Publications by authors named "Beth Zamboni"

23 Publications

  • Page 1 of 1

Satisfaction and Technology Acceptance of Staff Regarding Use of Continuous Video Monitoring in Comparison With Sitters.

J Nurs Adm 2021 Feb;51(2):60-62

Author Affiliations: Senior Clinician (Dr Hebb) and Programmatic Nurse Specialist (Dr George), UPMC Shadyside Hospital; and Program Director of Healthcare Data Analytics and Health Management (Dr Kistler), and Mathematics and Data Analytics Department Chair (Dr Zamboni), Carlow University, Pittsburgh, Pennsylvania. This study was conducted while Dr. Hebb was a DNP student at Carlow University.

Objective: The purpose of this study was to determine staff satisfaction and technology acceptance of continuous video monitoring (CVM) in comparison to sitters.

Background: Traditionally, sitters have been used to prevent falls in hospitals. Continuous video monitoring has emerged to reduce costs associated with sitters while maintaining safety.

Methods: A descriptive online survey using a modified version of the Technology Acceptance Model was used to gain insight on technology acceptance and satisfaction levels of clinical staff related to CVM.

Results: Only 12.73% found CVM to be as effective as sitters. Statistical significance was shown comparing sitters with CVM. A positive correlation was found with perceived ease of use and perceived usefulness of CVM.

Conclusions: Understanding staff satisfaction and technology acceptance is imperative for nurse leaders and administration when implementing new technologies.
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http://dx.doi.org/10.1097/NNA.0000000000000970DOI Listing
February 2021

Patterns and characteristics associated with surface contamination of hazardous drugs in hospital pharmacies.

Am J Health Syst Pharm 2019 Apr;76(9):591-598

University of North Carolina at Chapel Hill Eshelman School of Pharmacy, Chapel Hill, NC.

Purpose: The surface contamination levels of 5 commonly used hazardous drugs in hospital pharmacies are summarized, identifying practice patterns associated with contamination.

Methods: Contamination testing data were compiled to evaluate surface contaminants of 5 hazardous drugs (docetaxel, paclitaxel, cyclophosphamide, ifosfamide, and 5-fluorourcil). Data from 5,842 wipes over 6 years were collected from 338 hospital pharmacies. The contamination level for each drug was categorized as nondetectable (ND; ≤10 ng/ft2), low (between 10 and ≤100 ng/ft2), medium (between 100 and ≤1,000 ng/ft2) or high (>1,000 ng/ft2). Surface exposures for each drug were summarized based on location, contamination at first and subsequent wipe events, and the use of a closed system transfer device (CSTD).

Results: The majority of contamination results corresponded to locations at or near hazardous drug preparation, but also occurred in areas where hazardous drugs were not prepared. There was a higher incidence of contamination levels (high, medium, and low, respectively) at first wipe event (10.2%, 17.4%, and 17.7%) compared to subsequent wipe events (5.8%, 12.2%, and 13.6%) (p < 0.0001). There was a lower incidence of contamination levels at institutions that used CSTDs (6.3%, 12.8%, and 14.4%) compared to institutions that did not use CSTDs (14.2%, 17.9%, and 17.3%) (p < 0.0001).

Conclusions: The majority of highest contamination levels corresponded to locations where hazardous drugs were prepared. While the rate of contamination was lower at subsequent wipe events and at institutions that used CSTDs, contamination was not completely eliminated in either scenario.
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http://dx.doi.org/10.1093/ajhp/zxz033DOI Listing
April 2019

Exertional Heat Illness Among Secondary School Athletes: Statewide Policy Implications.

J Sch Nurs 2018 Apr 23;34(2):156-164. Epub 2017 Apr 23.

3 Mathematics and Humanities Department, Carlow University, Pittsburgh, PA, USA.

Exertional heat illness (EHI) is a leading cause of preventable death among student athletes. While causes and preventative measures for EHI are known, school districts may not be implementing evidence-based practices. This descriptive, exploratory study explored school policies, resources, and practices of coaches in a mid-Atlantic state in the prevention and identification of EHI; 397 responded. Ninety-three percent knew of EHI, but only 52% scheduled acclimatization. Coaches reporting a heat emergency plan (56%) were significantly more likely to follow other evidence-based recommendations: altering equipment ( p < .0001, odds ratio [ OR] = 2.53), monitoring environment ( p < .0001, OR = 2.56), providing acclimatization ( p < .0001, OR = 2.50), having athletic trainers at practices ( p < .0001, OR = 4.75), and believed that they could handle the emergency until EMS arrival ( p < .001, OR = 2.48). School districts should comply with evidence-based guidelines. School nurses play a key role in education, developing emergency plans and training coaches in first aid.
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http://dx.doi.org/10.1177/1059840517706104DOI Listing
April 2018

Technetium Tc 99m sulfur colloid phenotypic probe for the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin in women with ovarian cancer.

Cancer Chemother Pharmacol 2016 Mar 28;77(3):565-73. Epub 2016 Jan 28.

Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill-Eshelman School of Pharmacy, 120 Mason Farm Road, Suite 1013, CB 7361, Chapel Hill, NC, 27599-7361, USA.

