PMID- 29797235 OWN - NLM STAT- MEDLINE DCOM- 20191018 LR - 20240328 IS - 1179-1926 (Electronic) IS - 0312-5963 (Print) IS - 0312-5963 (Linking) VI - 57 IP - 8 DP - 2018 Aug TI - Pharmacokinetic and Pharmacodynamic Modelling to Characterize the Tolerability of Alternative Up-Titration Regimens of Roflumilast in Patients with Chronic Obstructive Pulmonary Disease. PG - 1029-1038 LID - 10.1007/s40262-018-0671-4 [doi] AB - BACKGROUND: In the OPTIMIZE study, 4 weeks of roflumilast 250 microg once daily before escalation to the approved 500 microg 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. METHODS: OPTIMIZE was a multicentre, double-blind, phase III study in which patients with severe COPD were randomized 1:1:1 to receive oral roflumilast 250 mug once daily, 500 mug every other day, or 500 mug once daily for 4 weeks, followed by 500 mug 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). RESULTS: The 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 x 10(-5)). PK/time-to-event model analysis predicted that patients receiving the 250 mug up-titration regimen had significantly lower discontinuation rates and longer time to discontinuation compared with roflumilast 500 mug every other day or 500 mug once daily (p = 0.0014). CONCLUSIONS: In this PK/PD model, a 4-week up-titration regimen with roflumilast 250 microg 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 microg as maintenance dose. TRIAL REGISTRATION: OPTIMIZE: NCT02165826; REACT: NCT01329029. FAU - Facius, Axel AU - Facius A AD - thinkQ2 AG, Oberneuhofstr. 5, 6340, Baar, Switzerland. axel.facius@thinkq2.com. FAU - Marostica, Eleonora AU - Marostica E AD - LAP&P Consultants BV, Archimedesweg 31, 2333 CM, Leiden, The Netherlands. FAU - Gardiner, Philip AU - Gardiner P AD - RIA QCP, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden. FAU - Watz, Henrik AU - Watz H AD - Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Pulmonary Research Institute at Lung Clinic Grosshansdorf, Grosshansdorf, Germany. FAU - Lahu, Gezim AU - Lahu G AD - thinkQ2 AG, Oberneuhofstr. 5, 6340, Baar, Switzerland. LA - eng SI - ClinicalTrials.gov/NCT02165826 SI - ClinicalTrials.gov/NCT01329029 PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - Switzerland TA - Clin Pharmacokinet JT - Clinical pharmacokinetics JID - 7606849 RN - 0 (Aminopyridines) RN - 0 (Benzamides) RN - 0 (Cyclopropanes) RN - 0 (Phosphodiesterase 4 Inhibitors) RN - 0P6C6ZOP5U (Roflumilast) SB - IM MH - Aminopyridines/*administration & dosage/*pharmacokinetics/therapeutic use MH - Benzamides/*administration & dosage/*pharmacokinetics/therapeutic use MH - Cyclopropanes/administration & dosage/pharmacokinetics/therapeutic use MH - Double-Blind Method MH - Drug Monitoring MH - *Drug Tolerance MH - Humans MH - *Models, Biological MH - Phosphodiesterase 4 Inhibitors/*administration & dosage/*pharmacokinetics/therapeutic use MH - Pulmonary Disease, Chronic Obstructive/*drug therapy PMC - PMC6028881 COIS- FUNDING: This study was funded by Takeda Pharmaceuticals International GmbH, Zurich, Switzerland; AstraZeneca, Cambridge, UK, are the current study sponsors. CONFLICT OF INTEREST: Henrik Watz has received consulting fees and payment for lectures from Takeda and AstraZeneca. He has received support for travel to meetings for the study and manuscript preparation from AstraZeneca, and provided writing assistance to AstraZeneca. Philip Gardiner is an employee of AstraZeneca. Axel Facius was employed as pharmacometrician at Takeda Pharmaceuticals, who executed the studies reported in this manuscript. He further received travel support from AstraZeneca for the ATS2017 conference, where parts of the current manuscript were presented. Gezim Lahu was employed by Takeda, who executed the studies reported in this manuscript. Eleonora Marostica was a paid consultant for Takeda. ETHICAL APPROVAL: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. INFORMED CONSENT: Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article. EDAT- 2018/05/26 06:00 MHDA- 2019/10/19 06:00 PMCR- 2018/05/25 CRDT- 2018/05/26 06:00 PHST- 2018/05/26 06:00 [pubmed] PHST- 2019/10/19 06:00 [medline] PHST- 2018/05/26 06:00 [entrez] PHST- 2018/05/25 00:00 [pmc-release] AID - 10.1007/s40262-018-0671-4 [pii] AID - 671 [pii] AID - 10.1007/s40262-018-0671-4 [doi] PST - ppublish SO - Clin Pharmacokinet. 2018 Aug;57(8):1029-1038. doi: 10.1007/s40262-018-0671-4.