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). The laboratory is currently collaborating on 80 clinical trials to characterize the clinical pharmacology of novel chemotherapy agents. 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. Population pharmacokinetic modeling of Depsipeptide (FK228) using data from multiple CCR clinical trials determined that common polymorphisms in the ABCB1, CYP3A4 and CYP3A5 genes do not appreciably influence the PK of FK228. Furthermore, age, renal function, and body size and composition are anticipated to have little or no impact on the systemic exposure to FK228. The developed population PK model was validated and can be used for the future clinical trials simulation and prediction. Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. The objective of this study was to evaluate the effect of demographic, clinical, and pharmacogenetic covariates on the PK of romidepsin in patients with T-cell lymphoma. PK assessment was done in 98 patients enrolled in a phase II study who received 14 or 18 mg/m2 of romidepsin as a 4-hour infusion on day 1 during their first treatment cycle. Population modeling was done using a nonlinear mixed effects modeling approach to explore the effects of polymorphic variations in CYP3A4, CYP3A5, SLCO1B3, and ABCB1, all of which encode genes thought to be involved in romidepsin disposition. A two-compartment model with linear kinetics adequately described the romidepsin disposition. Population clearance was 15.9 L/h with between-patient variability of 37%. ABCB1 T/A variant alleles tended toward a reduced clearance and lower volume of tissue distribution, but this was not supported by a statistical significance. Genetic variations in CYP3A4/5 and SCLO1B3 had no effect on the systemic exposure. The population PK analysis indicates moderate interindividual variability in romidepsin PK and no clinically relevant covariates associated with the unexplained PK variability of romidepsin in this population. Population PK analysis of sorafenib in patients with solid tumors: Sorafenib is a multikinase inhibitor with activity against B-raf, C-raf, VEGFR2, PDGFRb and FGFR1. Sorafenib is clinically approved for the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). The PK of sorafenib are highly variable between subjects. Sorafenib exposure increases less than dose proportionally (likely due to limited solubility). Sorafenib undergoes enterohepatic recycling (EHC). This is the first study to characterize the PK of sorafenib using a model based on sorafenib's known disposition characteristics such as delayed/solubility-limited GI absorption and EHC. The parameterization of the EHC model used a square wave function to describe the gall bladder emptying. This study evaluated the effect of baseline bodyweight, BSA, age, gender, liver function parameters, kidney function parameters and genotype with respect to CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5 on sorafenib PK. This model can be used to simulate and explore alternative dosing regimens and to develop exposure-response relationships for sorafenib. We characterized the PK of sorafenib in patients with solid tumors and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5) covariates on the disposition of sorafenib. PK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400mg was administered twice daily as a single agent or in combination therapy. Population PK analysis was performed by using nonlinear mixed effects modeling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis. A one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter-individual variability (IIV). Overall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified. The CPP conducted population PK analysis of a phase 1 study of olaparib with cisplatin and gemcitabine in adults with solid tumors to characterize the effects of gemcitabine on the disposition of oral olaparib. Olaparib PK 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. PD studies showed olaparib inhibited PARP in PBMCs and tumor tissue, although PAR levels were less effectively inhibited when olaparib was used for a short duration. Retrospective PK modeling was conducted on a previously published study of docetaxel in combination with the p-glycoprotein antagonist tariquidar in patients with lung, ovarian and cervical cancer. Using sophisticated PK analyses, an effect of tariquidar on the rate of docetaxel distribution throughout the body was identified. Correlative pharmacodynamic analyses were performed by the CPP on a phase 2 study cediranib in post-docetaxel, castration-resistant prostate cancer. Fifty-eight docetaxel-treated patients with hormone-insensitive prostate cancer were enrolled and given 20mg of cediranib daily. The study used dynamic contrast enhanced MRI to evaluate the intra-tumoral blood-flow and the CPP identified of early-response MRI characteristics that could have predictive value for overall survival in these patients. A population PK analysis of a phase I study of TRC105, in adults with solid tumors was conducted. TRC105 is a human/murine chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth via endothelial cell growth inhibition. The analysis characterized dose-specific clearance and target-mediated disposition of the antibody. TRC105 clearance decreased above the MTD resulting in drug accumulation and hypoproliferative anemia with weekly dosing. The nonlinearity in clearance was attributed to saturating target-mediated disposition, consistent with binding to proliferating endothelial cells. We conducted a population PK analysis of a phase I study of TRC102, in adults with solid tumors. TRC102 (methoxyamine) is a small molecule inhibitor of base-excision repair intended to reverse resistance to alkylator and antimetabolite chemotherapy. The analysis demonstrated that patient gender and serum creatinine were significantly influential on the clearance of TRC102.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Scientific Cores Intramural Research (ZIC)
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National Cancer Institute Division of Basic Sciences
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Gordon, Michael S; Rosen, Lee S; Mendelson, David et al. (2013) A phase 1 study of TRC102, an inhibitor of base excision repair, and pemetrexed in patients with advanced solid tumors. Invest New Drugs 31:714-23
Amiri-Kordestani, Laleh; Luchenko, Victoria; Peer, Cody J et al. (2013) Phase I trial of a new schedule of romidepsin in patients with advanced cancers. Clin Cancer Res 19:4499-507
Azad, Nilofer S; Posadas, Edwin M; Kwitkowski, Virginia E et al. (2008) Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 26:3709-14