Purpose: Significant variability in the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin (PLD) exists. PLD undergoes clearance via the mononuclear phagocyte system (MPS). Technetium Tc 99m sulfur colloid (TSC) is approved for imaging MPS cells. We investigated TSC as a phenotypic probe of PLD pharmacokinetics and pharmacodynamics in women with epithelial ovarian cancer.

Methods: TSC 10 mCi IVP was administered and followed by dynamic planar and SPECT/CT imaging and blood pharmacokinetics sampling. PLD 30-40 mg/m(2) IV was administered with or without carboplatin, followed by plasma pharmacokinetics sampling.

Results: There was a linear relationship between TSC clearance and encapsulated doxorubicin clearance (R(2) = 0.61, p = 0.02), particularly in patients receiving PLD alone (R(2) = 0.81, p = 0.04). There was a positive relationship (ρ = 0.81, p = 0.01) between maximum grade palmar-plantar erythrodysesthesia toxicity developed and estimated encapsulated doxorubicin concentration in hands.

Conclusions: TSC is a phenotypic probe for PLD pharmacokinetics and pharmacodynamics and may be used to individualize PLD therapy in ovarian cancer and for other nanoparticles in development.
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http://dx.doi.org/10.1007/s00280-015-2945-yDOI Listing
March 2016

Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors.

Int J Nanomedicine 2015 10;10:1201-9. Epub 2015 Feb 10.

UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA ; UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA ; UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA ; Carolina Center for Cancer Nanotechology Excellence, University of North Carolina, Chapel Hill, NC, USA.

IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged <60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years. There was an inverse relationship between patient age and percent decrease in monocytes at nadir, ie, younger patients have a higher percent decrease in monocytes. Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11. The pharmacokinetics and pharmacodynamics of IHL-305 are consistent with those of other PEGylated liposomal carriers. Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes.
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http://dx.doi.org/10.2147/IJN.S62911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334335PMC
May 2016

Population pharmacokinetics of PEGylated liposomal CPT-11 (IHL-305) in patients with advanced solid tumors.

Eur J Clin Pharmacol 2013 Dec 30;69(12):2073-81. Epub 2013 Aug 30.

UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA.

Purpose: To investigate pharmacokinetics (PK) of encapsulated CPT-11, released CPT-11 and the active metabolite SN-38 following administration of IHL-305 and to identify factors that may influence IHL-305 PK.

Methods: Plasma samples from 39 patients with solid tumors were collected in a phase I study. IHL-305 was administered as a 1 h IV infusion with doses ranging from 3.5 to 210 mg/m(2). Plasma concentrations of encapsulated CPT-11, released CPT-11 and SN-38 were used to develop a population PK model using NONMEM®.

Results: PK of encapsulated CPT-11 was described by 1-compartment model with nonlinear clearance and PK of released CPT-11 was described by a 1-compartment model with linear clearance for all patients. PK of the active metabolite SN-38 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that gender was a significant covariate for volume of distribution of encapsulated CPT-11. Vencap in male patients is 1.5-fold higher compared with female patients.

Conclusions: The developed population PK modeling approach is useful to predict PK exposures of encapsulated and released drug and can be applied to the more than 300 other nanoparticle formulations of anticancer agents that are currently in development. The effect of gender on PK of IHL-305 needs to be further evaluated.
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http://dx.doi.org/10.1007/s00228-013-1580-yDOI Listing
December 2013

Meta-analysis of inter-patient pharmacokinetic variability of liposomal and non-liposomal anticancer agents.

Nanomedicine 2014 Jan 24;10(1):109-17. Epub 2013 Jul 24.

Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina (UNC) Eshelman School of Pharmacy, Chapel Hill, NC, USA; Translational Oncology and Nanoparticle Drug Development Initiative (TOND(2)I) Lab, UNC, Chapel Hill, NC, USA; Molecular Therapeutics, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA; UNC GLP Bioanalytical Facility, Chapel Hill, NC, USA; Institute for Pharmacogenomics and Individualized Therapy (IPIT), Chapel Hill, NC, USA; Carolina Center of Cancer Nanotechnology Excellence (C-CCNE), Chapel Hill, NC, USA; North Carolina Biomedical Innovation Network (NC BIN), Chapel Hill, NC, USA. Electronic address:

Unlabelled: A meta-analysis was conducted to evaluate the inter-patient pharmacokinetic (PK) variability of liposomal and small molecule (SM) anticancer agents. Inter-patient PK variability of 9 liposomal and SM formulations of the same drug was evaluated. PK variability was measured as coefficient of variance (CV%) of area under the plasma concentration versus time curve (AUC) and the fold-difference between AUCmax and AUCmin (AUC range). CV% of AUC and AUC ranges were 2.7-fold (P<0.001) and 16.7-fold (P=0.13) greater, respectively, for liposomal compared with SM drugs. There was an inverse linear relationship between the clearance (CL) of liposomal agents and PK variability with a lower CL associated with greater PK variability (R(2)=0.39). PK variability of liposomal agents was greater when evaluated from 0-336 h compared with 0-24h. PK variability of liposomes is significantly greater than SM. The factors associated with the PK variability of liposomal agents need to be evaluated.

