Over the years, the CPP has developed analytical methods for a wide range of therapeutics, numerous which have been published, including depsipeptide, TNP-470, phenylacetate, phenylbutyrate, tamoxifen, UCN-01, CAI, thalidomide, COL-3, suramin, melphalan, erlotinib, perifosine, SU5416, 2ME, MS-275, ketoconazole, lenalidomide, romidepsin, AZD2281 and gemicitabine, sorafenib, finasteride, nelfinavir, 17-DMAG, clopidogrel and and its MPB-derivatized active thiol-metabolite (CAMD), 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, and valproic acid. We have developed a sensitive and selective ultra-high performance liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) method for the quantification of temozolomide in nonhuman primate (NHP) plasma, cerebrospinal fluid (CSF), and brain extracellular fluid (ECF) following microdialysis. We have recently developed a UHPLC-MS/MS assay for simultaneous quantitation of cyclophosphamide and the 4-hydroxycyclophosphamide metabolite in human plasma. 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. 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, 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 at the University of Oklahoma, 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. Visible and near IR-activatable prodrug, exhibiting the combined effects of PDT and local chemotherapy, showed better efficacy than photodynamic therapy (PDT) alone, without systemic side effects. Site-specifically released chemotherapeutic drugs killed cancer cells surviving from rapid PDT damage via bystander effects. We recently developed a paclitaxel (PTX) prodrug that targets folate receptors and established a quantitative systems pharmacology (QSP) approach to simulate PK profiles of the prodrug and the released PTX. We used a physiologically-based pharmacokinetic model for rational optimization of the site-specific chemo-photodynamic therapy with far-red light-activatable paclitaxel prodrug. 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. The CPP has validated assays for such compounds as 3-deazaneplanocin (DZ-Nep), PV1162, schweinfurthin G, englerin A, aza-englerin, XZ-419 and recently 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. Such projects allow for more accurate dosing estimates for first-in-human studies, if the compound progresses to that stage. We are involved in the preclinical development of several compounds involving assessment of pharmacokinetics in xenograft models including novel fluoroindenoisoquinoline non-camptothecin topoisomerase I inhibitors and entinostat. 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 (MTL) and the Natural Products Branch (NPB), 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. 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 hypothesized that such differences were caused by known sex-related variability in alcohol dehydrogenase (ADH) expression. Results showed castrated male rats exhibited zolpidem pharmacokinetics similar to that of female rats, suggesting that zolpidem PK are androgen-driven. These findings indicate 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.
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