An Adaptive Study to Determine the Optimal Dose of the Tablet Formulation of the PARP Inhibitor Olaparib
An Adaptive Study to Determine the Optimal Dose of the Tablet Formulation of the PARP Inhibitor Olaparib
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DOI：
10.1007/s11523-016-0435-8
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发表时间：
2016-06-01
影响因子：
5.4
通讯作者：
Molife, L. R.
中科院分区：
文献类型：
--
作者：
Mateo, J.;Moreno, V.;Molife, L. R.
奥拉帕尼是难溶性的，需要先进的药物输送技术才能获得充分的生物利用度。批准的每日两次400毫克剂量需要16粒胶囊/天；为减轻药片负担，研制了片剂配方。本临床试验评估了片剂配方的最佳剂量和给药计划。顺序入组的两个阶段：第一阶段，比较片剂和胶囊制剂在晚期实体肿瘤患者中的药代动力学特性；第二阶段，在实体瘤和BRCAm乳腺癌/卵巢癌患者中，以感兴趣的剂量/时间表扩大片剂剂量递增队列。奥拉帕尼200 mg片的C-max、C-ss与400 mg片相似，但AUC（ss）和C-min、C-ss较低。在多次给药后，每千分之一剂量的片剂（300毫克）的稳态暴露与400毫克胶囊的剂量相当或超过。剂量增加后，基于血液学毒性，400 mg每日两次是片剂的最大耐受剂量，65%的随机扩展期患者最终需要剂量减少到300 mg。间歇性给药对耐受性没有显著改善。300和400毫克片剂和400毫克胶囊组的肿瘤缩小相似。奥拉帕尼片在III期临床试验中的推荐单药剂量为300mg，每日2次，将给药从16粒胶囊简化为每天4粒。NCT00777582 (ClinicalTrials.gov)。
Olaparib is poorly soluble, requiring advanced drug delivery technologies for adequate bioavailability. Sixteen capsules/day are required for the approved 400 mg twice-daily dose; a tablet formulation was developed to reduce pill burden. This clinical trial evaluated the optimal dose and administration schedule of the tablet formulation.Two stages of sequentially enrolled cohorts: stage 1, pharmacokinetic properties of tablet and capsule formulations were compared in patients with advanced solid tumours; stage 2, tablet dose escalation with expansion cohorts at doses/schedules of interest in patients with solid tumours and BRCAm breast/ovarian cancers.Olaparib 200 mg tablets displayed similar C-max,C-ss, but lower AUC(ss) and C-min,C-ss than 400 mg capsules. Following multiple dosing, steady-state exposure with tablets a parts per thousand yen300 mg matched or exceeded that of 400 mg capsules. After dose escalation, while 400 mg twice daily was the tablet maximum tolerated dose based on haematological toxicity, 65 % of patients in the randomized expansion phase eventually required dose reduction to 300 mg. Intermittent tablet administration did not significantly improve tolerability. Tumour shrinkage was similar for 300 and 400 mg tablet and 400 mg capsule cohorts.The recommended monotherapy dose of olaparib tablet for Phase III trials was 300 mg twice daily, simplifying drug administration from 16 capsules to four tablets per day.NCT00777582 (ClinicalTrials.gov).