UNC Institute for Pharmacogenomics and Individualized Therapy

Chapel Hill, NC, United States

UNC Institute for Pharmacogenomics and Individualized Therapy

Chapel Hill, NC, United States
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Patel J.N.,UNC Institute for Pharmacogenomics and Individualized Therapy | Mandock K.,Yale New Haven Hospital | McLeod H.L.,UNC Institute for Pharmacogenomics and Individualized Therapy
Journal of Oncology Pharmacy Practice | Year: 2014

Background: The number of pharmacogenetic assays available is continuously expanding as more molecularly targeted anticancer drugs are under clinical development. While the literature regarding drug-gene associations and therapeutic implications is often robust, reviews regarding clinical assay availability and profiling methodologies of commonly used cancer biomarkers are often lacking. Objective: To concisely identify and describe cancer biomarkers and their respective pharmacogenetic assays currently available in clinical practice. Discussion: Analysis of germ-line DNA mutations can often help to predict pharmacokinetic and pharmacodynamic responses, whereas somatic DNA mutations are particularly useful in predicting tumor response. Molecular profiling and pre-emptive identification of cancer biomarkers can help to predict disease prognosis as well as response to anticancer therapy. Dozens of pharmacogenetic assays, utilizing several common methodologies, are currently available in clinical practice. It is essential for clinicians to understand the molecular pathways for anticancer drugs, the therapeutic implications of mutations within these pathways, the clinical assay(s) available to test for pharmacogenetic differences, and the common profiling methodology employed. Conclusion: As research continues to unveil more drug-gene and disease-gene associations, it is critical that clinicians understand which pharmacogenetic assays are available to identify inter-individual differences that predict safety and efficacy of anticancer drugs as we move toward the concept of personalized medicine. © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.


Lucas A.T.,University of North Carolina at Chapel Hill | Madden A.J.,University of North Carolina at Chapel Hill | Zamboni W.C.,University of North Carolina at Chapel Hill | Zamboni W.C.,UNC Institute for Pharmacogenomics and Individualized Therapy | Zamboni W.C.,Lineberger Comprehensive Cancer Center
Expert Opinion on Drug Metabolism and Toxicology | Year: 2015

Introduction: Major advances in carrier-mediated agents (CMAs), which include nanoparticles and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages such as increased exposure duration, greater solubility and delivery to tumor sites over their small molecule counterparts, there is substantial variability in how individual CMA formulations affect the pharmacology, pharmacokinetics and pharmacodynamics (efficacy and toxicity) of these agents.Areas covered: CMA formulations are complex in nature compared to their small molecule counterparts and consist of multiple components and variables that can affect the pharmacological profile. This review provides an overview of factors that affect the pharmacologic profiles observed in CMA-formulated chemotherapy, primarily in liposomal formulations, that are currently in preclinical or early clinical development.Expert opinion: Despite the numerous advantages that CMA formulations provide, their clinical use is still in its infancy. It is critical that we understand the mechanisms and effects of CMAs in navigating biological barriers and how these factors affect their biodistribution and delivery to tumors. Future studies are warranted to better understand the complex pharmacology and interaction between CMA carriers and biological systems, such as the mononuclear phagocyte system and tumor microenvironment. © 2015 © Informa UK, Ltd.


Ko E.M.,Penn Medicine | Ko E.M.,University of Pennsylvania | Lippmann Q.,University of North Carolina at Chapel Hill | Lippmann Q.,University of San Diego | And 6 more authors.
Gynecologic Oncology | Year: 2013

Introduction Studies have shown that body composition, age, gender, changes in monocyte count and repeated dosing alter pharmacokinetic properties of PEGylated liposomal doxorubicin (PLD). However, limited information exists regarding the clinical risk factors of ovarian cancer patients who develop palmar plantar erythrodysesthesia (PPE) while receiving PLD for cancer recurrence. Methods We conducted a retrospective cohort analysis of consecutive patients with recurrent ovarian and primary peritoneal cancer who were treated with PLD from 2005 to 2009. Clinical and pathologic data were abstracted from electronic medical records. Statistical analyses were performed using univariate and bivariate analyses, logistic regression, and log rank-tests. Results Twenty-three percent (31/133) of patients developed PPE. Age, body mass index (BMI), race, stage, and histology did not significantly differ between PPE and non-PPE patients. There was a possible trend for decreasing PPE with increasing body mass index (BMI) (24.5% of normal weight, 27.5% of overweight; 23.8% of obese class I; 13.3% of obese class II; and 0% of obese class III), though not statistically significant. The number of chemotherapy regimens prior to PLD, and the mean cycles of PLD received did not differ between patients with and without PPE. 77.4% of PPE cases occurred within the first 3 infusion cycles. PPE was not associated with time to progression. Conclusion Nearly one-quarter of ovarian cancer patients receiving PLD will develop PPE. Further investigation of factors such as BMI associated with PPE may aid in patient selection for PLD, and future development of other nanoparticle and liposomal agents. © 2013 Elsevier Inc.


