Using Clinical Pharmacology Principles to Develop New Anticancer Therapies

利用临床药理学原理开发新的抗癌疗法

• 批准号: 10262789
• 负责人: William Douglas Figg
• 金额: $ 88.8万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262789
• 关键词: ABCB1 gene; ABCG2 gene; Adverse effects; Affect; Affinity; Age; Androgens; Antineoplastic Agents; Azacitidine; BAY 54-9085; Binding; Binding Proteins; Biological; Biological Assay; Biological Availability; Bortezomib; Brain; CCR; CYP17A1 gene; Camptothecin; Cancer Cell Growth; Carboplatin; Castration; Chemoembolization; Child; Cisplatin; Clinical; Clinical Pharmacology; Clinical Research; Clinical Trials; Clinical Trials Design; Collaborations; Communities; Concentration measurement; Conduct Clinical Trials; Continuous Intravenous Infusion; Coupled; Cyclophosphamide; Data; Depsipeptides; Detection; Development; Dose; Drug Costs; Drug Delivery Systems; Drug Formulations; Drug Interactions; Drug Kinetics; Drug Targeting; Enrollment; Equation; Erlotinib; Esters; Etoposide; Excretory function; Extramural Activities; Female; Finasteride; Fluorescence; Formulation; Frequencies; Future; Gender; Goals; Guidelines; Hepatic; High Pressure Liquid Chromatography; Human; Imatinib; Immune checkpoint inhibitor; Immunotoxins; In Vitro; Incidence; Injections; Interleukin-15; Intravenous; Ketoconazole; Kinetics; Laboratories; Light; Liquid substance; MS-275; Macaca mulatta; Malignant Neoplasms; Malignant neoplasm of prostate; Mathematics; Measurement; Measures; Mediating; Melphalan; Metabolism; Methods; Midazolam; Modality; Modeling; Modification; Molecular Target; Monoclonal Antibodies; Mus; Natural Products; Nelfinavir; Neurofibromatosis 1; Oral; Outcome; P-Glycoprotein; PUVA Photochemotherapy; Paclitaxel; Pancreatic Adenocarcinoma; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase I Clinical Trials; Phase I/II Trial; Phase II Clinical Trials; Phenylacetates; Phenylbutyrates; Phyllanthus; Physiological; Physiological Processes; Pilot Projects; Plants; Plexiform Neurofibroma; Plicamycin; Population; Pre-Clinical Model; Prodrugs; Program Development; Randomized; Recurrence; Regimen; Renal Cell Carcinoma; Reproducibility; Research Personnel; Role; Route; SU 5416; Sampling; Scheme; Sex Differences; Site; Solid Neoplasm; Stimulus; Suramin; TNP470; TRPC4 ion channel; Tamoxifen; Tariquidar; Testing; Thalidomide; Therapeutic; Therapeutic Equivalency; Time; Tissues; Topoisomerase-I Inhibitor; Topotecan; Toxic effect; United States National Institutes of Health; Valproic Acid; Variant; Vascular Endothelial Growth Factor Receptor-1; Woman; Xenograft Model; abiraterone; absorption; aldehyde dehydrogenases; analog; analytical method; androgen deprivation therapy; anti-cancer; aurora kinase A; base; bevacizumab; cancer therapy; castration resistant prostate cancer; chemotherapeutic agent; clinical center; clopidogrel; cytokine; detector; docetaxel; drug clearance; drug development; drug disposition; drug metabolism; first-in-human; flavopiridol; improved; in silico; in vivo; inhibitor/antagonist; instrument; interest; intraperitoneal; irinotecan; kinase inhibitor; lapatinib; lenalidomide; male; mass spectrometer; mathematical model; men; mesothelin; method development; nanoparticle drug; nonhuman primate; novel; novel anticancer drug; novel therapeutics; open label; pharmacodynamic model; pharmacokinetic model; pharmacokinetics and pharmacodynamics; phase 2 study; phase I trial; phase II trial; pomalidomide; pre-clinical; preclinical development; programs; simulation; temozolomide; trafficking; tumor; zolpidem

