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. In addition, the CPP provides direct PK support for many studies performed elsewhere in the extramural community. Within the section, we utilize compartmental and noncompartmental approaches to define the disposition of agents. Also, we are often required to 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, PMEA, AZT, PSC 833, CAI, DAB486IL2, IgG-RFB4-SMPT-dgA CD22, IgG-HD37-SMPT-dgA CD19, ormaplatin, UCN-01, flavopiridol, thalidomide, 9AC, intraperitoneal cisplatin, intraperitoneal carboplatin, docetaxel, paclitaxel, 17-DMAG, sorafenib, nelfinavir, and bevacizumab. Currently, we are conducting the pharmacokinetic analyses of imatinib, belinostat, clopidrogrel, bortezomib, and irinotecan. During the FY2011, 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. The CPP conducted an interim 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 pharmacokinetic interactions than previous Pgp antagonists. Although tariquidar is not associated with increases in docetaxel pharmacokinetics (PK);however, the impact of variants in ABCB1 have not been studied with this combination. We hypothesized that individuals carrying variants associated with decreased ABCB1 expression and efflux capability would have greater changes in docetaxel PK following tariquidar. Preliminary analyses suggest that individuals carrying ABCB1 variants have similar baseline plasma docetaxel AUC (i.e. exposure) when compared to those carrying wild-type alleles;however, the Vss (i.e., tissue distribution) of an ABCB1 model substrate (99mTc-sestamibi) at baseline appears be greater in extrahepatic tissues of those carrying variant ABCB1 diplotypes. Tariquidar coadministration with docetaxel and sestamibi appears to alter plasma pharmacokinetics and tissue distribution of these compounds differently based on ABCB1 genotype. Therefore, it appears that ABCB1 alleles heavily influence the biodistribution of docetaxel and sestamibi into the bodily tissues thereby affecting toxicity and efficacy. 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. Induction of CYP3A4 by vinblastine: Several microtubule targeting agents are capable of inducing cytochrome P450 3A4 (CYP3A4) via activation of the pregnane X receptor (PXR;NR1I2). In this study, we evaluated the CYP3A4 induction potential of vinblastine both clinically and in vitro and determined the involvement of the nuclear receptors NR1I2 and NR1I3 (CAR;NR1I3). Midazolam PK was evaluated in a total of six patients, who were enrolled on a phase I/II study of infusional vinblastine given in combination with the ABCB1 (P-glycoprotein) antagonist valspodar (PSC 833) and received the CYP3A4 phenotyping probe midazolam on more than one occasion. In the six patients, vinblastine increased the median (95%CI) clearance of the CYP3A4 phenotyping probe midazolam from 21.7 (12.6-28.1) L/h to 32.3 (17.3-53.9) L/h (P = 0.0156, Wilcoxon test). Furthermore, cell-based reporter gene assays using transiently transfected HepG2 and NIH3T3 cells indicated that vinblastine (150-4,800 ng/mL) weakly activated human and mouse full length NR1I2, but had no influence on the constitutive androstane receptor. Collectively, these findings suggest that vinblastine is able to induce CYP3A4, at least in part, via an NR1I2-dependent mechanism, and thus has the potential to facilitate its own elimination and cause interactions with other CYP3A4 substrates. Midazolam as CYP3A4 probe in mice with Gp78 knockout: Gp78 is a ubiquitin ligase that targets CYP3A4 in the smooth endoplasmic reticulum for proteasomal degradation. In gp78-knockout transgenic mice, it was hypothesized that CYP3A4 would be more abundant due to the lack of proteasomal degradation. Studies are underway to evaluate differences in the PK parameters of midazolam in wildtype vs Gp78-knockout mice. Studies are ongoing in a collaboration with FDA and the University of Maryland, which 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.
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