35 research outputs found
Abstract 5042: Defining an optimal single time point sampling strategy representative of overall capecitabine pharmacokinetics
No full textAbstract
Background: Capecitabine is an oral chemotherapy pro-drug used to treat advanced colorectal cancer. Patients may experience hand-foot syndrome and diarrhea, among other side effects, that affect quality of life and may necessitate dose modification or discontinuation. There is significant regional variation in capecitabine tolerability, related to a myriad of factors including pharmacogenomics, dietary and cultural differences. Capecitabine dose modification, when necessary, is empirical based on toxicity suggesting a personalized dosing approach might better optimize therapy. Objective: In phase I of a personalized dosing approach, our objective was to define an optimal time point for blood sampling that best represented overall exposure of capecitabine and its metabolites.
Methods: A single-arm prospective pharmacokinetic cohort study of patients with advanced or metastatic colorectal cancer prescribed capecitabine monotherapy was done. Blood samples were collected pre-dose and at timed intervals between 0 and 8 hours post-dose. Plasma concentration of capecitabine and its major metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouracil (5'-DFUR), were measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).
Results: 26 patients were enrolled; 65% were male and 42.3% had metastatic disease. Mean capecitabine dose was 2854 ± 944 mg. Hand-foot symptoms (60%), fatigue (53%) and diarrhea (30%) were the most common adverse drug reactions. Dose normalized mean (SD) AUC0-8h for capecitabine, 5’-DFCR and 5’-DFUR were 6.74 (3.0), 4.19 (1.5) and 6.33 (2.8) ng/ml*h, respectively. Spearman correlation between dose normalized concentrations and AUC at each blood draw was performed. The best estimated time points for capecitabine, 5’-DFCR and 5’-DFUR were 1.5, 2 and 2 hours with r2 values of 0.6 (p <0.01), 0.64 (p <0.001) and 0.51 (p <0.01), respectively. There was a significant correlation seen between capecitabine AUC and need for subsequent dose reduction (p<0.05).
Conclusions: Blood samples obtained between 1.5 and 2 hours post-dose provide the best estimate of capecitabine exposure. Further pharmacokinetic analysis in this cohort is ongoing. This blood draw strategy will be used in a larger trial intended to develop a personalized capecitabine dosing algorithm.
Citation Format: Stephen Welch, Wendy Teft, John Lenehan, Rommel Tirona, Karen Lumsden, Eric Winquist, Richard B. Kim. Defining an optimal single time point sampling strategy representative of overall capecitabine pharmacokinetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5042. doi:10.1158/1538-7445.AM2017-5042</jats:p
Structure-Function analysis of the CTLA-4 interaction with PP2A
No full textBackgroundCTLA-4 functions primarily as an inhibitor of T cell activation. There are several candidate explanations as to how CTLA-4 modulates T cell responses, but the exact mechanism remains undefined. The tail of CTLA-4 does not have any intrinsic enzymatic activity but is able to associate with several signaling molecules including the serine/threonine phosphatase PP2A. PP2A is a heterotrimeric molecule comprised of a regulatory B subunit associated with a core dimer of a scaffolding (A) and a catalytic (C) subunit.ResultsHere, we performed an analysis of the human CTLA-4 interface interacting with PP2A. We show that PP2A interacts with the cytoplasmic tail of CTLA-4 in two different sites, one on the lysine rich motif, and the other on the tyrosine residue located at position 182 (but not the tyrosine 165 of the YVKM motif). Although the interaction between CTLA-4 and PP2A was not required for inhibition of T cell responses, it was important for T cell activation by inverse agonists of CTLA-4. Such an interaction was functionally relevant because the inverse agonists induced IL-2 production in an okadaic acid-dependent manner.ConclusionOur studies demonstrate that PP2A interacts with the cytoplasmic tail of human CTLA-4 through two motifs, the lysine rich motif centered at lysine 155 and the tyrosine residue 182. This interaction and the phosphatase activity of PP2A are important for CTLA-4-mediated T cell activation
Pharmacogenomics of Aromatase Inhibitor Associated Arthralgia: Personalized Medicine for Patients with ER + Breast Cancer
No full textPharmacogenomics Guided-Personalization of Warfarin and Tamoxifen
No full textThe use of pharmacogenomics to personalize drug therapy has been a long-sought goal for warfarin and tamoxifen. However, conflicting evidence has created reason for hesitation in recommending pharmacogenomics-guided care for both drugs. This review will provide a summary of the evidence to date on the association between cytochrome P450 enzymes and the clinical end points of warfarin and tamoxifen therapy. Further, highlighting the clinical experiences that we have gained over the past ten years of running a personalized medicine program, we will offer our perspectives on the utility and the limitations of pharmacogenomics-guided care for warfarin and tamoxifen therapy
Endoxifen, the Active Metabolite of Tamoxifen, Is a Substrate of the Efflux Transporter P-Glycoprotein (Multidrug Resistance 1)
No full textStructure-Function analysis of the CTLA-4 interaction with PP2A
No full textAbstract Background CTLA-4 functions primarily as an inhibitor of T cell activation. There are several candidate explanations as to how CTLA-4 modulates T cell responses, but the exact mechanism remains undefined. The tail of CTLA-4 does not have any intrinsic enzymatic activity but is able to associate with several signaling molecules including the serine/threonine phosphatase PP2A. PP2A is a heterotrimeric molecule comprised of a regulatory B subunit associated with a core dimer of a scaffolding (A) and a catalytic (C) subunit. Results Here, we performed an analysis of the human CTLA-4 interface interacting with PP2A. We show that PP2A interacts with the cytoplasmic tail of CTLA-4 in two different sites, one on the lysine rich motif, and the other on the tyrosine residue located at position 182 (but not the tyrosine 165 of the YVKM motif). Although the interaction between CTLA-4 and PP2A was not required for inhibition of T cell responses, it was important for T cell activation by inverse agonists of CTLA-4. Such an interaction was functionally relevant because the inverse agonists induced IL-2 production in an okadaic acid-dependent manner. Conclusion Our studies demonstrate that PP2A interacts with the cytoplasmic tail of human CTLA-4 through two motifs, the lysine rich motif centered at lysine 155 and the tyrosine residue 182. This interaction and the phosphatase activity of PP2A are important for CTLA-4-mediated T cell activation.</p
Profound reduction in tamoxifen active metabolite endoxifen in a breast cancer patient treated with rifampin prior to initiation of an anti-TNFα biologic for ulcerative colitis: a case report
No full textAbstract 1703: Importance of pregnane X receptor (PXR) and P-glycoprotein (MDR1) to tamoxifen response and endoxifen disposition
No full textAdditional file 1: of Profound reduction in tamoxifen active metabolite endoxifen in a breast cancer patient treated with rifampin prior to initiation of an anti-TNFÎą biologic for ulcerative colitis: a case report
No full textSpreadsheet of analyte concentrations and metabolite/parent ratios for tamoxifen and its metabolites. (XLSX 10 kb
