Population Pharmacokinetic Modelling of Roflumilast and Roflumilast N-Oxide by Total Phosphodiesterase-4 Inhibitory Activity and Development of a Population Pharmacodynamic-Adverse Event Model

Lahu, Gëzim; Hünnemeyer, Andreas; Diletti, E; Elmlinger, Martin W.; Ruth, Peter; Zech, K.; McCracken, Nigel W.; Facius, Axel

doi:10.2165/11536600-000000000-00000

Cited by 31 publications

(64 citation statements)

References 43 publications

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“…Furthermore, the modelling results suggest that PDE4 inhibitors carry the potential to keep HbA 1c at starting levels in db/db mice based on the estimated EMAX of 1. As the estimated PDE 50 of 27.1 in db/db mice is approximately 27-fold higher than the tPDE4i of 1.03 in humans at the effective dose of 500 μg [30], db/db mice seem to require higher exposures for efficacy than humans. This should be considered in the translation of results from mice to humans.…”

Section: Discussionmentioning

confidence: 88%

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

Vollert

Kaessner²,

Heuser

et al. 2012

Diabetologia

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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.

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Section: Discussionmentioning

confidence: 88%

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

Vollert

Kaessner²,

Heuser

et al. 2012

Diabetologia

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“…28). A thorough analysis of the pharmacokinetics of these two and their variability, as they relate to contribution to activity, has been done (Lahu et al, 2010). In this analysis the following equation was used:…”

Section: Procainamidementioning

confidence: 99%

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Obach

2013

Pharmacol Rev

138

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“…This approach might carry the advantage of being able to discriminate between different shapes of PK profiles and their effect on PD end points. However, it has been demonstrated that tPDE4i is a suitable measure to describe the relation between exposure and PD effect 12. Consequently, for this early development project, the model simplification via AUC and tPDE4i was considered to be sufficient to obtain an estimate of human efficacious dose.…”

Section: Discussionmentioning

confidence: 99%

“…Practically, the PDE 50 values obtained from the PK/PD model were linked via the tPDE4i value of 1.03 calculated for the clinically effective roflumilast dose of 500 μg12 to determine the required tPDE4i value of TAK‐648 in humans, using the following equation:

\begin{matrix} true \\ left required tPDE 4 i_{TAK - 648, human} \\ left = \frac{PDE 5 0_{TAK - 648, mouse} \cdot tPDE 4 i_{roflumilast + roflumilast - normalN - oxide, human}}{PDE 5 0_{roflumilast + roflumilast - normalN - oxide, mouse}} \end{matrix}

…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Modeling of the PDE4 Inhibitor TAK‐648 in Type 2 Diabetes: Early Translational Approaches for Human Dose Prediction

Plock

Vollert²,

Mayer

et al. 2017

Clinical Translational Sci

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TAK‐648 is a PDE4 inhibitor with demonstrated preclinical antidiabetic properties. Our objective was to develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for human type 2 diabetes (T2D) dose prediction using HbA1c results from a db/db mouse study. Estimated parameters in combination with tPDE4i values calculated for the clinical roflumilast dose of 500 μg were used to translate preclinical effects of TAK‐648 to required exposure in humans. A first‐in‐human study with single TAK‐648 doses of 0.05–0.85 mg in healthy volunteers yielded mean maximum TAK‐648 concentrations (Cmax) and area under the curve (AUC) values from 0.62–11.9 μg/L and 4.58–93.8 μg*h/L, respectively. Based on the performed pharmacokinetic/pharmacodynamic analysis and clinical PK results, clinical efficacy would be expected at a daily dose of 0.1 mg, which is well within the investigated clinical dose range. This result significantly enhanced the confidence in TAK‐648 for type 2 diabetes treatment and underlines the necessity of translational approaches in early preclinical phases.

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Population Pharmacokinetic Modelling of Roflumilast and Roflumilast N-Oxide by Total Phosphodiesterase-4 Inhibitory Activity and Development of a Population Pharmacodynamic-Adverse Event Model

Abstract: Covariate effects have a limited impact on tPDE4i. There was a general association between tPDE4i and the occurrence of common AEs in patients with COPD.

Cited by 31 publications

References 43 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

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Pharmacokinetic/Pharmacodynamic Modeling of the PDE4 Inhibitor TAK‐648 in Type 2 Diabetes: Early Translational Approaches for Human Dose Prediction

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