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 and pharmacodynamic concepts in the development of novel anticancer agents. The CPP is directly responsible for the pharmacokinetic/pharmacodynamic analysis of numerous Phase I and II clinical trials conducted within the NCI. In addition, the CPP provides direct pharmacokinetic 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, and paclitaxel. Currently, we are characterizing the interaction between ketoconazole and docetaxel as well as understanding the pharmacokinetics of MS275, perifosine, depsipeptide, lenolidomide, 17-DMAG, sorafenib, nelfinavir, bevacizumab, and clopidegral. Influence of a dual ABCB1 and ABCG2 inhibitor on imatinib disposition. Imatinib, a tyrosine kinase inhibitor currently approved for treatment of several malignancies, has been shown to be a substrate for multiple efflux-transporter proteins, including ABCB1 (P-glycoprotein) and ABCG2 (BCRP). The effect of inhibiting these transporters on tissue exposure to imatinib remains unclear. To assess the role of these transporters on drug disposition, 50 mg/kg imatinib was administered to Balb/C mice, 30 minutes after receiving tariquidar (10 mg/kg), an inhibitor of both ABCB1 and ABCG2, or vehicle, via oral gavage. Quantitative determination of imatinib in mouse plasma, liver and brain was performed using a newly-developed and validated liquid-chromatography-mass spectrometric method. Results: Exposure to imatinib was 2.2-fold higher in plasma, liver and brain in mice that received tariquidar, as compared to those that received the vehicle (P = 0.001). The peak plasma concentration did not increase substantially, suggesting that tariquidar is affecting the distribution, metabolism and/or excretion of imatinib, rather than absorption. Though tariquidar increased the absolute exposure of imatinib, the brain-to-plasma ratio of imatinib was unaffected. This study suggests that intentional inhibition of ABCB1 and ABCG2 function at the blood-brain barrier is unlikely to significantly improve clinical outcome of imatinib with currently used dosing regimens. Effects of tariquidar on docetaxel pharmacokinetics: The primary goal of this study (TQTA) was to evaluate the effects of tariquidar on docetaxel pharmacokinetics. To generate equivalent pharmacokinetic data, 40 mg/m2 of docetaxel was administered on both day 1 and 8 of cycle 1, and patients were randomized to receive tariquidar 150 mg on either day 1 or day 8 of cycle 1. Tariquidar was given intravenously over 40 minutes before initiation of the 1 hr docetaxel infusion. Pharmacokinetics were evaluable in a total of 46 patients, for a total of 84 cycles;42 with tariquidar and 42 without. Thirty-eight patients had evaluable pharmacokinetics on both C1D1 and C1D8, allowing for assessment of the effect of tariquidar on docetaxel disposition. An increase in systemic concentration approximately 24 hours after the start of the docetaxel infusion was observed in approximately 1/3 of patients. This precluded the calculation of terminal phase parameters such as half-life, clearance or AUCinf. 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. As genetic variation in ABCB1 has been related to the activity of the p-glycoprotein transporter, current studies are underway to determine whether these polymorphisms would be related to docetaxel pharmacokinetics, especially in those patients treated with tariquidar. 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 pharmacokinetics were 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.
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