目的:Adavosertib可能改变对细胞色素P450(CYP)家族酶底物的暴露。这项研究评估了其对CYP3A(咪达唑仑)探针底物混合物的药代动力学的影响,CYP2C19(奥美拉唑),和CYP1A2(咖啡因)。
方法:第1期:局部晚期或转移性实体瘤患者接受“鸡尾酒”:咖啡因200毫克,奥美拉唑20毫克,和咪达唑仑2毫克(单剂量);第2期:在7至14天的冲洗后,患者在第1-3天(五剂)每天两次接受adavosertib225mg,在第三天喝鸡尾酒。在单独使用鸡尾酒或与adavosertib联合使用后,对探针底物及其各自的代谢物黄嘌呤进行24小时药代动力学采样,5-羟基奥美拉唑(5-HO),和1'-羟基咪唑安定(1'-HM)。在整个过程中对安全性进行了评估。
结果:在33名患者中(中位年龄60.0岁,范围41-83)接收鸡尾酒,30人收到adavosertib。Adavosertib联合给药增加了咖啡因,奥美拉唑,咪达唑仑暴露量为49%,80%,和55%(AUC0-12),AUC0-t分别增加61%,98%,和55%。最大血浆药物浓度(Cmax)增加4%,46%,39%。Adavosertib联合给药使5-HO和1'-HM暴露增加了43%和54%(AUC0-12)和49%和58%(AUC0-t),分别;黄嘌呤暴露量不变。Adavosertib联合给药可将对黄嘌呤和5-HO的Cmax降低19%和7%;1'-HM的Cmax增加33%。收到adavosertib后,19例(63%)患者出现治疗相关不良事件(6例[20%]≥3级)。
结论:Adavosertib(225mgbid)是CYP1A2、CYP2C19和CYP3A的弱抑制剂。
结果:GOV:NCT03333824。
Adavosertib may alter exposure to substrates of the cytochrome P450 (CYP) family of enzymes. This
study assessed its effect on the pharmacokinetics of a cocktail of probe substrates for
CYP3A (midazolam), CYP2C19 (omeprazole), and CYP1A2 (caffeine).
Period 1: patients with locally advanced or metastatic solid tumors received \'cocktail\': caffeine 200 mg, omeprazole 20 mg, and midazolam 2 mg (single dose); period 2: after 7- to 14-day washout, patients received adavosertib 225 mg twice daily on days 1-3 (five doses), with cocktail on day 3. After cocktail alone or in combination with adavosertib administration, 24-h pharmacokinetic sampling occurred for probe substrates and their respective metabolites paraxanthine, 5-hydroxyomeprazole (5-HO), and 1\'-hydroxymidazolam (1\'-HM). Safety was assessed throughout.
Of 33 patients (median age 60.0 years, range 41-83) receiving cocktail, 30 received adavosertib. Adavosertib co-administration increased caffeine, omeprazole, and midazolam exposure by 49%, 80%, and 55% (AUC0-12), respectively; AUC0-t increased by 61%, 98%, and 55%. Maximum plasma drug concentration (Cmax) increased by 4%, 46%, and 39%. Adavosertib co-administration increased 5-HO and 1\'-HM exposure by 43% and 54% (AUC0-12) and 49% and 58% (AUC0-t), respectively; paraxanthine exposure was unchanged. Adavosertib co-administration decreased Cmax for paraxanthine and 5-HO by 19% and 7%; Cmax increased by 33% for 1\'-HM. After receiving adavosertib, 19 (63%) patients had treatment-related adverse events (six [20%] grade ≥ 3).
Adavosertib (225 mg bid) is a weak inhibitor of CYP1A2, CYP2C19, and
CYP3A.
GOV: NCT03333824.