thinkQ2 AG, Oberneuhofstr. 5, 6340, Baar, Switzerland.
LAP&P Consultants BV, Archimedesweg 31, 2333 CM, Leiden, The Netherlands.
Clin Pharmacokinet. 2018 Aug;57(8):1029-1038. doi: 10.1007/s40262-018-0671-4.
In 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.
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 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).
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 × 10). 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).
In 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.
OPTIMIZE: NCT02165826; REACT: NCT01329029.
在 OPTIMIZE 研究中，4 周的罗氟司特 250μg 每日一次递增至批准的 500μg 每日一次维持剂量可减少治疗中断，并提高慢性阻塞性肺疾病（COPD）患者对罗氟司特的耐受性。在这项研究中，我们呈现 OPTIMIZE 的药代动力学（PK）结果和 PK/药效学（PD）建模数据。
OPTIMIZE 是一项多中心、双盲、III 期研究，将严重 COPD 患者以 1:1:1 的比例随机分配，分别接受口服罗氟司特 250μg 每日一次、500μg 每两天一次或 500μg 每日一次，共 4 周，然后再接受 500μg 每日一次，共 8 周。一个群体 PK（popPK）模型描述了罗氟司特的暴露水平（总磷酸二酯酶-4 抑制 [tPDE4i]）。此外，模型还描述了具有不良事件（AE）的患者比例（PK/AE 模型）和因 AE 而停药的时间（PK/时间至事件模型）。
popPK 模型充分描述了 1238 名患者的平均血浆浓度和变异性。具有 AE 患者的比例随着预测的 tPDE4i 暴露增加而增加（logit 尺度斜率 0.484；置信区间 0.262-0.706；p=2×10）。PK/时间至事件模型分析预测，接受 250μg 递增方案的患者与罗氟司特 500μg 每两天一次或 500μg 每日一次相比，停药率显著降低，停药时间延长（p=0.0014）。
在这个 PK/PD 模型中，发现罗氟司特 250μg 每日一次递增方案 4 周可减少停药，并提高耐受性，证实了 OPTIMIZE 研究的主要临床发现。然而，使用这种较低剂量作为长期维持治疗可能无法诱导足够的磷酸二酯酶-4 抑制以发挥临床疗效，支持批准 500μg 作为维持剂量。
OPTIMIZE：NCT02165826；REACT：NCT01329029。
