Cancer Chemotherapy Center, Osaka Medical College Hospital, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.
Second Department of Internal Medicine, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.
Asian Pac J Cancer Prev. 2021 Mar 1;22(3):871-877. doi: 10.31557/APJCP.2021.22.3.871.
Fosaprepitant, an NK1 receptor antagonist, inhibits and induces cytochrome P450 3A4 (CYP3A4) as its substrate. Contrarily dexamethasone is metabolized by CYP3A4. Therefore, in combination therapy wherein both agents interact with each other, it is recommended that the dexamethasone dose be reduced in the first two days. Thus far, there are only a few studies on the optimum dose of dexamethasone after day 3. Thus, we aimed to determine the pharmacokinetics of dexamethasone on day3 when administered together with fosaprepitant and investigate the dose-dependent differences in its antiemetic effect in patients with cancer.
Twelve patients with esophageal, stomach, or lung cancer received primary highly emetogenic chemotherapy (HEC). We intravenously administered 9.9 mg and 6.6 mg of dexamethasone on days 1 and 2, respectively, and 6.6 mg or 13.2 mg on day 3 together with the administration of 150 mg fosaprepitant and 0.75 mg palonosetron. We assessed the pharmacokinetics of dexamethasone on day 3 by dose and examined the dose-dependent antiemetic effect.
No differences were observed in the time-to-maximum concentration and blood half-life of dexamethasone between patient groups that received dexamethasone at doses of 6.6 mg and 13.2 mg. In contrast, the area under the blood concentration-time curve and the maximum concentration of dexamethasone correlated with its dose. Moreover, the blood dexamethasone concentration on day 3 increased by twofold after the administration of a higher dose than after a lower dose. The severity of nausea in the delayed phase significantly decreased in a dose-dependent manner.
Administration of a higher dexamethasone dose on day 3 improved the antiemetic effect of the combined regimen in patients with cancer who underwent HEC.
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福沙匹坦是一种 NK1 受体拮抗剂，作为其底物，可抑制并诱导细胞色素 P4503A4（CYP3A4）。相反，地塞米松是由 CYP3A4 代谢的。因此，在联合治疗中，如果两种药物相互作用，建议在前两天减少地塞米松剂量。到目前为止，关于第 3 天后地塞米松的最佳剂量只有少数研究。因此，我们旨在确定福沙匹坦联合使用时第 3 天地塞米松的药代动力学，并研究其在癌症患者中的止吐作用的剂量依赖性差异。
12 名患有食管癌、胃癌或肺癌的患者接受了原发性高度致吐化疗（HEC）。我们分别在第 1 天和第 2 天静脉注射 9.9 毫克和 6.6 毫克地塞米松，在第 3 天同时给予 150 毫克福沙匹坦和 0.75 毫克帕洛诺司琼时，给予 6.6 毫克或 13.2 毫克地塞米松。我们通过剂量评估第 3 天地塞米松的药代动力学，并检查剂量依赖性止吐作用。
接受 6.6 毫克和 13.2 毫克地塞米松剂量的患者组之间，地塞米松的达峰时间和血半衰期无差异。相比之下，地塞米松的血药浓度-时间曲线下面积和最大浓度与剂量相关。此外，与低剂量相比，高剂量给药后第 3 天的血地塞米松浓度增加了一倍。迟发性恶心的严重程度呈剂量依赖性显著降低。
在接受 HEC 的癌症患者中，第 3 天给予较高剂量的地塞米松可改善联合方案的止吐效果。
