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 60 clinical trials to characterize the clinical pharmacology of novel chemotherapy agents. Analysis of pharmacokinetic 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. Pharmacokinetics have been completed for the histone deacetylase inhibitor MS-275, in a clinical trial which investigated the effects of food on drug disposition. Fasting prior to and immediately after MS-275 was administered orally, on a once-weekly schedule, was found to result in decreased interindividual variability in drug exposure. 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 pharmacokinetics 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 pharmacokinetic 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 pharmacokinetics of romidepsin in patients with T-cell lymphoma. Pharmacokinetic 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 2677G>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 pharmacokinetic analysis indicates moderate interindividual variability in romidepsin pharmacokinetics and no clinically relevant covariates associated with the unexplained pharmacokinetic variability of romidepsin in this population. Population pharmacokinetic 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 pharmacokinetics (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. No clinically important covariates were identified. This model can be used to simulate and explore alternative dosing regimens and to develop exposure-response relationships for sorafenib. We characterized the pharmacokinetics (PK) of sorafenib in patients with solid tumours 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 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (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). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h(-1) (3.6-22.3 l h(-1) ), volume 213 l (50-1000 l), mean absorption transit time 1.98 h (0.5-13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h. Overall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified. The CPP completed PK analysis of the Phase II study of UCN-01, a protein kinase inhibitor, in relapsed and refractory anaplastic large-cell and mature T-cell lymphomas. Patients received UCN-01 at a dose of 45 mg/m/day over 72 hours for cycle 1 and at 45 mg/m/day over 36 hours thereafter. The PK evaluation characterized a difference in drug disposition in pediatric and adolescent versus adult patients. The results demonstrated the effect of 1 vs 3 week extended plasma sampling on the PK results of UCN-01, a drug with a long elimination half-life. The CPP conducted population PK analysis of a phase 1 study of olaparib with cisplatin and gemcitabine in adults with solid tumors. The analysis characterized the effects of gemcitabine on the disposition of oral olaparib in 23 patients. 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 (p<0.01). 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Scientific Cores Intramural Research (ZIC)
Project #
1ZICBC010548-09
Application #
8350099
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2011
Total Cost
$595,171
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Peer, Cody J; Goey, Andrew K L; Sissung, Tristan M et al. (2016) UGT1A1 genotype-dependent dose adjustment of belinostat in patients with advanced cancers using population pharmacokinetic modeling and simulation. J Clin Pharmacol 56:450-60
Goey, Andrew K L; Sissung, Tristan M; Peer, Cody J et al. (2016) Effects of UGT1A1 genotype on the pharmacokinetics, pharmacodynamics, and toxicities of belinostat administered by 48-hour continuous infusion in patients with cancer. J Clin Pharmacol 56:461-73
Goey, Andrew K L; Figg, William D (2016) UGT genotyping in belinostat dosing. Pharmacol Res 105:22-7
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
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Peer, Cody J; Sissung, Tristan M; Kim, Aerang et al. (2012) Sorafenib is an inhibitor of UGT1A1 but is metabolized by UGT1A9: implications of genetic variants on pharmacokinetics and hyperbilirubinemia. Clin Cancer Res 18:2099-107
Kelly, Ronan J; Draper, Deborah; Chen, Clara C et al. (2011) A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer. Clin Cancer Res 17:569-80
Holkova, Beata; Perkins, E Brent; Ramakrishnan, Viswanathan et al. (2011) Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms. Clin Cancer Res 17:3388-97

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