From The Clinical Editor: In this meta-analysis, the inter-patient pharmacokinetic variability of 9 liposomal and small molecule anti-cancer agents was studied. The authors determined that several parameters are in favor of the liposomal formulation; however, the PK variability of the formulation was higher compared with small molecule agents, the reason for which remains to be determined in future studies.
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http://dx.doi.org/10.1016/j.nano.2013.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877184PMC
January 2014

A review of study designs and outcomes of phase I clinical studies of nanoparticle agents compared with small-molecule anticancer agents.

Clin Cancer Res 2013 Jun 25;19(12):3309-15. Epub 2013 Apr 25.

Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina (UNC) Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, , Chapel Hill, NC 27599, USA.

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.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-3649DOI Listing
June 2013

Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients.

Int J Nanomedicine 2012 19;7:5555-64. Epub 2012 Oct 19.

UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.

S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional pharmacokinetic-pharmacodynamic (PK-PD) interaction between S-CKD602 and monocytes. Plasma concentrations of encapsulated CKD-602 and monocytes counts from 45 patients with solid tumors were collected following intravenous administration of S-CKD602 in the phase I study. The PK-PD models were developed and fit simultaneously to the PK-PD data, using NONMEM(®). The monocytopenia after administration of S-CKD602 was described by direct toxicity to monocytes in a mechanism-based model, and by direct toxicity to progenitor cells in bone marrow in a myelosuppression-based model. The nonlinear PK disposition of S-CKD602 was described by linear degradation and irreversible binding to monocytes in the mechanism-based model, and Michaelis-Menten kinetics in the myelosuppression-based model. The mechanism-based PK-PD model characterized the nonlinear PK disposition, and the bidirectional PK-PD interaction between S-CKD602 and monocytes.
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http://dx.doi.org/10.2147/IJN.S35751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480239PMC
April 2013

Genetically engineered cancer models, but not xenografts, faithfully predict anticancer drug exposure in melanoma tumors.

Oncologist 2012 19;17(10):1303-16. Epub 2012 Sep 19.

University of North Carolina Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, 1013 Genetic Medicine Building, CB 7361, Chapel Hill, North Carolina 27599-7361, USA.

Background: Rodent studies are a vital step in the development of novel anticancer therapeutics and are used in pharmacokinetic (PK), toxicology, and efficacy studies. Traditionally, anticancer drug development has relied on xenograft implantation of human cancer cell lines in immunocompromised mice for efficacy screening of a candidate compound. The usefulness of xenograft models for efficacy testing, however, has been questioned, whereas genetically engineered mouse models (GEMMs) and orthotopic syngeneic transplants (OSTs) may offer some advantages for efficacy assessment. A critical factor influencing the predictability of rodent tumor models is drug PKs, but a comprehensive comparison of plasma and tumor PK parameters among xenograft models, OSTs, GEMMs, and human patients has not been performed.

Methods: In this work, we evaluated the plasma and tumor dispositions of an antimelanoma agent, carboplatin, in patients with cutaneous melanoma compared with four different murine melanoma models (one GEMM, one human cell line xenograft, and two OSTs).

Results: Using microdialysis to sample carboplatin tumor disposition, we found that OSTs and xenografts were poor predictors of drug exposure in human tumors, whereas the GEMM model exhibited PK parameters similar to those seen in human tumors.

Conclusions: The tumor PKs of carboplatin in a GEMM of melanoma more closely resembles the tumor disposition in patients with melanoma than transplanted tumor models. GEMMs show promise in becoming an improved prediction model for intratumoral PKs and response in patients with solid tumors.
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http://dx.doi.org/10.1634/theoncologist.2012-0274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3481896PMC
June 2013

Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients.

Cancer Chemother Pharmacol 2012 Jan 18;69(1):43-50. Epub 2011 May 18.

UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Purpose: There is significant inter-patient variability in the pharmacokinetics of pegylated liposomal doxorubicin (PLD). Identification of factors affecting the pharmacokinetics of PLD would enable personalization of therapy. We previously reported that age, gender, body composition, and monocytes affect the clearance of other liposomal agents. Therefore, we evaluated how these factors affect the pharmacokinetics of PLD.

Methods: Pharmacokinetic studies of PLD were performed as part of phase I and II studies in 70 patients with solid tumors or Kaposi's sarcoma. The effects of monocyte count, age, gender, and body composition on PLD clearance were examined.

Results: There was a 15.3-fold variability in PLD clearance. Body surface area-based dosing did not significantly reduce the variability in PLD clearance. The mean ± SD clearance for patients <60 years old and ≥60 years old were 54.6 ± 28.5 and 23.3 ± 10.8 mL/h/m(2), respectively (P < 0.0001), and for female and male patients were 23.7 ± 18.8 and 55.6 ± 26.8 mL/h/m(2), respectively (P < 0.0001). A reduction in pre-cycle monocyte count was associated with a greater reduction in PLD clearance.