Over the years, the CPP has developed analytical methods for a wide range of therapeutics that include the following: depsipeptide, TNP-470, phenylacetate, phenylbutyrate, tamoxifen, UCN-01, CAI, thalidomide, COL-3, suramin, melphalan, erlotinib, perifosine, SU5416, 2ME, MS-275, ketoconazole, lenalidomide, romidepsin, AZD2281, gemicitabine, sorafenib, finasteride, nelfinavir, 17-DMAG, clopidogrel, Hsp90 inhibitor PF-04928473, irinotecan (its active metabolite SN38 and glucuronidated SN38), Trk kinase inhibitor AZD7451, pomalidomide, olaparib, sorafenib, belinostat, cediranib, abiraterone, cabozantinib, carfilzomib, midazolam, lapatinib, temozolomide, perifosine, valproic acid, temozolomide, cyclophosphamide and its 4-hydroxycyclophosphamide metabolite, as well as NLG207 (formerly CRLX-101, nanoparticle-drug conjugate of camptothecin). The CPP has provided PK support for various agents in phase I/II trials: suramin, TNP-470, CAI, UCN-01, docetaxel, flavopiridol, thalidomide, lenalidomide, pomalidomide, intraperitoneal cisplatin/carboplatin, paclitaxel, 17-DMAG, imatinib, sorafenib, nelfinavir, bevacizumab, romidepsin, clopidrogrel, bortezomib, TRC-105, vandetanib, olaparib, topotecan, irinotecan, mithramycin, durvalumab, abiraterone, belinostat with cisplatin and etoposide, and temozolomide. During the current fiscal year, the CPP provided PK support for several phase I/II clinical studies, including a phase I trial of the PD-L1 inhibitor durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women's cancers; phase I trial of IL-15 administered as a 10-day continuous intravenous infusion to patients with solid tumors; a pilot study comparing systemic and tissue pharmacokinetics of irinotecan and metabolites after hepatic drug-eluting chemoembolization; a phase II trial of selumetinib in children with neurofibromatosis type 1 and symptomatic plexiform neurofibroma; a phase I/II study of the mesothelin-targeted immunotoxin LMB-100 with Nab-paclitaxel for patients with advanced pancreatic adenocarcinoma; and phase 2 study of seviteronel (INO-464) in patients with metastatic castration-resistant prostate cancer after enzalutamide treatment. Over the years, we have conducted population PK modeling of the following compounds: depsipeptide, romidepsin, sorafenib, olaparib, docetaxel in combination with the p-glycoprotein antagonist tariquidar, TRC105, TRC102, belinostat, NLG207 and seviteronel. Recent efforts have focused on building a population PK model to understand the disposition kinetics of mithramycin in the body to best optimize dose. In collaboration with Dr. Sukyung Woo, we were involved in developing a quantitative mathematical modeling of the dynamics and intracellular trafficking of far-red light-activatable prodrugs to describe the implications in stimuli-responsive drug delivery system. We used a physiologically-based PK model for rational optimization of the site-specific chemo-photodynamic therapy with far-red light-activatable paclitaxel prodrug. With the advent of novel molecularly targeted anticancer modalities, it is becoming increasingly evident that optimal dose selection must necessarily be predicated on mechanistic characterization of the relationships between target exposure, drug-target interactions and pharmacodynamic endpoints. Nevertheless, efficacy has always been perceived as being exclusively synonymous with affinity-based measurements of drug-target binding. Using PK-PD modeling, we demonstrated how elucidating the slow, tight binding inhibition of CYP17A1 by abiraterone via in vitro and in silico analyses was pivotal in establishing the role of kinetic selectivity in mediating time-dependent CYP17A1 engagement and eventually downstream efficacy outcomes. In collaboration with Drs. Mark Ratain and Daniel Goldstein, we're evaluating in silico-based extended dosing regimens for monoclonal antibody immune checkpoint inhibitors. Based on patient-specific estimates for clearance, optimal alternative dosing strategies can be simulated to lower drug and cost burden yet maintain