Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours.
Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours.
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DOI：
10.1007/s00280-016-3106-7
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发表时间：
2016-09
影响因子：
3
通讯作者：
Takahashi, Yasuo
中科院分区：
文献类型：
--
作者：
Yonemori, Kan;Tamura, Kenji;Kodaira, Makoto;Fujikawa, Koshi;Sagawa, Tamotsu;Esaki, Taito;Shirakawa, Tsuyoshi;Hirai, Fumihiko;Yokoi, Yuki;Kawata, Toshio;Hatano, Ben;Takahashi, Yasuo
这是评估口服聚(腺苷二磷酸核糖)聚合酶抑制剂olaparib(Lynparza™)片剂对日本晚期实体肿瘤患者的安全性和耐受性的第一阶段研究。对奥拉帕利片的药代动力学和抗肿瘤活性进行了评价。在这项开放的多中心研究(D081BC00001；NCT01813474)中，在第1天单次服用奥拉帕利布(200或300 mg片剂)，48小时后多次服用(200或300 mg，每天两次[BID])，共28天。剂量在连续的队列中升级，扩展队列登记的最高剂量在剂量升级期间被确认为可耐受的。28例患者入选，23例接受治疗(分别为200、300和300 mg BID，n=4、7和12)。没有患者经历剂量限制性毒性，因此最大耐受剂量没有定义。最常见的不良事件是恶心(43.5%)、食欲下降(30.4%)、贫血(26.1%)和便秘(26.1%)。没有患者剂量减少，两名患者剂量中断，两名患者因不良事件而停止治疗。奥拉帕利在单次和多次给药后吸收迅速，单次给药后血药浓度呈双相下降。没有患者有确认的抗肿瘤反应。对于患有晚期实体肿瘤的日本患者，200和300 mg的奥拉帕利片剂量被认为是可以耐受的。与全球olaparib计划一致，300 mg Bid被选为未来研究的推荐片剂剂量。NCT01813474。
This was the first Phase I study to assess the safety and tolerability of the tablet formulation of olaparib (Lynparza™), an oral poly(ADP-ribose) polymerase inhibitor, in Japanese patients with advanced solid tumours. The pharmacokinetic profile and antitumour activity of olaparib tablets were also assessed. In this open-label, multicentre study (D081BC00001; NCT01813474), a single dose of olaparib (200 or 300 mg, tablets) was administered on day 1, followed 48 h afterwards by multiple dosing (200 or 300 mg twice daily [bid]) for 28-day cycles. Doses were escalated in successive cohorts, with an expansion cohort enrolled at the highest dose that was confirmed to be tolerable during dose escalation. Twenty-eight patients were enrolled and 23 were treated (n = 4, 7 and 12 at 200, 300 and 300 [expansion] mg bid, respectively). No patients experienced a dose-limiting toxicity, so the maximum tolerated dose was not defined. The most frequent adverse events were nausea (43.5 %), decreased appetite (30.4 %), anaemia (26.1 %) and constipation (26.1 %). No patient had dose reductions, two had dose interruptions, and two discontinued treatment because of adverse events. Absorption of olaparib was rapid following single and multiple dosing, and plasma concentrations declined biphasically after single dosing. No patients had a confirmed antitumour response. Olaparib tablet doses of 200 and 300 mg bid were considered tolerable in Japanese patients with advanced solid tumours. Consistent with the global olaparib programme, 300 mg bid was selected as the recommended tablet dose for future studies. NCT01813474.
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DOI：
10.1073/pnas.0806092105
发表时间：
2008-11-04
影响因子：
11.1
作者：
Rottenberg, Sven;Jaspers, Janneke E.;Jonkers, Jos
通讯作者：
Jonkers, Jos
影响因子：
11.5
作者：
Evers, Bastiaan;Drost, Rinske;Jonkers, Jos
通讯作者：
Jonkers, Jos
影响因子：
168.9
作者：
Audeh, M. William;Carmichael, James;Tutt, Andrew
通讯作者：
Tutt, Andrew
影响因子：
51.1
作者：
Ledermann, Jonathan;Harter, Philipp;Matulonis, Ursula
通讯作者：
Matulonis, Ursula
影响因子：
168.9
作者：
Tutt, Andrew;Robson, Mark;Carmichael, James
通讯作者：
Carmichael, James