Conclusions: Age, gender, and monocyte counts appear to correlate with PLD clearance. Further investigation of the association between these factors, PLD pharmacokinetics, and clinical outcomes (efficacy and toxicity) is warranted. These effects on the pharmacokinetics of PLD may be an approach for personalizing PLD therapy and may affect other pegylated liposomes and nanoparticle agents.
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http://dx.doi.org/10.1007/s00280-011-1664-2DOI Listing
January 2012

Pharmacologic and phenotypic study of docetaxel in patients with ovarian or primary peritoneal cancer.

Cancer Chemother Pharmacol 2011 Nov 25;68(5):1255-62. Epub 2011 Mar 25.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 1013 Genetic Medicine Building, CB 7361, Chapel Hill, NC 27599, USA.

Purpose: The objectives of this study were to determine whether the midazolam clearance predicted docetaxel pharmacokinetics, CA-125 change, and response and to assess the impact of cytochrome P450 (CYP) 3A5 and ATP-binding cassette, subfamily B, member 1 (ABCB1) genotypes on docetaxel pharmacokinetics and pharmacodynamics in ovarian or primary peritoneal cancer patients.

Methods: Thirty-four patients with advanced ovarian and primary peritoneal cancer were administered docetaxel at 75 mg/m(2) as a 1-h infusion in combination with carboplatin IV over 30 min at a target AUC of 5 mg/ml min. Cycles were repeated every 21 days for 6 cycles. Midazolam was administered at 2 mg as a 30-min IV infusion the day prior to cycle one of docetaxel administration. Pharmacokinetic studies of docetaxel and CYP3A5 and ABCB1 genotype studies were performed.

Results: There was an inverse relationship between midazolam clearance (CL) and CA-125 level after cycle 6 where a higher midazolam CL was associated with a CA-125 <10 U/ml (P = 0.007) and CA-125 <15 U/ml (P = 0.048). The CA-125 categories were associated with response achieved (complete response/partial response) (CR/PR), stable disease (SD), and progressive disease (PD) at the end of therapy (P = 0.0173). Docetaxel CL was not related to midazolam CL or genotype. Docetaxel exposure and genotypes were not related to toxicity or response (P > 0.05).

Conclusions: The midazolam CL predicted CA-125 levels and response that was independent of other factors including docetaxel pharmacokinetics. Future studies need to evaluate the mechanism for the relationship between midazolam CL and response in patients with ovarian cancer.
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http://dx.doi.org/10.1007/s00280-011-1609-9DOI Listing
November 2011

Population pharmacokinetics of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies.

J Clin Pharmacol 2012 Feb;52(2):180-94

University of North Carolina (UNC) Eshelman School of Pharmacy, UNC, Chapel Hill, North CarolinaUNC Lineberger Comprehensive Cancer Center, UNC, Chapel Hill, North CarolinaUNC Institute for Pharmacogenomics and Individualized Therapy, UNC, Chapel Hill, North CarolinaCarolina Center for Cancer Nanotechology Excellence, UNC, Chapel Hill, North CarolinaUniversity of Pittsburgh Cancer Institute, Pittsburgh, PennsylvaniaSchool of Medicine, University of Pittsburgh, PittsburghDepartment of Mathematics, Carlow University, PittsburghCKD Research Institute, Chonan, KoreaSeoul National University Hospital, Seoul, Korea.

S-CKD602 is a pegylated long-circulating liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. A population pharmacokinetic (PK) model for encapsulated and released CKD-602 following administration of S-CKD602 was developed to assess factors that may influence S-CKD602 PK. Plasma samples from 45 patients with solid tumors were collected in a phase 1 study. S-CKD602 was administered as a 1-hour intravenous infusion with doses ranging from 0.1 to 2.5 mg/m(2) . Plasma concentrations of encapsulated and released CKD-602 were used to develop a population PK model using NONMEM. PK of encapsulated CKD-602 was described by a 1-compartment model with nonlinear clearance, and PK of released CKD-602 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that tumor in the liver was a significant covariate for clearance of encapsulated CKD-602 and that age significantly influenced the release rate of CKD-602 from S-CKD602. Maximum elimination rate in patients with liver tumor is 1.5-fold higher compared with patients without liver tumor. Release rate of CKD-602 from S-CKD602 in patients less than 60 years old was 2.7-fold higher compared with patients 60 years old or older. These observations have potential implications in the optimal dosing of liposomal agents.
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http://dx.doi.org/10.1177/0091270010394851DOI Listing
February 2012

Bidirectional pharmacodynamic interaction between pegylated liposomal CKD-602 (S-CKD602) and monocytes in patients with refractory solid tumors.

J Liposome Res 2011 Jun 14;21(2):158-65. Epub 2010 Jul 14.

Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA.

Background:  STEALTH(®) liposomal CKD-602 (S-CKD602), a camptothecin analog, is eliminated by the reticuloendothelial system (RES), which consists of cells, including monocytes. We evaluated the relationship between monocyte and absolute neutrophil counts (ANCs) in the blood and pharmacokinetic disposition of S-CKD602 and nonliposomal CKD-602 (NL-CKD602) in patients.

