Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands.
Br J Clin Pharmacol. 2019 May;85(5):986-992. doi: 10.1111/bcp.13889. Epub 2019 Mar 21.
Docetaxel has been approved for the treatment of metastatic prostate cancer in combination with prednisone. Since prednisone is known to induce the cytochrome P450 iso-enzyme CYP3A4, which is the main metabolizing enzyme of docetaxel in the liver, a potential drug-drug interaction may occur. In this prospective randomized pharmacokinetic cross-over study we investigated docetaxel exposure with concomitant prednisone, compared to docetaxel monotherapy in men with metastatic prostate cancer.
Patients scheduled to receive at least 6 cycles of docetaxel (75 mg/m ) and who gave written informed consent were randomized to receive either the 1 3 cycles, or the last 3 consecutive cycles with prednisone (twice daily 5 mg). Pharmacokinetic blood sampling was performed during cycle 3 and cycle 6. Primary endpoint was difference in docetaxel exposure, calculated as area under the curve (AUC ) and analysed by means of a linear mixed model. Given the cross-over design the study was powered on 18 patients to answer the primary, pharmacokinetic, endpoint.
Eighteen evaluable patients were included in the trial. Docetaxel concentration with concomitant prednisone (AUC 2784 ngh/mL, 95% confidence interval 2436-3183 ngh/mL) was similar to the concentration of docetaxel monotherapy (AUC 2647 ngh/mL, 95% confidence interval 2377-2949 ngh/mL). Exploratory analysis showed no toxicity differences between docetaxel monotherapy and docetaxel cycles with prednisone.
No significant difference in docetaxel concentrations was observed. In addition, we found similar toxicity profiles in absence and presence of prednisone. Therefore, from a pharmacokinetic point of view, docetaxel may be administrated with or without prednisone.
多西他赛已被批准与泼尼松联合用于治疗转移性前列腺癌。由于泼尼松已知可诱导细胞色素 P450 同工酶 CYP3A4，而 CYP3A4 是肝脏中多西他赛的主要代谢酶，因此可能会发生药物相互作用。在这项前瞻性随机药代动力学交叉研究中，我们研究了转移性前列腺癌男性患者同时使用泼尼松和单独使用多西他赛时多西他赛的暴露情况。
计划接受至少 6 个周期 75mg/m 的多西他赛治疗且签署书面知情同意书的患者被随机分为接受前 3 个周期或最后 3 个连续周期的泼尼松（每日 2 次，每次 5mg）治疗。在第 3 周期和第 6 周期进行药代动力学血样采集。主要终点是多西他赛暴露的差异，通过曲线下面积（AUC）计算，并通过线性混合模型进行分析。由于交叉设计，该研究在 18 名患者中进行了功效评估，以回答主要的药代动力学终点问题。
18 名可评估患者纳入了该试验。同时使用泼尼松的多西他赛浓度（AUC 2784ngh/mL，95%置信区间 2436-3183ngh/mL）与单独使用多西他赛的浓度（AUC 2647ngh/mL，95%置信区间 2377-2949ngh/mL）相似。探索性分析表明，多西他赛单独治疗和多西他赛联合泼尼松治疗周期之间没有毒性差异。
未观察到多西他赛浓度有显著差异。此外，我们发现泼尼松存在和不存在时的毒性谱相似。因此，从药代动力学角度来看，多西他赛可与或不与泼尼松联合使用。