therapeutic levels, especially as the clearance of the drug decreases over time. We are also interested in alternative methods of drug delivery and/or drug formulations. To this end, we initiated a single-dose randomized, open-label, 2-way crossover pilot bioequivalence study to compare two oral formulations of enzalutamide; the trial is currently open for accrual and enrollment is ongoing. The CPP participates in several preclinical pharmacology projects in order to study drug metabolism, PK, drug formulation and bioavailability, as well as efficacy in preclinical models of drug development to allow for more accurate dosing estimates for future first-in-human studies. The CPP has validated assays for the following compounds: 3-deazaneplanocin (DZ-Nep), PV1162, schweinfurthin G, englerin A, aza-englerin, XZ-419 and the dual aurora kinase A/B inhibitor SCH-1473759. The CPP also provided full PK analysis for DZ-Nep, PV1162, a purified human heterodimeric form of interleukin-15 cytokine upon injection in rhesus macaques, and the intranasal delivery of select chemotherapeutic agents in a non-human primate model to determine proof of principle of CNS delivery, as well as determine the bioavailability data for schweinfurthin G, englerin A, and aza-englerin. We are involved in the preclinical development of several compounds involving assessment of PK in xenograft models including novel fluoroindenoisoquinoline non-camptothecin topoisomerase I inhibitors and entinostat. We collaborate with both intramural and extramural investigators to evaluate the preclinical PK of various novel therapeutics in mouse tumor models and/or non-human primate models including 5-azacytidine, pexidartinib, photo-activatable paclitaxel prodrug, and panobinostat. We recently investigated whether the natural product botryllamide G is viable for in vivo inhibition of ABCG2 using lapatinib as a probe for ABCB1 and ABCG2-mediated efflux from the brain, in wild-type and Mdr1a/Mdr1b (-/-) mice. In collaboration with the Molecular Targets Laboratory and the Natural Products Branch, the CPP provided preclinical PK support to study the bioavailability of two new classes of analogs of englerin A (extracted from the Tanzanian plant Phyllanthus engleri Pax on the basis of its high potency and selectivity for inhibiting renal cancer cell growth). The first class of analogs are modified at the esters to improves stability and oral bioavailability, while the second class of analogs are modified on the bridgehead of the seven-membered ring within the main englerin body of the compound. Replacement of the isopropyl group by other, larger substituents yielded compounds which displayed excellent selectivity and potency comparable to the natural product. Selected compounds were also evaluated for their effect on the ion channel TRPC4 and for intravenous toxicity in mice, and these had lower potency in both assays compared to englerin A. In collaboration with the FDA, we conducted a preclinical PK study to understand of the observed clinical differences in zolpidem PK and PD between males and females. Zolpidem is affected by both age and gender, with an increased incidence of adverse effects in women over men, resulting in a reduction of the recommended dose of zolpidem for women. We demonstrated that sex differences in zolpidem PK are influenced by variation in the expression of ADH/ALDH due to gonadal androgens. We initiated a pilot clinical trial to evaluate the effect of castration on the PK of a single 5-mg dose of zolpidem in patients with prostate cancer undergoing androgen deprivation therapy (pre- vs. post-castration therapy) compared to normal healthy females; the trial is currently open for accrual and patient enrollment is ongoing.