Methods:  As part of a phase I study of S-CKD602 and phase I and II studies of NL-CKD602, the percent decreases in ANC and monocytes at their nadir were calculated. After S-CKD602, the amount of CKD-602 recovered in urine was measured.

Results:  For S-CKD602 in patients <60 years, the percent decrease in ANC and monocytes were 43  ±  31 and 58  ±  26%, respectively (P = 0.001). For S-CKD602 in patients ≥60, the percent decrease in ANC and monocytes were 41  ±  31 and 45  ±  36%, respectively (P =  0.50). For NL-CKD602 (n = 42), the percent decrease in ANC and monocytes were similar (P >  0.05). For S-CKD602, the relationship between the percent decrease in monocytes and CKD-602 recovered in urine was stronger in patients <60 (R(2) =  0.82), compared with patients ≥60 (R(2) =  0.30).

Conclusions:  Monocytes are more sensitive to S-CKD602, compared with neutrophils, and the increased sensitivity is related to the liposomal formulation, not CKD-602. These results suggest that monocytes engulf S-CKD602, which causes the release of CKD-602 from the liposome and toxicity to the monocytes, and that the effects are more prominent in patients <60.
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http://dx.doi.org/10.3109/08982104.2010.496085DOI Listing
June 2011

Tumor disposition of pegylated liposomal CKD-602 and the reticuloendothelial system in preclinical tumor models.

J Liposome Res 2011 Mar 9;21(1):70-80. Epub 2010 Jun 9.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599-7360, USA.

Liposomes, such as pegylated-liposomal CKD-602 (S-CKD602), undergo catabolism by macrophages and dendritic cells (DCs) of the reticuloendothelial system (RES). The relationship between plasma and tumor disposition of S-CKD602 and RES was evaluated in mice bearing A375 melanoma or SKOV-3 ovarian xenografts. Area under the concentration-time curves (AUCs) of liposomal encapsulated, released, and sum total (encapsulated + released) CKD-602 in plasma, tumor, and tumor extracellular fluid (ECF) were estimated. A375 and SKOV-3 tumors were stained with cd11b and cd11c antibodies as measures of macrophages and DC. The plasma disposition of S-CKD602 was similar in both xenograft models. The ratio of tumor sum total AUC to plasma sum total AUC was 1.7-fold higher in mice bearing human SKOV-3 xenografts, compared with A375. The ratio of tumor ECF AUC to tumor sum total AUC was 2-fold higher in mice bearing human SKOV-3 xenografts, compared with A375. The staining of cd11c was 4.5-fold higher in SKOV-3, compared with A375 (P < 0.0001). The increased tumor delivery and release of CKD-602 from S-CKD602 in the ovarian xenografts, compared with the melanoma xenografts, was consistent with increased cd11c staining, suggesting that variability in the RES may affect the tumor disposition of liposomal agents.
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http://dx.doi.org/10.3109/08982101003754385DOI Listing
March 2011

Conditional survival and the choice of conditioning set for patients with colon cancer: an analysis of NSABP trials C-03 through C-07.

J Clin Oncol 2010 May 20;28(15):2544-8. Epub 2010 Apr 20.

Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

Purpose: Colon cancer overall survival (OS) is usually computed from the time of diagnosis. Survival gives the initial prognosis but does not reflect how prognosis changes with changing hazard rates over time. Conditional survival (probability of surviving y additional years given they have survived x years [CS or OS|OS]) is an alternative measure that accounts for elapsed time since diagnosis, providing more relevant prognostic information. We extend the concept of CS to condition on the set of patients alive, recurrence-free, and second primary cancer-free (disease-free survival [OS|DFS]).

Patients And Methods: Using data from National Surgical Adjuvant Breast and Bowel Project trials C-03 through C-07, 5-year OS|DFS was calculated on patients who were disease free up to 5 years after diagnosis, stratified by age, stage, nodal status, and performance status (PS).

Results: For stage II, OS|DFS improved from 87% to 92% at 5 years. For stage III, OS|DFS improved from 69% to 88%. Patients younger than 50 years showed OS|DFS improvement from 79% to 95%; those older than 70 years showed no sustained increase in OS|DFS. Node-negative patients with > or = 12 nodes resected showed little change (89% to 94%); those with more than four positive nodes showed an improvement (57% to 86%). Patients with a PS of 0 or 1 demonstrated a small improvement; those with a PS of 2 did not (64% to 58%).

Conclusion: Prognosis improves over time for almost all groups of patients with colon cancer, especially those with positive nodes. OS|DFS is a more relevant measure of prognosis for those who have already survived disease free a period of time after diagnosis.
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http://dx.doi.org/10.1200/JCO.2009.23.0573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881729PMC
May 2010

Phase I and pharmacokinetic study of pegylated liposomal CKD-602 in patients with advanced malignancies.

Clin Cancer Res 2009 Feb 3;15(4):1466-72. Epub 2009 Feb 3.

Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Molecular Therapeutics, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599-7360, USA.

Purpose: S-CKD602 is a pegylated liposomal formulation of CKD602, a semisynthetic camptothecin analogue. Pegylated (STEALTH) liposomes can achieve extended drug exposure in plasma and tumor. Based on promising preclinical data, the first phase I study of S-CKD602 was done in patients with refractory solid tumors.

