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. Over the years, 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, and abiraterone. During the FY2018, the CPP provided PK support for several phase I/II clinical studies, including a phase I trial of belinostat with cisplatin and etoposide in advanced solid tumors, with a focus on neuroendocrine and small cell cancers of the lung; phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS-FLI1 fusion transcript; a phase II food effect study of abiraterone acetate; a study to evaluate the effect of an adenosine A2A agonist on intratumoral concentrations of temozolomide in patients with recurrent glioblastoma. In order to optimize therapy, a full understanding of the pharmacokinetics of any systemic therapy is desired. We routinely model the pharmacokinetic (PK) data of agents being tested for antitumor activity and correlate that with activity and/or toxicity (pharmacodynamics modeling). We utilize compartmental and noncompartmental approaches to define the disposition of agents. Analysis of PK data (using concentration measurements provided by sample analysis using validated assays) allows for assessment of drug disposition, including the absorption, distribution, metabolism and excretion of a drug. Modeling this data, essentially describing these physiological processes as a mathematical equation, allows for optimization of drug administration (including dose and frequency of dosing,) in silico. Over the years, we have conducted population pharmacokinetic modeling of the following compounds: depsipeptide, romidepsin, sorafenib, olaparib, docetaxel in combination with the p-glycoprotein antagonist tariquidar, TRC105, and TRC102. Recent efforts have focused on building a population PK model to understand the disposition kinetics of mithramycin in the body to best optimize dose. We also performed population PK (PPK) modeling and simulation of belinostat, a second-generation histone deacetylase inhibitor (HDI) predominantly metabolized by UGT1A1-mediated glucuronidation. Two common polymorphisms (UGT1A1*28 and UGT1A1*60) were previously associated with impaired drug clearance and thrombocytopenia risk, likely from increased drug exposure. We conducted a PPK model to include a pharmacodynamic (PD) model describing the change in platelet levels in patients with cancer administered belinostat as a 48-h continuous intravenous infusion, along with cisplatin and etoposide. Several covariates were explored, including sex, body weight, UGT1A1 genotype status, liver, and kidney function, but none significantly improved the model. Platelet levels rebounded to baseline within 21 days, before the next cycle of therapy. Simulations predicted that higher belinostat drug exposure does cause lower thrombocyte nadirs compared to lower belinostat levels. However, platelet levels rebound by the start of the next belinostat cycle. This model suggests a q3week schedule allows for sufficient platelet recovery before the next belinostat infusion is optimal. We were also 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. 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 and PV1162, and 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. 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 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) and its aza-derivative, aza-englerin analogues. In collaboration with Dr. Kathy Warren (POB, CCR, NCI), we evaluated the feasibility and pharmacokinetics (plasma and CSF) of intranasal delivery using select chemotherapeutic agents in a non-human primate (NHP) model to determine proof of principle of CNS delivery, assess tolerability and feasibility, and to evaluate whether certain drug characteristics were associated with increased CNS exposure. We collaborated with Dr. George Pavlakis (Vaccine Branch, NCI) to investigate the pharmacokinetic and pharmacodynamic profile and toxicity of purified human heterodimeric form of interleukin-15 (hetIL-15) cytokine upon injection in rhesus macaques. 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 are initiating 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.
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