Application of population pharmacokinetic modeling to explore the impact of alternative roflumilast dosing regimens on tolerability

Lahu, Gëzim; Facius, Axel

doi:10.5414/cp201906

Cited by 10 publications

(14 citation statements)

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“…In contrast to the discontinuation rates in these pivotal studies 3 , clinicians experience frequent adverse events in clinical practice. Alternative dosing strategies including dose escalation have not been clinically investigated.…”

Section: Discussionmentioning

confidence: 96%

“…However, population pharmacokinetic/pharmacodynamics modeling 3 found that an alternative dose regimen, i.e., 250 µg once daily and the approved dose (500 µg) every other day regimens had minimal impact on efficacy and may reduce the risk of related adverse effects. Similarly, the frequencies of diarrhea, nausea, and headache were about two-fold lower in patients taking 250 µg roflumilast once daily than in those taking the approved 500 µg once daily regimen 3 . In the present study, of the 53 patients who increased to 500 µg roflumilast, 38 suffered no adverse effects.…”

Section: Discussionmentioning

confidence: 99%

“…Inflammation in COPD is characterized by increased numbers of neutrophils, macrophages, and cytotoxic T cells, as well as by the presence of several inflammatory mediators, such as cytokines, chemokines, and growth factors 2 3 . The search for an anti-inflammatory treatment for COPD is now focusing on inhibitors of phosphodiesterase (PDE) 4, the major cAMP hydrolase in inflammatory cells 4 .…”

Section: Introductionmentioning

confidence: 99%

“…However, adverse events appear more frequently in clinical practice than was observed in clinical trials. The frequency and severity of gastrointestinal adverse events from roflumilast are dose-dependent 3 . Therefore, the focus of this study is to explore whether the incidence of adverse effects can be reduced by an alternative dosing regimen.…”

Section: Introductionmentioning

confidence: 99%

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Effect of a Dose-Escalation Regimen for Improving Adherence to Roflumilast in Patients with Chronic Obstructive Pulmonary Disease

et al. 2015

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BackgroundThe adverse effects of the phosphodiesterase-4 inhibitor roflumilast, appear to be more frequent in clinical practice than what was observed in chronic obstructive pulmonary disease (COPD) clinical trials. Thus, we designed this study to determine whether adverse effects could be reduced by starting roflumilast at half the dose, and then increasing a few weeks later to 500 µg daily.MethodsWe retrospectively investigated 85 patients with COPD who had taken either 500 µg roflumilast, or a starting dose of 250 µg and then increased to 500 µg. We analyzed all adverse events and assessed differences between patients who continued taking the drug after dose escalation and those who had stopped.ResultsAdverse events were reported by 22 of the 85 patients (25.9%). The most common adverse event was diarrhea (10.6%). Of the 52 patients who had increased from a starting dose of 250 µg roflumilast to 500 µg, 43 (82.7%) successfully maintained the 500 µg roflumilast dose. No difference in factors likely to affect the risk of adverse effects, was detected between the dose-escalated and the discontinued groups. Of the 26 patients who started with the 500 µg roflumilast regimen, seven (26.9%) discontinued because of adverse effects. There was no statistically significant difference in discontinuation rate between the dose-escalated and the control groups (p=0.22).ConclusionEscalating the roflumilast dose may reduce treatment-related adverse effects and improve tolerance to the full dose. This study suggests that the dose-escalated regimen reduced the rate of discontinuation. However, longer-term and larger-scale studies are needed to support the full benefit of a dose escalation strategy.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of a Dose-Escalation Regimen for Improving Adherence to Roflumilast in Patients with Chronic Obstructive Pulmonary Disease

et al. 2015

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“…These AEs, which reduced compliance to treatment, were confirmed by real-life studies 12,13 . Although the frequency and severity of AEs are dose-dependent 11 , a doseescalation regimen starting from 250 µg and then increased to 500 µg, did not significantly improve the adherence to the treatment 14,15 .…”

