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,TNP470, CAI, UCN-01, docetaxel, flavopiridol, thalidomide, lenalidomide, intraperitoneal cisplatin/carboplatin, paclitaxel, 17DMAG, imatinib, sorafenib, nelfinavir, bevacizumab, romidepsin, clopidrogrel, bortezomib, TRC105, vandetanib, olaparib, topotecan, and irinotecan. 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, PV1162, schweinfurthin G, englerin A, aza-englerin, and recently the dual aurora kinase A/B inhibitor SCH1473759. The CPP also provided full PK analysis for 3-deazaneplanocin 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. In collaboration with Dr. R. Mark Simpson (LCBG, CCR, NCI), the CPP was also involved in the preclinical PK assessments of a study that demonstrated synergistic targeted inhibition of MEK and dual PI3K/mTOR diminishes viability and inhibits tumor growth of canine melanoma underscoring its utility as a preclinical model for human mucosal melanoma. 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. 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. 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. A pilot clinical trial is currently being planned to evaluate the effect of castration on the PKof 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. During the FY2017, the CPP provided PK support for several phase I/II clinical studies, including mithramycin, durvalumab, TRC105, olaparib/carboplatin, sorafenib, pomalidomide, and lenalidomide. We provided the PK support for a trial to determine that the programmed death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or cediranib combinations are tolerable and active in recurrent women's cancers. Exposure to durvalumab increased cediranib area under the curve and maximum plasma concentration on the daily, but not intermittent, schedules. The intermittent cediranib schedule was associated with sufficient washout to avoid significant PK changes for cediranib in the presence of durvalumab, as evidenced by constant plasma exposure, and clea ance. We also provided PK support for trials on TRC105, is a chimeric immunoglobulin G1 monoclonal ant body that binds endoglin (CD105). In a phase I study of TRC105 in combination with sorafenib for hepatocellar carcinoma, we observed increases in peak TRC105 serum concentrations were moderately well correlated with dose, increasing in an apparent linear (dose-proportional) manner. There were no differences in TRC105 trough concentrations between doses however, suggesting lack of antibody accumulation. We also conducted a phase Ib study of sorafenib in patients with Kaposi Sarcoma (KS) to evaluate the drug-drug interactions between sorafenib (a CYP3A4 substrate) and ritonavir (a potent CYP3A2 inhibitor). Steady-state area under the curve of the dosing interval (AUCtau) of sorafenib was not significantly affected by ritonavir; however, a trend for decreased AUCtau of the CYP3A4 metabolite sorafenib-N-oxide (3.8-fold decrease; p=0.08) suggests other metabolites may be increased. Although this study did not conclusively show that ritonavir affected sorafenib metabolism, the results are suggestive, and concurrent ritonavir or other strong CYP3A4 inhibitors should be avoided. In a separate Karposi sarcoma study, we evaluated pomalidomide in patients with symptomatic KS and found that PK studies showed no differences in pomalidomide absorption or elimination in HIV-infected patients, and no evidence of accumulation even among patients receiving tenofovir. In addition, we are currently providing PK support for a trial on pomalidomide in combination with liposomal doxorubicin in patients with advanced or refractory Kaposi Sarcoma as well as another study on lenalidomide combined with modified DA-EPOCH and rituximab in primary effusion lymphoma of Kaposi sarcoma herpesvirus-associated large cell lymphoma. Data on drug disposition during high cutoff (HCO) dialysis are lacking, so we were involved in analyzing the disposition of pomalidomide and lenalidomide during HCO dialysis in patients with multiple myeloma and kidney failure. We evaluated sequence-specific pharmacokinetic and pharmacodynamic effects, safety, and activity of the combination in a phase I/Ib study of olaparib tablets and carboplatin in women's cancer. Olaparib clearance was increased approximately 50% when carboplatin was given 24 hours before olaparib. In vitro experiments demonstrated carboplatin preexposure increased olaparib clearance due to intracellular olaparib uptake. These results suggest drug sequence may improve upon clinical benefit by optimizing drug administration. Further pharmacokinetic parameters from our study and in vitro experiments will be reported in detail.
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