Experimental Design: S-CKD602 was administered i.v. every 3 weeks. Modified Fibonacci escalation was used (three to six patients/cohort), and dose levels ranged from 0.1 to 2.5 mg/m2. Serial plasma samples were obtained over 2 weeks and total (lactone+hydroxyl acid) concentrations of encapsulated, released, and sum total (encapsulated+released) CKD602 measured by liquid chromatography-tandem mass spectrometry.

Results: Forty-five patients (21 males) were treated. Median age, 62 years (range, 33-79 years) and Eastern Cooperative Oncology Group status, 0 to 1 (43 patients) and 2 (2 patients). Dose-limiting toxicities of grade 3 mucositis occurred in one of six patients at 0.3 mg/m2, grade 3 and 4 bone marrow suppression in two of three patients at 2.5 mg/m2, and grade 3 febrile neutropenia and anemia in one of six patients at 2.1 mg/m2. The maximum tolerated dose was 2.1 mg/m2. Partial responses occurred in two patients with refractory ovarian cancer (1.7 and 2.1 mg/m2). High interpatient variability occurred in the pharmacokinetic disposition of encapsulated and released CKD602.

Conclusions: S-CKD602 represents a promising new liposomal camptothecin analogue with manageable toxicity and promising antitumor activity. Phase II studies of S-CKD602 at 2.1 mg/m2 i.v. once every 3 weeks are planned. Prolonged plasma exposure over 1 to 2 weeks is consistent with STEALTH liposomes and provides extended exposure compared with single doses of nonliposomal camptothecins.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-1405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428134PMC
February 2009

Plasma and tissue disposition of non-liposomal DB-67 and liposomal DB-67 in C.B-17 SCID mice.

Invest New Drugs 2008 Oct 2;26(5):399-406. Epub 2008 Feb 2.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15213, USA.

Purpose: DB-67 is a silatecan, 7-silyl-modified camptothecin, with enhanced lipophilicity and increased blood stability of the active-lactone ring. The generation of a liposomal formulation of DB-67 may be an attractive method of intravenous (IV) administration and may maintain DB-67 in the active-lactone form. We evaluated the tissue and plasma disposition of DB-67 lactone and hydroxy acid after administration of non-liposomal (NL) and liposomal (L) DB-67 in severe combined immunodeficient (SCID) mice.

Methods: NL-DB-67 and L-DB-67 10 mg/kg IV x 1 were administered via a tail vein in SCID mice. After dosing, mice (n = 3 per time point) were euthanized and blood ( approximately 1 ml) and tissue were collected from 5 min to 48 h after administration. DB-67 lactone and hydroxy acid concentrations in plasma and DB-67 total (sum of lactone and hydroxyl acid) concentrations in tissues were determined by high-performance liquid chromatography (HPLC) with fluorescence detection.

Results: Clearance of DB-67 lactone after administration of NL-DB-67 and L-DB-67 were 1.6 and 3.5 l/h/m(2), respectively; DB-67 lactone half-lives after administration of NL-DB-67 and L-DB-67 were 1.4 and 0.9 h, respectively. The percentages of DB-67 lactone in plasma after administration of NL-DB-67 and L-DB-67 were 92% and 89%, respectively. Liver, kidney, spleen, and lung tissues had longer exposure times to DB-67 after administration of L-DB-67 compared with NL-DB-67.

Conclusion: In plasma, the majority of DB-67 remained in the lactone form after administration of NL-DB-67 and L-DB-67. The plasma disposition of DB-67 was similar after administration of NL-DB-67 and L-DB-67, suggesting that most of the DB-67 is immediately released from the L-DB-67 formulation. Following administration of L-DB-67, the higher and longer exposure of DB-67 in the spleen, as compared with NL-DB-67, is consistent with splenic clearance of liposomes by the reticuloendothelial system.
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http://dx.doi.org/10.1007/s10637-007-9109-9DOI Listing
October 2008

Plasma, tumor, and tissue disposition of STEALTH liposomal CKD-602 (S-CKD602) and nonliposomal CKD-602 in mice bearing A375 human melanoma xenografts.

Clin Cancer Res 2007 Dec;13(23):7217-23

Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Purpose: S-CKD602 is a STEALTH liposomal formulation of CKD-602, a camptothecin analogue. The cytotoxicity of camptothecin analogues is related to the duration of exposure in the tumor. STEALTH liposomal formulations contain lipid conjugated to methoxypolyethylene glycol and have been designed to prolong drug circulation time, increase tumor delivery, and improve the therapeutic index. For STEALTH liposomal formulations of anticancer agents to achieve antitumor effects, the active drug must be released into the tumor extracellular fluid (ECF).