Section: Introductionmentioning

confidence: 94%

Drug safety evaluation of roflumilast for the treatment of COPD: a meta-analysis

Rogliani

Calzetta

Cazzola

et al. 2016

Expert Opinion on Drug Safety

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The safety profile of roflumilast administered in combination with further drugs for the treatment of COPD should be investigated through specifically designed RCTs, and the post-marketing surveillance might help to characterize the real risk of very SAEs. Roflumilast may provide more benefit than harm in patients at high risk of severe exacerbations, and the therapy discontinuation may be reduced by a correct education of patients on the generally transient and mild-to-moderate nature of gastrointestinal AEs induced by this drug.

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Pharmacokinetic and Pharmacodynamic Modelling to Characterize the Tolerability of Alternative Up-Titration Regimens of Roflumilast in Patients with Chronic Obstructive Pulmonary Disease

Facius¹,

Marostica²,

Philip

et al. 2018

Clin Pharmacokinet

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BackgroundIn the OPTIMIZE study, 4 weeks of roflumilast 250 µg once daily before escalation to the approved 500 µg once daily maintenance dose reduced treatment discontinuations and improved tolerability to roflumilast among patients with chronic obstructive pulmonary disease (COPD). In this study, we present the pharmacokinetic (PK) results and PK/pharmacodynamic (PD) modelling data from OPTIMIZE.MethodsOPTIMIZE was a multicentre, double-blind, phase III study in which patients with severe COPD were randomized 1:1:1 to receive oral roflumilast 250 μg once daily, 500 μg every other day, or 500 μg once daily for 4 weeks, followed by 500 μg once daily for 8 weeks. A population PK (popPK) model characterized roflumilast exposure levels (total phosphodiesterase-4 inhibition [tPDE4i]). Furthermore, models characterized the percentage of patients with adverse events (AEs) of interest (PK/AE model), and time to discontinuation due to such AEs (PK/time-to-event model).ResultsThe popPK model adequately described average plasma concentrations and variability from 1238 patients. The percentage of patients with AEs of interest increased with predicted tPDE4i exposure (logit scale slope 0.484; confidence interval 0.262–0.706; p = 2 × 10−5). PK/time-to-event model analysis predicted that patients receiving the 250 μg up-titration regimen had significantly lower discontinuation rates and longer time to discontinuation compared with roflumilast 500 μg every other day or 500 μg once daily (p = 0.0014).ConclusionsIn this PK/PD model, a 4-week up-titration regimen with roflumilast 250 µg once daily was found to reduce discontinuations and improve tolerability, confirming the main clinical findings of the OPTIMIZE study. However, use of this lower dose as long-term maintenance therapy may not induce sufficient phosphodiesterase-4 inhibition to exert clinical efficacy, supporting the approval of 500 µg as maintenance dose.Trial RegistrationOPTIMIZE: NCT02165826; REACT: NCT01329029.Electronic supplementary materialThe online version of this article (10.1007/s40262-018-0671-4) contains supplementary material, which is available to authorized users.

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Application of population pharmacokinetic modeling to explore the impact of alternative roflumilast dosing regimens on tolerability

Abstract: Reduction of roflumilast dose in the first few weeks of therapy may be able to reduce the incidence of treatment-related AEs. Clearly, modeling provides only the basis for hypothesis generation, and must be supported with clinical evidence from carefully designed trials.

Cited by 10 publications

References 0 publications

Effect of a Dose-Escalation Regimen for Improving Adherence to Roflumilast in Patients with Chronic Obstructive Pulmonary Disease

Effect of a Dose-Escalation Regimen for Improving Adherence to Roflumilast in Patients with Chronic Obstructive Pulmonary Disease

Drug safety evaluation of roflumilast for the treatment of COPD: a meta-analysis

Pharmacokinetic and Pharmacodynamic Modelling to Characterize the Tolerability of Alternative Up-Titration Regimens of Roflumilast in Patients with Chronic Obstructive Pulmonary Disease

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