Introduction

ModraDoc006 is a novel docetaxel tablet formulation that is co-administrated with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r.

Objectives

This study evaluated the effect of food consumed prior to administration of ModraDoc006/r on the pharmacokinetics of docetaxel and ritonavir.

Methods

Patients with advanced solid tumours were enrolled in this randomized crossover study to receive ModraDoc006/r in a fasted state in week 1 and after a standardized high-fat meal in week 2 and vice versa. Pharmacokinetic sampling was conducted until 48 h after both study drug administrations. Docetaxel and ritonavir plasma concentrations were determined using liquid chromatography with tandem mass spectrometry. Safety was evaluated with the Common Terminology Criteria for Adverse Events, version 4.03.

Results

In total, 16 patients completed the food-effect study. The geometric mean ratio (GMR) for the docetaxel area under the plasma concentration–time curve (AUC)_0–48, AUC_0–inf and maximum concentration (C_max) were 1.11 (90% confidence interval [CI] 0.93–1.33), 1.19 (90% CI 1.00–1.41) and 1.07 (90% CI 0.81–1.42) in fed versus fasted conditions, respectively. For the ritonavir C_max, the GMR was 0.79 (90% CI 0.69–0.90), whereas the AUC_0–48 and AUC_0–inf were bioequivalent. The most frequent treatment-related toxicities were grade ≤ 2 diarrhoea and fatigue. Hypokalaemia was the only observed treatment-related grade 3 toxicity.

Conclusions

The docetaxel and ritonavir exposure were not bioequivalent, as consumption of a high-fat meal prior to administration of ModraDoc006/r resulted in a slightly higher docetaxel exposure and lower ritonavir C_max. Since docetaxel exposure is the only clinically relevant parameter in our patient population, the overall conclusion is that combined ModraDoc006 and ritonavir treatment may be slightly affected by concomitant intake of a high-fat meal. In view of the small effect, it is most likely that the intake of a light meal will not affect the systemic exposure to docetaxel.

ClinicalTrials.gov Identifier

NCT03147378, date of registration: May 10 2017.

中文翻译：

---

食物对晚期实体瘤患者口服多西他赛片ModraDoc006联合利托那韦（ModraDoc006 / r）的药代动力学的影响

介绍

ModraDoc006是一种新型多西他赛片剂，与细胞色素P450 3A4和P-糖蛋白抑制剂ritonavir（r）：ModraDoc006 / r共同给药。

目标

这项研究评估了在服用ModraDoc006 / r之前食用的食物对多西他赛和利托那韦的药代动力学的影响。

方法

患有晚期实体瘤的患者参加了这项随机交叉研究，以在第1周以禁食状态接受ModraDoc006 / r，并在第2周以标准高脂餐后接受，反之亦然。两次研究药物给药后均进行药代动力学采样直至48小时。使用液相色谱-串联质谱法测定多西他赛和利托那韦的血浆浓度。使用“不良事件通用术语标准” 4.03版对安全性进行了评估。

结果

总共有16位患者完成了食物效果研究。血浆浓度-时间曲线（AUC）_0-48，AUC _0-inf和最大浓度（C _max）下多西紫杉醇区域的几何平均比（GMR）为1.11（90％置信区间[CI] 0.93-1.33）进食与禁食相比，分别为1.19（90％CI 1.00–1.41）和1.07（90％CI 0.81–1.42）。对于利托那韦C _max，其GMR为0.79（90％CI为0.69-0.90），而AUC _0-48和AUC _0-inf具有生物等效性。与治疗相关的最常见毒性为2级腹泻和疲劳。低钾血症是唯一观察到的与治疗有关的3级毒性。

结论

多西紫杉醇和利托那韦的暴露量没有生物等效性，因为在施用ModraDoc006 / r之前食用高脂膳食会导致多西他赛的暴露量稍高，而利托那韦的C _max较低。由于多西他赛暴露是我们患者人群中唯一的临床相关参数，因此总体结论是，同时摄入高脂膳食可能会稍微影响ModraDoc006和利托那韦的联合治疗。鉴于影响很小，便餐的摄入很可能不会影响多西他赛的全身暴露。

ClinicalTrials.gov标识符

NCT03147378，注册日期：2017年5月10日。