Experimental Design: S-CKD602 at 1 mg/kg or nonliposomal CKD-602 at 30 mg/kg was administered once via tail vein to mice bearing A375 human melanoma xenografts. Mice (n = 3 per time point) were euthanized at 0.083 to 24 h, 48 h, and 72 h after S-CKD02 and from 0.083 to 24 h after nonliposomal CKD-602. Plasma samples were processed to measure encapsulated, released, and sum total (encapsulated plus released) CKD-602, and tumor and tissue samples were processed to measure sum total CKD-602. Microdialysis samples of tumor ECF were obtained from 0 to 2 h, 4 to 7 h, and 20 to 24 h after nonliposomal CKD-602 and from 0 to 2 h, 24 to 27 h, 48 to 51 h, and 72 to 75 h after S-CKD602. A liquid chromatography-mass spectrometry assay was used to measure the total (sum of lactone and hydroxyl acid) CKD-602. The area under the concentration-versus-time curves (AUC) from 0 to infinity and time >1 ng/mL in tumor were estimated.

Results: For S-CKD602, the CKD-602 sum total AUC in plasma and tumor and the CKD-602 AUC in tumor ECF were 201,929, 13,194, and 187 ng/mL h, respectively. For S-CKD602, 82% of CKD-602 remains encapsulated in plasma. For nonliposomal CKD-602, the CKD-602 AUC in plasma and tumor and the CKD-602 AUC in tumor ECF were 9,117, 11,661, and 639 ng/mL.h, respectively. The duration of time the CKD-602 concentration was >1 ng/mL in tumor ECF after S-CKD602 and nonliposomal CKD-602 was >72 and approximately 20 h, respectively. For S-CKD602, the CKD-602 sum total exposure was 1.3-fold higher in fat as compared with muscle. The ratio of CKD-602 sum total exposure in fat to muscle was 3.8-fold higher after administration of S-CKD602 compared with nonliposomal CKD-602.

Conclusion: S-CKD602 provides pharmacokinetic advantages in plasma, tumor, and tumor ECF compared with nonliposomal CKD-602 at 1/30th of the dose, which is consistent with the improved antitumor efficacy of S-CKD602 in preclinical studies. The distribution of S-CKD602 is greater in fat compared with muscle whereas the distribution of nonliposomal CKD-602 is greater in muscle compared with fat. These results suggest that the body composition of a patient may affect the disposition of S-CKD602 and released CKD-602.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-1035DOI Listing
December 2007

Transgenic mice overexpressing hepatocyte growth factor in the airways show increased susceptibility to lung cancer.

Carcinogenesis 2006 Aug 2;27(8):1547-55. Epub 2006 Mar 2.

Department of Pharmacology, University of Pittsburgh Cancer Institute, PA 15261, USA.

Several studies have suggested a possible role of the hepatocyte growth factor (HGF)/c-Met system in lung tumor development and progression. Extent of expression of both HGF and c-Met have been shown to be negative prognostic indicators of survival and recurrence in non-small-cell lung cancer, especially adenocarcinoma. To further define a role for HGF in lung cancer development and growth, we have generated transgenic mice that overexpress HGF in the airway epithelium. HGF transgenic and wild-type mice were exposed to the tobacco carcinogen, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), or saline control and killed 10-38 weeks after exposure. Lungs were formalin inflated, paraffin embedded and sectioned. It was verified that the HGF transgene was expressed only in the lungs of transgenic mice. The transgenic mouse lung histology exhibited congestion in the alveolar spaces, excess production of blood vessels and a convoluted pattern of airways with wide bifurcations. The number of lung tumors from NNK-treated transgenic animals versus the number of lung tumors from NNK-treated wild-type animals was significantly higher (P = 0.0001, Poisson regression). The percentage of animals with tumors was 75% in the transgenic group compared with 48.8% in the wild-type group. The main effect was an increase in tumor multiplicity; average size of tumors was not different between the groups. Additionally, the tumors that arose in the transgenic mice contained increased HGF protein compared with tumors from the wild-type mice. These results indicate that lung carcinogenesis induced by a tobacco carcinogen is enhanced by expression of the HGF transgene. This model recapitulates the phenotype of aggressive lung adenocarcinoma that overexpresses HGF and will be useful in evaluating antitumor agents that target either the HGF/c-Met pathway or downstream effects such as angiogenesis or invasion.
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http://dx.doi.org/10.1093/carcin/bgl003DOI Listing
August 2006

Decreased STAT1 expression by promoter methylation in squamous cell carcinogenesis.

J Natl Cancer Inst 2006 Feb;98(3):181-9

Department of Otolaryngology, University of Pittsburgh School of Medicine, Cancer Institute, Pittsburgh, PA, USA.

Background: Dysregulation of signal transducers and activators of transcription (STATs) is associated with many cancers, but no role of STAT1 in human tumor progression has been demonstrated.

Methods: We compared STAT1 protein expression in squamous cell carcinoma of the head and neck (SCCHN) tumors (n = 28) and normal oropharyngeal mucosa samples (n = 10) from patients without cancer as assessed by immunoblotting. Stable clones were established from SCCHN 1483 cells that were transfected with a STAT1 expression construct; cell growth and cisplatin-induced apoptosis of the clones and vector control-transfected 1483 cells were compared using trypan blue exclusion and Annexin V staining and expression of the cyclin-dependent kinase inhibitor p21 was assayed by immunoblotting. The growth of STAT1-overexpressing SCCHN 1483 xenograft tumors was compared with that of xenograft tumors derived from cells transfected with vector control DNA. DNA from SCCHN tumors (n = 16) and paired peripheral blood lymphocytes were analyzed for STAT1 mutations and promoter methylation using methylation-specific polymerase chain reaction and bisulfite sequencing. SCCHN cell lines (PCI-15b, 1483, and UM-22B) were treated with the demethylating agent azacytidine alone or in combination with the cytotoxic drug cisplatin, and expression of STAT1 and p21 were monitored by immunoblotting. All statistical tests were two-sided.

