A successful drug development program requires a complete understanding of the clinical pharmacology of the agents being evaluated. The Clinical Pharmacology Program (CPP) has as its primary interest the use of pharmacokinetic (PK) and pharmacodynamic (PD) concepts in the development of novel anticancer agents. The CPP is directly responsible for the PK/PD analysis of numerous Phase I and II clinical trials conducted within the NCI and also provides direct PK support for many studies performed elsewhere in the extramural community. We utilize compartmental and noncompartmental approaches to define the disposition of agents. We also often characterize the plasma protein binding properties and metabolism of new agents through in vitro techniques. Several of our clinical trials have used adaptive control with a feedback mechanism to target particular plasma concentrations (e.g., suramin, CAI). The drugs with which the CPP has had its greatest experience include: suramin, phenylacetate, phenylbutyrate, TNP-470, CAI, DAB486IL2, IgG-RFB4-SMPT-dgA CD22, IgG-HD37-SMPT-dgA CD19, ormaplatin, UCN-01, docetaxel, flavopiridol, thalidomide, 9AC, intraperitoneal cisplatin, intraperitoneal carboplatin, paclitaxel, 17-DMAG, imatinib, sorafenib, nelfinavir, bevacizumab, romidepsin, clopidrogrel, bortezomib, topotecan and irinotecan. During the FY2014, the CPP provided PK support for several phase I/II clinical studies, including oral topotecan, YM155 (a survivin protein suppressor), romidepsin, intravenous sodium nitrate infusion, UCN-01 and flavopiradol, TRC-105, cabozantinib, vandetanib, lenalidomide, olaparib, AZD7451 (tropomyosin-receptor kinase inhibitor), belinostat (HDAC inhibitor), and 7-hydroxystaurosporine and fludararbine phosphate. The CPP conducted a PK study of a humanized Mik-Beta-1 monoclonal antibody in T cell large granular lymphocytic leukemia, and in Human T-lymphotropic virus type-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The interim analyses in thirteen patients permitted an FDA request to expand the study in a new cohort of patients. We also conducted a preclinical evaluation of recombinant IL-15, which supported an FDA application to test whether IL-15 is superior to IL-2 in cancer therapy. Effects of tariquidar on docetaxel pharmacokinetics: P-glycoprotein (Pgp) antagonists have been difficult to develop because of complex PK interactions and a failure to show meaningful results. We provided the PK support for this trial involving a third-generation, potent, noncompetitive inhibitor of Pgp, tariquidar (XR9576), in combination with docetaxel. No significant difference in docetaxel disposition was observed based on pairwise comparison with and without tariquidar, though substantial interindividual variability was observed. Similarly, no effect of sequence was observed, by comparison of docetaxel clearance when administered as a single agent on either C1D1 or C1D8. From this study, tariquidar is well tolerated with less observed systemic PK interactions than previous Pgp antagonists. Impact of ABCB1 allelic variants on QTc interval prolongation: Although the ABCB1 (P-glycoprotein) drug transporter is a constituent of several blood-tissue barriers (i.e., blood-brain and blood-nerve), its participation in a putative blood-heart barrier has been poorly explored. ABCB1 could decrease the intracardiac concentrations of drugs that cause QT prolongation and cardiotoxicity. ABCB1-related romidepsin transport kinetics were explored in LLC-PK1 cells transfected with different ABCB1 genetic variants. ABCB1 plasma and intracardiac concentrations were determined in Abcb1a/1b (-/-) mice and wild-type FVB controls. These same mice were used to evaluate romidepsin-induced heart rate-corrected QT interval (QTc) prolongation over time. Finally, a cohort of 83 individuals with available QTcB and ABCB1 genotyping data were used to compare allelic variation in ABCB1 versus QTc-prolongation phenotype. Here, we show that mice lacking the ABCB1-type P-glycoprotein have higher intracardiac concentrations of a model ABCB1 substrate, romidepsin, that correspond to changes in QT prolongation from baseline over time. Consistent with this observation, we also show that patients carrying genetic variants that could raise ABCB1 expression in the cardiac endothelium have lower changes in QTc following a single dose of romidepsin. To our knowledge, this is the first evidence that Abcb1-type P-glycoprotein can limit intracardiac exposure to a drug that mediates QT prolongation and suggests that certain commonly inherited polymorphisms in ABCB1 may serve as markers for QT prolongation following the administration of ABCB1-substrate drugs. We were also involved in PK analysis of a phase I trial of a new schedule of romidepsin in patients with advanced cancers. We provided PK support for the first-in-human, phase 1, open label study assessed safety, pharmacokinetics, and antitumor activity of TRC105, a chimeric IgG1 monoclonal antibody that binds CD105 (endoglin), in patients with advanced refractory solid tumors. Fifty patients were treated with escalating doses of TRC105. The maximum tolerated dose was exceeded at 15 mg/kg every week due to dose-limiting hypoproliferative anemia. TRC105 exposure increased with increasing dose, and continuous serum concentrations that saturate CD105 receptors were maintained at 10 mg/kg weekly (the maximum tolerated dose) and 15 mg/kg every 2 weeks. We also provided PK support to a phase 1 study of TRC102, an inhibitor of base excision repair, and pemetrexed in patients with advanced solid tumors. We provided PK support to the phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors. Olaparib pharmacokinetics appeared to be influenced by coadministration of gemcitabine and olaparib exposure may be modestly increased by concomitant gemcitabine administration at doses of at least 400 mg/m2. We were also involved in the PK analysis of a phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer. Furthermore, in a collaboration with FDA and the University of Maryland, we performed PK analyses on the prodrug clopidogrel and its active metabolite (CAM) in human plasma to assess the extent of metabolism and efficacy between CYP2C19 extensive, intermediate, or poor metabolizers. The results show that a 300mg daily dose is needed for poor metabolizers to achieve the same efficacy as a 75mg daily dose in extensive metabolizers. This is different than previous clinical studies that suggest a 150mg dose is sufficient for poor metabolizers. The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response. We also found that the CYP2C19*17 variant is not independently associated with clopidogrel response.
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