Jensen B.C.,UNC McAllister Heart Institute | McLeod H.L.,UNC Institute for Pharmacogenomics and Individualized Therapy
Pharmacogenomics | Year: 2013

Damage to the heart can result from both traditional chemotherapeutic agents, such as doxorubicin, and newer 'targeted therapies, such as trastuzumab. This chemotherapeutic cardiotoxicity is potentially life-threatening and necessitates limiting or discontinuing an otherwise-effective cancer treatment. Clinical strategies focus on surveillance rather than prevention, although there are no specific therapies for this highly morbid adverse effect. Current models for prospectively predicting risk of chemotherapeutic cardiotoxicity are limited. Cardiotoxicity can occur idiosyncratically in patients without obvious demographic risk factors, suggesting a genetically determined susceptibility, and candidate-gene studies have identified a limited number of variants that increase risk. In this commentary we indicate a need for more powerful means to identify risk prospectively, and suggest that broad pharmacogenomic approaches may be fruitful. © 2013 Future Medicine Ltd.


Caron W.P.,University of North Carolina at Chapel Hill | Morgan K.P.,University of North Carolina at Chapel Hill | Zamboni B.A.,Carlow University | Zamboni W.C.,University of North Carolina at Chapel Hill | And 2 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Nanoparticles or carrier-mediated agents have been designed to prolong drug circulation time, increase tumor delivery, and improve therapeutic index compared to their small-molecule counterparts. The starting dose for phase I studies of small molecules and nanoparticles anticancer agents is based on the toxicity profile of the most sensitive species (e.g., rat or canine), but the optimal animal model for these studies of nanoparticles is unclear. The objective of this study was to evaluate the design, progression, and outcomes of phase I studies of nanoparticles compared with small-molecule anticancer agents. Experimental design: In preclinical studies, the maximum tolerated dose (MTD) in rats and dogs was evaluated for nanoparticles and their respective small molecules. In phase I clinical trials in patients with advanced solid tumors, the basis for starting dose, the number of dose escalations, number of patients enrolled, and the ratio of MTD to starting dose was determined for nanoparticles and small molecules. Results: The mean ratio of MTD to starting dose in clinical phase I studies was significantly greater for nanoparticles (13.9 ± 10.8) compared with small molecules (2.1 ± 1.1; P = 0.005). The number of dose levels in a clinical phase I study was also significantly greater for nanoparticles (7.3 ± 2.9) compared with small molecules (4.1 ± 1.5; P = 0.008). Conclusions: The degree of dose escalation from starting dose to MTD was significantly greater for nanoparticles as compared with small-molecule anticancer drugs. These findings necessitate the need to identify the most appropriate preclinical animal model to use when evaluating nanoparticles toxicity. © 2013 American Association for Cancer Research.


Schipani A.,University of Liverpool | Siccardi M.,University of Liverpool | Siccardi M.,University of Turin | D'Avolio A.,University of Turin | And 17 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2010

Atazanavir (ATV) plasma concentrations are influenced by CYP3A4 and ABCB1, which are regulated by the pregnane X receptor (PXR; NR1I2). PXR expression is correlated with CYP3A4 in liver in the absence of enzyme inducers. The PXR single nucleotide polymorphism (SNP) 63396C→T (rs2472677) alters PXR expression and CYP3A4 activity in vitro, and we previously showed an association of this polymorphism with unboosted ATV plasma concentrations. The aim of this study was to develop a population pharmacokinetic analysis to quantify the impact of 63396C→T and diurnal variation on ATV clearance. A population analysis was performed with 323 plasma samples from 182 randomly selected patients receiving unboosted ATV. Two hundred fifty-nine of the blood samples were collected at random time points, and 11 patients had a full concentration-time profile at steady state. Nonlinear mixed effects modeling was applied to explore the effects of PXR 63396C→T, patient demographics, and diurnal variation. A one-compartment model with first-order absorption and lag time best described the data. Population clearance was 19.7 liters/h with interpatient variability or coefficient of variation (CV) of 21.5%. Homozygosity for the T allele for PXR 63396 was associated with a 17.0% higher clearance that was statistically significant. Evening dosing was associated with 34% higher bioavailability than morning dosing. Patient demographic factors had no effect on ATV clearance. These data show an association of PXR 63396C→T and diurnal variation on unboosted ATV clearance. The association is likely to be mediated through an effect on hepatic PXR expression and therefore expression of its target genes (e.g., CYP3A4, SLCO1B1, and ABCB1), which are known to be involved in ATV clearance. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Madden A.J.,University of North Carolina at Chapel Hill | Rawal S.,University of North Carolina at Chapel Hill | Sandison K.,University of North Carolina at Chapel Hill | Schell R.,University of North Carolina at Chapel Hill | And 8 more authors.
Journal of Nanoparticle Research | Year: 2014