Results: STAT1 levels were statistically significantly lower in the SCCHN tumors than normal mucosa (median = 0.8 relative units versus 2.4, difference = 1.6, 95% confidence interval [CI] = 1.3 to 2.0, P < .001). Overexpression of STAT1 abrogated the growth of SCCHN cells and xenograft tumors and increased p21 expression. STAT1 expression levels of the tumors with STAT1 promoter methylation (n = 12) were lower than those of tumors (n = 4) without promoter methylation of STAT1 (P = .008). Azacytidine treatment increased expression of STAT1 and p21 in SCCHN cell lines and increased apoptosis in cisplatin-treated 1483 cells compared with cisplatin treatment alone (mean = 61.3% versus 25.8%, difference = 35.5%, 95% CI = 24.5% to 43.4%; P = .028).

Conclusion: STAT1 can function as a tumor suppressor in SCCHN cells. Silencing of the STAT1 gene via promoter methylation may contribute to SCCHN tumor cell growth.
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http://dx.doi.org/10.1093/jnci/djj020DOI Listing
February 2006

Phase I and pharmacokinetic study of weekly docetaxel, cisplatin, and daily capecitabine in patients with advanced solid tumors.

Clin Cancer Res 2005 Aug;11(16):5942-9

Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

Purpose: Docetaxel, cisplatin, and capecitabine are three active chemotherapeutic agents with different mechanisms of action. This phase I study investigated the feasibility and pharmacokinetics of this combination given on a weekly schedule.

Experimental Design: Docetaxel and cisplatin were given i.v. over 30 minutes on days 1 and 8 and capecitabine was given orally bid on days 1 to 14 (every 21 days). Escalation occurred in cohorts of three patients until the maximum tolerated dose was defined. Pharmacokinetics studies of docetaxel and total and ultrafiltrate platinum after cisplatin administration were done on cycle 1 (with capecitabine) and cycle 2 (without capecitabine).

Results: Twenty-five patients were enrolled. Two of six patients at dose level 5 had a dose-limiting infection and diarrhea. One of six evaluable patients at dose level 4 (27 mg/m2 docetaxel, 27 mg/m2 cisplatin, 825 mg/m2 capecitabine) had a dose-limiting hypomagnesemia. Pharmacokinetics of docetaxel were similar on cycles 1 and 2. Area under the plasma concentrations versus time curves of total platinum was significantly greater in cycle 2 compared with cycle 1 (P = 0.001). There was no difference in the disposition of docetaxel on cycles 1 and 2.

Conclusions: The recommended docetaxel, cisplatin, and capecitabine dose for phase II studies is 27/27/825 mg/m2. The alteration in total and ultrafiltrate platinum disposition on cycle 2 compared with cycle 1 may be inherent to sequential cisplatin administration; however, prior treatment with capecitabine cannot be ruled out as a factor.
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http://dx.doi.org/10.1158/1078-0432.CCR-05-0116DOI Listing
August 2005

The gender gap in a surgical subspecialty: analysis of career and lifestyle factors.

Arch Otolaryngol Head Neck Surg 2004 Jun;130(6):695-702

Eye and Ear Institute, Department of Otolaryngology, School of Medicine, University of Pittsburgh, PA 15213, USA.

Background: Although the percentage of women in surgical subspecialties is increasing, little is known about the experiences of these women compared with their male counterparts.

Objective: To identify career and lifestyle factors that distinguish female otolaryngologists.

Design, Setting, And Participants: Otolaryngologists were asked to respond to a confidential 119-item questionnaire. The instrument was sent to all 502 female members of the American Academy of Otolaryngology-Head and Neck Surgery who had finished their residency training and were practicing medicine. For response comparison, the survey was mailed to 2 male otolaryngologists who were matched to each female survey recipient for years since completion of training, geographic region, and practice type.

Results: Of the 673 respondents (52.6% response rate), women were more likely to be divorced or separated (P =.001) and have fewer children (P <.001). In contrast to men, women reduced their work hours in conjunction with having more children (P <.001). Controlling for professional hours and hours spent in the operating room per week, type of practice, and years since completion of residency, women earned 15% to 20% less per year than men (P <.001). Men relied more on their spouse or partner for household responsibilities and child care (P <.001), and 34.3% of the women (compared with 7.1% of the men) spent 21 to 40 h/wk on household management (P <.001).

Conclusion: Although male and female otolaryngologists receive equal training opportunities, women earn less money for performing similar jobs and have increased family responsibilities, which may effect their career advancement.
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http://dx.doi.org/10.1001/archotol.130.6.695DOI Listing
June 2004