy.

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“…Однако, поскольку по своей ак тивности рофлумиласт и его активный метаболит почти не различаются, изменения скорости мета болизма не имеют существенного клинического зна чения [15]. В исследованиях лекарственных вза имодействий не было выявлено необходимости коррекции дозы рофлумиласта при одновременном назначении анатцидов [16], эритромицина [17], ке токоназола [18] и дигоксина [15]. Тем не менее на Рис.…”

Section: рофлумиласт в сравнении с теофиллиномunclassified

Clinical pharmacology of roflumilast

Архипов¹

2012

Pulʹmonologiâ (Mosk.)

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Пульмонология 2'2012Фосфодиэстеразы (ФДЭ) -семейство ферментов, участвующих в регуляции сигнальных путей, связан ных с рецепторами на поверхности клеточной мемб раны (β адренорецепторы, M холинорецепторы и т. д.). Целый ряд процессов, например стимуляция β адренорецепторов, блокада M холинорецепторов или взаимодействие глюкогона с рецепторами на поверхности клеток, приводит к синтезу и накопле нию в клетках циклического аденозинмонофосфата (цАМФ) или циклического гуанозинмонофосфата (цГМФ). В свою очередь цАМФ и цГМФ служат вто ричными посредниками, активируя или замедляя некоторые биологические процессы в клетках. Так, цАМФ участвует в регуляции тонуса гладких мышц, уменьшает синтез медиаторов воспаления, регули рует процессы дифференциации и апоптоза клеток, активирует глюкогенез и влияет на активность ион ных каналов.После стимуляции соответствующего рецептора количество цАМФ и цГМФ внутри клетки превышает количество действующего на клетку медиатора при мерно в 100 раз. Это обеспечивает "эффект домино": даже небольшое количество гормона или лекарствен ного вещества, взаимодействуя с единичными рецеп торами на поверхности клетки вызывают мощный биологический ответ. Благодаря цАМФ ингаляция незначительного количества формотерола (6 ×10 -6 г) способна купировать выраженный бронхоспазм, а ад реналин значимо повышает число сердечных сокра щений в дозе < 10 -7 г / кг веса больного. Однако, эффекты цАМФ могут принести вред от дельным клеткам и организму в целом, если они не будут ограничены по времени и интенсивности. ФДЭ катализируют расщепление цАМФ и цГМФ, предохраняя клетки от избыточного воздействия гормонов и медиаторов [1]. С другой стороны, при целом ряде заболеваний усиление внешних стиму лов может иметь важное терапевтическое значение. Например, ингибирование ФДЭ в мышечном слое бронхов увеличивает продукцию цАМФ в ответ на воздействие катехоламинов или бронхолитиков. Та ким образом, снижение активности ФДЭ обеспечи вает бронходилатацию для пациентов с бронхиаль ной астмой (БА) или хронической обструктивной болезнью легких (ХОБЛ).С точки зрения химического строения и функци ональных особенностей принято выделять 11 типов ФДЭ [1]. ФДЭ 4, 7 и 8 го типов катализируют рас щепление цАМФ до АМФ. ФДЭ 5, 6 и 9 го типов отвечают за расщепление цГМФ. ФДЭ 1-3 го и 10-11 го типов взаимодействуют как с цАМФ, так и с цГМФ. Распределение отдельных типов ФДЭ в органах и тканях существенно отличаются. При этом в одних и тех же клетках всегда присутствуют ФДЭ различных типов.Препараты, способные ингибировать активность ФДЭ, могут отличаться селективностью к опреде ленному типу фермента (выделяют селективные ин гибиторы ФДЭ3, ФДЭ4 и ФДЭ5) или ингибировать любой тип ФДЭ (теофиллин). Фармакологические свойства селективных ингибиторов ФДЭ существен но различаются в зависимости от типа ФДЭ, с кото рым способен взаимодействовать препарат [2].Например, селективный ингибитор ФДЭ3 мил ринон обладает выраженным инотропным действи ем и применяется для лечения острой сердечной недостаточности. Ингибиторы ФДЭ4 оказывают положительное вл...

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Magnesium Hydroxide/Aluminium Hydroxide‐Containing Antacid Does Not Affect the Pharmacokinetics of the Targeted Phosphodiesterase 4 Inhibitor Roflumilast

Cited by 17 publications

References 26 publications

No Dose Adjustment on Coadministration of the PDE4 Inhibitor Roflumilast With a Weak CYP3A, CYP1A2, and CYP2C19 Inhibitor: An Investigation Using Cimetidine

No Dose Adjustment on Coadministration of the PDE4 Inhibitor Roflumilast With a Weak CYP3A, CYP1A2, and CYP2C19 Inhibitor: An Investigation Using Cimetidine

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

Clinical pharmacology of roflumilast

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