Malhi Vikram, Budha Nageshwar, Sane Rucha, Huang Jian, Liederer Bianca, Meng Raymond, Patel Premal, Deng Yuzhong, Cervantes Andres, Tabernero Josep, Musib Luna
Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA.
Clinical Pharmacology, BeiGene, San Mateo, CA, USA.
Cancer Chemother Pharmacol. 2021 Dec;88(6):921-930. doi: 10.1007/s00280-021-04344-9. Epub 2021 Sep 1.
To examine the single- and multiple-dose pharmacokinetics (PK), CYP3A inhibition potential of ipatasertib, and effect of food on PK of ipatasertib in patients with refractory solid tumors and a dedicated food effect assessment in healthy subjects.
The Phase I dose-escalation study enrolled patients with solid tumors in a standard 3 + 3 design with a 1 week washout after the first dose, followed by once-daily dosing on a 3-week-on/1-week-off schedule. In the expansion cohort, the effect of ipatasertib on CYP3A substrate (midazolam) was assessed by examining the change in midazolam exposure when dosed in the absence and presence of steady-state ipatasertib at 600 mg. The effect of food on ipatasertib PK was studied with ipatasertib administered in fed or fasted state (6 patients from Phase I patient study and 18 healthy subjects from the dedicated food effect study).
Ipatasertib was generally well tolerated at doses up to 600 mg given daily for 21 days. Ipatasertib showed rapid absorption (t, 0.5-3 h), was dose-proportional over a range of 200-800 mg, had a median half-life (range) of 45.0 h (27.8-66.9 h), and had approximately two-fold accumulation following once-daily dosing. Midazolam exposure (AUC) increased by 2.2-fold in the presence of ipatasertib. PK was comparable in subjects administered ipatasertib in a fed or fasted state.
Ipatasertib exhibited rapid absorption and was dose-proportional over a broad dose range. Ipatasertib appeared to be a moderate CYP3A inhibitor when administered at 600 mg and could be administered with or without food in clinical studies.
NCT01090960 (registered March 23, 2010); NCT02536391 (registered August 31, 2015).
研究ipatasertib在难治性实体瘤患者中的单剂量和多剂量药代动力学（PK）、CYP3A抑制潜力，以及食物对ipatasertib药代动力学的影响，并在健康受试者中进行专门的食物效应评估。
I期剂量递增研究采用标准的3+3设计招募实体瘤患者，首剂后有1周的洗脱期，随后按3周用药/1周停药的方案每日给药一次。在扩展队列中，通过检测在不存在和存在稳态600 mg ipatasertib时给予咪达唑仑后咪达唑仑暴露量的变化，评估ipatasertib对CYP3A底物（咪达唑仑）的影响。在进食或禁食状态下给予ipatasertib，研究食物对ipatasertib药代动力学的影响（来自I期患者研究的6例患者和来自专门食物效应研究的18例健康受试者）。
ipatasertib每日剂量达600 mg，持续给药21天，一般耐受性良好。Ipatasertib吸收迅速（t，0.5 - 3小时），在200 - 800 mg范围内呈剂量正比关系，中位半衰期（范围）为45.0小时（27.8 - 66.9小时），每日给药一次后有大约两倍的蓄积。在存在ipatasertib的情况下，咪达唑仑暴露量（AUC）增加了2.2倍。在进食或禁食状态下给予ipatasertib的受试者中，药代动力学具有可比性。
Ipatasertib吸收迅速，在较宽的剂量范围内呈剂量正比关系。当给予600 mg时，ipatasertib似乎是一种中度CYP3A抑制剂，在临床研究中给药时可与食物同服或空腹服用。
NCT01090960（2010年3月23日注册）；NCT02536391（2015年8月31日注册）。