Over the years, the CPP has developed analytical methods for a wide range of therapeutics that include the following: depsipeptide, TNP-470, phenylacetate, phenylbutyrate, tamoxifen, UCN-01, CAI, thalidomide, COL-3, suramin, melphalan, erlotinib, perifosine, SU5416, 2ME, MS-275, Ketoconazole，Lenalidomide，romidepsin，AZD2281，Gemicitabine，Sorafenib，Finastalide，Nelfinavir，Nelfinavir，17-DMAG，Clopidogrel，Hsp90抑制剂PF-04928473，Irinotecan，Irinotecan，Irinotecan（Irinotecan）（其活跃的Sn38和Glucabolite SN38和Gluculite Sn38 an38 in38 in38 an38 in38 in38 in 38 AZD7451, pomalidomide, olaparib, sorafenib, belinostat, cediranib, abiraterone, cabozantinib, carfilzomib, midazolam, lapatinib, temozolomide, perifosine, valproic acid, temozolomide, cyclophosphamide and its 4-hydroxycyclophosphamide metabolite, as well as NLG207（以前为CRLX-101，camptothecin的纳米颗粒 - 药物结合）。 The CPP has provided PK support for various agents in phase I/II trials: suramin, TNP-470, CAI, UCN-01, docetaxel, flavopiridol, thalidomide, lenalidomide, pomalidomide, intraperitoneal cisplatin/carboplatin, paclitaxel, 17-DMAG, imatinib, sorafenib, nelfinavir, bevacizumab, romidepsin, clopidrogrel, bortezomib, TRC-105, vandetanib, olaparib, topotecan, irinotecan, mithramycin, durvalumab, abiraterone, belinostat with cisplatin and etoposide, and temozolomide.在当前财政年度，CPP为多项I/II期临床研究提供了PK支持，包括PD-L1抑制剂Durvalumab的I期试验，结合了PARP抑制剂Olaparib和VEGFR1-3抑制剂Cediranib，Cediranib，在经常出现的女性癌症中； IL-15的I期试验作为对实体瘤患者的10天连续静脉输注。一项试点研究，比较了肝药洗脱化学栓塞后的伊立替康和代谢产物的全身和组织药代动力学； Selumetinib对1型神经纤维瘤病儿童和有症状的神经纤维瘤的II期试验；对患有晚期胰腺腺癌患者的NAB-甲列酰胺的间皮素靶向免疫毒素LMB-100的I/II期研究； SEVITERONEL（INO-464）对enzalutamide治疗后耐castration castration前列腺癌的患者进行了第二阶段研究（INO-464）。多年来，我们对以下化合物进行了人群PK建模：二肽，romidepsin，sorafenib，olaparib，多西他赛与p-糖蛋白拮抗剂塔里奎达，TRC105，TRC102，TRC102，Belinostat，belinostat，nlg207和Seviteronel结合使用。最近的努力集中在建立人口PK模型，以了解体内毛霉素的处置动力学，以最好地优化剂量。与Sukyung Woo博士合作，我们参与了对远红色的光 - 可行前药的动力学和细胞内运输的定量数学建模，以描述刺激反应性药物输送系统的影响。我们使用基于生理的PK模型来利用远红色的轻度紫杉醇前药对位点特异性化学化学疗法的合理优化。随着新型分子靶向抗癌模式的出现，越来越明显的是，最佳剂量选择必须必然是基于目标暴露，药物目标相互作用和药效动力学终点之间关系的机械表征。然而，疗效一直被认为是基于基于亲和力的药物靶向结合的测量的独家代名词。使用PK-PD建模，我们证明了Abiraterone通过体外和计算机分析阐明CYP17A1缓慢，紧密的结合抑制是如何在确定动力学选择性在介导时间依赖性CYP17A1互动中的作用方面的关键。与Drs合作。 Mark Ratain和Daniel Goldstein，我们正在评估单克隆抗体免疫检查点抑制剂的基于硅的扩展剂量方案。根据患者特定的清除率估计，可以模拟最佳的替代剂量策略以降低药物和成本负担，但要保持治疗水平，尤其是随着药物的清除随着时间的推移而减少。我们还对药物输送和/或药物制剂的替代方法感兴趣。为此，我们启动了一项单剂量随机，开放标签的2向跨界飞行员生物均等研究，以比较enzalutamide的两种口服配方。该试验目前正在为应计而开放，并且正在进行招生。 CPP参与了几个临床前药理学项目，以研究药物代谢，PK，药物制剂和生物利用度，以及在药物开发的临床前模型中的疗效，以便为将来的首次首次人类研究提供更准确的给药估算。 CPP已验证了以下化合物的测定法：3-二苯甲环素（DZ-NEP），PV1162，Schweinfurthin G，Englerin A，Aza-Englerin，Aza-Englerin，XZ-419和Dual Aurora激酶A/B抑制剂SCH-14737559。 The CPP also provided full PK analysis for DZ-Nep, PV1162, a purified human heterodimeric form of interleukin-15 cytokine upon injection in rhesus macaques, and the intranasal delivery of select chemotherapeutic agents in a non-human primate model to determine proof of principle of CNS delivery, as well as determine the bioavailability data for schweinfurthin G, englerin A, and Aza-Englerin。我们参与了多种化合物的临床前开发，这些化合物涉及对PK评估的异种移植模型，包括新型的荧光内烯醇喹啉非氨基氨基甲氨基甲甲苯蛋白酶拓扑异构酶I抑制剂和Entinostat。我们与壁内和壁外研究人员合作评估了小鼠肿瘤模型和/或非人类灵长类动物模型中各种新型疗法的临床前PK，包括5-余丁替丁，pexidartinib，可激活的paclitaxel Prodrug和Panobinostat。我们最近研究了使用Lapatinib作为ABCB1和ABCG2介导的大脑，野生型和MDR1A/MDR1B（ - / - ）小鼠的天然产物 - 氢酰胺G对ABCG2的体内抑制是否可行。 CPP与分子靶标实验室和天然产品分支合作，提供了临床前PK支持，以研究Englerin A的两种类似物的生物利用度（从坦桑尼亚植物Phyllanthus Engleri Pax提取的基于其高效力和抑制肾脏癌细胞生长的基础上）。一类模拟物在酯上进行了修改，以提高稳定性和口服生物利用度，而第二类模拟可以在该材料的主恩格林体内的七元环的桥头上修改。其他较大的取代基的替代异丙基产生的化合物表现出极好的选择性和效能，可与天然产物相当。还评估了所选化合物对离子通道TRPC4和小鼠静脉毒性的影响，与Englerin A.与FDA合作，这两种测定法的效力都较低，我们进行了一项临床前PK研究，以了解Zolpidem PK和PD中观察到的临床差异。 Zolpidem受年龄和性别的影响，女性对男性的不良反应发生率增加，从而减少了Zolpidem剂量的女性剂量。我们证明，唑吡坦PK的性别差异受性腺雄激素引起的ADH/ALDH表达的变化影响。我们启动了一项试验临床试验，以评估与正常健康女性相比，在接受雄激素剥夺疗法接受雄激素剥夺疗法（PE-PRE-pre-predivation治疗）患者中，与正常健康的女性相比，在接受雄激素剥夺疗法（预疗法和术后治疗）的前列腺癌患者中，对PK的PK进行了评估；该试验目前正在为应计而开放，并且正在进行患者入学率。