Speaker: Wun -Han Huang Date : 2012. 06. 19

1. Preclinical Pharmacokinetic and Pharmacodynamic Evaluation of Novel Anticancer Agents, ON01910.Na and ON013105, for Brain Tumor Chemotherapy Speaker: Wun-Han Huang Date: 2012. 06. 19

2. Brain Tumor-Gliomas • Malignant gliomas are the most lethal cancers that originate in the central nervous system. • Brain glioma can cause headaches, nausea and vomiting, seizures, and cranial nerve disorders as a result of increased intracranial pressure. • Despite standard medical interventions of surgery and intensive use of radiation and chemotherapy, the median survival is 12–15 months for patients.

3. ON01910.Na • Asynthetic low molecular-weight drug (473.47 Da) belonging to the class of benzyl styrylsulfones. • It pharmacological activity is attributed to the free acid. • It is a non-ATP competitive compound and is under evaluation as an anticancer agent. • Having completed a Phase I trial , ON01910.Na is currently in Phase II clinical trials

4. ON01910 inhibits mitotic progression by arresting cells at the G2/M phase of the cell cycle leading to selective apoptosis in tumor cells, but not in normal cells. • ON01910 was reported to interfere with cell signaling, wherein it was shown to downregulatecyclin D1 by suppressing cyclin D1 mRNA translation and induced apoptosis via the mitochondrial pathway by inhibition of the PI3K/Akt/mTOR pathway.

5. Complete regression of tumor growth and angiogenesis was also observed in mice bearing intracranial SNB19 human gliomaxenografts; however in this case ON01910.Na was administered by direct intratumoral injection bypassing the blood–brain barrier (BBB). • Even though direct injection into the brain tumor suggested a problem with BBB penetration following systemic administration, it also provided the initial motivation to further evaluate ON01910.Na in brain tumor models.

6. Blood–brain barrier (BBB) • Low molecular weight compounds with appreciable lipophilicity values show better BBB permeability owing to their transport across the cell membrane by simple diffusion.

7. ON013105 and ON013100 • They are structural analogs of ON01910.Na, belonging to the class of styrylbenzyl sulfones • It is a non-ATP competitive compound novel antineoplasticagents. • ON013105, being a water soluble phosphate prodrug, is converted to an active dephosphorylatedform, ON013100

8. ON013100 • ON013100, which exhibited potent cytotoxicityagainst various human tumor cell lines including drug resistant tumor cell lines at nanomolarconcentrations. • Typically with IC50 values of less than 10 nMthat surpass the activity of ON01910 whose IC50 values ranged from 50 to 170 nM in various cancer cell lines.

9. Aim • Given the favorable antitumor activity of ON01910, its potential antiangiogenic activity, and the absence of data on its brain tumor penetration, we pursued a preclinical pharmacokinetic/pharmacodynamicevaluation of it as a new treatment for brain tumors. • Subsequent to these analyses, a structural analog, ON013100, with appreciable glioma cell toxicity was also evaluated for brain and brain tumor distribution.

10. Pharmacokinetic -NoncompartmentalModle

11. Pharmacokinetic -NoncompartmentalModle

12. Pharmacokinetic -NoncompartmentalModle

13. Time courses of mean plasma concentrations of ON01910

14. PK Parameters of ON01910 in Plasma Noncompartmental Analysis of Plasma Concentrations

15. Fraction of ON01910 Excreted Unchanged in Urine and Feces

16. Brain and Brain Tumor Disposition of ON01910 in Brain Tumor Model

17. Time courses of mean plasma concentrations of ON013105 and ON013100

18. PK Parameters of Prodrug, ON013105 and its Active Form, ON013100 in Plasma Noncompartmental Analysis of Plasma Concentrations

19. Brain and Brain Tumor Disposition of Prodrug, ON013105 and its Active Form, ON013100

20. CONCLUSION • A more lipophilic derivative of ON01910.Na, ON013100 showed appreciable brain tumor penetration and potent in vitro cytotoxicitysuggesting its potential for further investigation in brain tumor chemotherapy. • ON013105, notON01910.Na, was identified as a potential anticancer drug candidate for further investigation in brain tumor chemotherapy based on the properties of ON013100.

21. Thanks for your attention !

22. 非-房室模型PK分析法： 非-模型PK分析法(non-compartmental pharmacokinetic analysis)是以实测的血药浓度-时间曲线按梯形法得到的AUC和实测Cmax、tmax末端相半衰期基础上进行PK分析的方法。因为这种方法不受模型影响故用于等效性研究。梯形法则计算AUC： 按求梯形法则(Tapezoid rule)：求出血药浓度-时间曲线中每两个时间点ti和ti+1(相应浓度为Ci和Ci+1)面积，AUC(ti-ti+1) = (ti+1 - ti)×(Ci + Ci+1)/2，然后求出各面积相加的总和即AUC0-tz,其中tz为最末测定时间点。Cmax： 最高血浆或血浓度(maximal Concentration)，也称峰浓度。CSSmax： 多次给药达到稳态(Steady state, SS)时的峰浓度。CSSmin： 多次给药达到稳态时的低谷浓度(minimal Concentration)。半衰期t1/2： 描述药物在血中消除速度的参数，至血浓度降低原始浓度一半时所需时间为半衰期(half-life)。末端半衰期t1/2 ： 血浓度-时间曲线末端(terminal half-life)部分呈指数(对数坐标呈直线)消除时相的半衰期(elimination phase half-life)。常用于设计给药方案。Q12h(bid)，Qd，tid，每周1次, Q2w： 给药方案每12 h给药1次，每天1次，每天2次，每周1次，每2周1次AUC： 药物浓度-时间曲线下面积(Area Under Concentration-time Curve)AUC0-∞，AUC0-t，τ： AUC的不同下标分别表示从0时至无限时浓度-时间曲线下面积 = ∫0∞C dt，从0时至特定时间t时的浓度-时间曲线下面积= ∫0tC dt；或多次给药时的给药间隔(τ) 浓度-时间曲线下的面积。= ∫0τC dt

23. tmax： 达峰时间(maximal concentration time, time of peak concentration)CLS： 全身清除率(systemic or total Clearance) = 剂量 / AUC，下标S (systemic)指示全身。CL/F： 表观清除率(apparent Clearance)，F为生物利用度，表示非静脉给药时的分布容积。CLR： 肾清除率(renal Clearance)，用一段时间收集尿和分析药量借助下面公式可测定肾清除率，其中K为肾清除率，CU为尿浓度(如mg/mL)，Q为尿流量(体积/时 间)而CB为血浆浓度(如mg/mL)。对于只通过肾小球过滤率，计算所得到的清除率即肾小球过滤率。上述公式只适用稳态。VC： 为静脉注射线性房室模型中央室(central)或测定浓度部位的分布容积。VD/F： 为非静脉注射时的表观分布容积，F为生物利用度。VSS： 稳态(Steady state, SS)分布容积(Steady State volume of distribution)