The pharmacokinetics (PK) of carrier-mediated agents (CMA) is dependent upon the carrier system. As a result, CMA PK differs greatly from the PK of small molecule (SM) drugs. Advantages of CMAs over SMs include prolonged circulation time in plasma, increased delivery to tumors, increased antitumor response, and decreased toxicity. In theory, CMAs provide greater tumor drug delivery than SMs due to their prolonged plasma circulation time. We sought to create a novel PK metric to evaluate the efficiency of tumor and tissue delivery of CMAs and SMs. We conducted a study evaluating the plasma, tumor, liver, and spleen PK of CMAs and SMs in mice bearing subcutaneous flank tumors using standard PK parameters and a novel PK metric entitled relative distribution over time (RDI-OT), which measures efficiency of delivery. RDI-OT is defined as the ratio of tissue drug concentration to plasma drug concentration at each time point. The standard concentration versus time area under the curve values (AUC) of CMAs were higher in all tissues and plasma compared with SMs. However, 8 of 17 SMs had greater tumor RDI-OT AUC0–last values than their CMA comparators and all SMs had greater tumor RDI-OT AUC0–6 h values than their CMA comparators. Our results indicate that in mice bearing flank tumor xenografts, SMs distribute into tumor more efficiently than CMAs. Further research in additional tumor models that may more closely resemble tumors seen in patients is needed to determine if our results are consistent in different model systems. © 2014, Springer Science+Business Media Dordrecht.


Petschauer J.S.,University of North Carolina at Chapel Hill | Madden A.J.,University of North Carolina at Chapel Hill | Kirschbrown W.P.,University of North Carolina at Chapel Hill | Song G.,University of North Carolina at Chapel Hill | And 2 more authors.
Nanomedicine | Year: 2015

Major advances in carrier-mediated agents, which include nanoparticles, nanosomes and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages, such as greater solubility, duration of exposure and delivery to the site of action over their small-molecule counterparts, there is substantial variability in systemic clearance and distribution, tumor delivery and pharmacologic effects (efficacy and toxicity) of these agents. This review provides an overview of factors that affect the pharmacokinetics and pharmacodynamics of carrier-mediated agents in preclinical models and patients. © 2015 Future Medicine Ltd.


Murray B.,UNC Hospitals and Clinics | Hawes E.,UNC Hospitals and Clinics | Lee R.-A.,University of North Carolina at Chapel Hill | Watson R.,026 Burnett Womack Building | And 3 more authors.
Pharmacogenomics | Year: 2013

Advances in the management of patients after solid organ transplantation have led to dramatic decreases in rates of acute rejection, but long-term graft and patient survival have remained unchanged. Individualized therapy after transplant will ideally provide adequate immunosuppression while limiting the adverse effects of drug therapy that significantly impact graft survival. Therapeutic drug monitoring represents the best approximation of individualized drug therapy in transplant at this time; however, obtaining pharmacogenomic data in transplant patients has the potential to enhance our current practice. Polymorphisms of target genes that impact pharmacokinetics have been identified for most immunosuppressants, including tacrolimus, cyclosporine, mycophenolate, azathioprine and sirolimus. In the future, pre-emptive assessment of a patients genetic profile may inform drug selection and provide information on specific doses that will improve efficacy and limit toxicity. © 2013 Future Medicine Ltd.


PubMed | UNC Institute for Pharmacogenomics and Individualized Therapy
Type: Journal Article | Journal: Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners | Year: 2014

The number of pharmacogenetic assays available is continuously expanding as more molecularly targeted anticancer drugs are under clinical development. While the literature regarding drug-gene associations and therapeutic implications is often robust, reviews regarding clinical assay availability and profiling methodologies of commonly used cancer biomarkers are often lacking.To concisely identify and describe cancer biomarkers and their respective pharmacogenetic assays currently available in clinical practice.Analysis of germ-line DNA mutations can often help to predict pharmacokinetic and pharmacodynamic responses, whereas somatic DNA mutations are particularly useful in predicting tumor response. Molecular profiling and pre-emptive identification of cancer biomarkers can help to predict disease prognosis as well as response to anticancer therapy. Dozens of pharmacogenetic assays, utilizing several common methodologies, are currently available in clinical practice. It is essential for clinicians to understand the molecular pathways for anticancer drugs, the therapeutic implications of mutations within these pathways, the clinical assay(s) available to test for pharmacogenetic differences, and the common profiling methodology employed.As research continues to unveil more drug-gene and disease-gene associations, it is critical that clinicians understand which pharmacogenetic assays are available to identify inter-individual differences that predict safety and efficacy of anticancer drugs as we move toward the concept of personalized medicine.

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